Cross Talk: The Microbiota and Neurodevelopmental Disorders

Abstract

Humans evolved within a microbial ecosystem resulting in an interlinked physiology. The gut microbiota can signal to the brain via the immune system, the vagus nerve or other host-microbe interactions facilitated by gut hormones, regulation of tryptophan metabolism and microbial metabolites such as short chain fatty acids (SCFA), to influence brain development, function and behavior. Emerging evidence suggests that the gut microbiota may play a role in shaping cognitive networks encompassing emotional and social domains in neurodevelopmental disorders. Drawing upon pre-clinical and clinical evidence, we review the potential role of the gut microbiota in the origins and development of social and emotional domains related to Autism spectrum disorders (ASD) and schizophrenia. Small preliminary clinical studies have demonstrated gut microbiota alterations in both ASD and schizophrenia compared to healthy controls. However, we await the further development of mechanistic insights, together with large scale longitudinal clinical trials, that encompass a systems level dimensional approach, to investigate whether promising pre-clinical and initial clinical findings lead to clinical relevance.

Introduction

From an evolutionary-based perspective, the host and its microbiome evolved as a cooperative unit (Rosenberg et al., 2007; Zilber-Rosenberg and Rosenberg, 2008; Martin et al., 2015; Douglas and Werren, 2016). All stages in the evolution of the human brain occurred within this microbial ecosystem (McFall-Ngai et al., 2013; Bordenstein and Theis, 2015). The predominant theory to account for the evolution of the enlargement of the human brain implicates social interaction. Brain areas such as the prefrontal cortex and the amygdala have undergone pronounced changes in the evolution of social mammals (Kolb et al., 2012; Janak and Tye, 2015). Brains of social species exhibit a set of features that need to integrate for group living to become advantageous, and the development of the complex neural circuitry underlying social and emotional cognition is of fundamental importance to neurodevelopmental disorders, such as ASD and schizophrenia (Adolphs, 2001; Lederbogen et al., 2011; Janak and Tye, 2015; Averbeck and Costa, 2017).

Neurodevelopment requires the intricate interplay of genetic expression, influenced by pre-and post-natal environmental events. Critical periods or “windows” of brain development exist, during which time neural circuits are particularly sensitive to, and require, the influence of appropriate environmental inputs, in order to develop properly. Human brain development begins in the third gestational week (Stiles and Jernigan, 2010) and at time of birth approximately 86 billion neurons (Azevedo et al., 2009) with up to 100 trillion connections are produced. These connections form simple circuits, and when reinforced through repeated use, under the influence of environmental cues, form more complex interconnected circuits, leading to complex networks (Bassett and Sporns, 2017). The developmental trajectory of social, emotional and cognitive brain domains occur in parallel, though social cognition may be linked to certain specific subnetworks (Dunbar, 2012; Sliwa and Freiwald, 2017).

The development of this neural circuitry requires precise regulation from molecular signaling pathways. Hormones, such as oxytocin (Kirsch et al., 2005), neurotransmitters, such as serotonin (Whitaker-Azmitia, 2001), and the immune system (Bilbo et al., 2012), all play pivotal roles in sculpting the neural circuitry underlying social cognition, emotion and behavior. Many of the brain regions involved and the molecular substrates subserving relevant functions are also responsive to microbiome-gut-brain axis signaling (Clarke et al., 2013; Semple et al., 2013; Montiel et al., 2014; Dinan et al., 2015; Erny et al., 2015; Buffington et al., 2016; Vuong and Hsiao, 2017) Figure 1.

Figure 1

The trajectory of early post-natal brain development overlaps with the acquisition and reorganization of the gut microbiota (Borre et al., 2014; Chu et al., 2017). The gut microbiota in the initial days of life is unstable and of low diversity (Arrieta et al., 2014). By age three, a stage by which verbal communication and Theory of Mind develops (the ability to infer and reason about the intentions, emotions and thoughts of others) (Grosse Wiesmann et al., 2017), the gut microbiota composition stabilizes into a pattern that more resembles an adult-like profile (Voreades et al., 2014). These social, cognitive and emotional domains, and their neurodevelopment, are compromised in neurodevelopmental disorders, such as ASD and schizophrenia. Deciphering the gut microbiota compositional trajectories and profiles, corresponding metabolic output and precise signaling pathways that play a pertinent role in molding the neural circuitry underlying the social-communicative domains of the brain, is one of the great challenges of modern neuroscience (Chen et al., 2013; Mayer et al., 2014a; Dinan and Cryan, 2017; Sherwin et al., 2017).

Autism spectrum disorders (ASD)

ASD is a heterogeneous neurodevelopmental disorder, affecting approximately 1 in 68 children (Christensen et al., 2016). It is characterized by deficits in social communication, social interaction and restricted/repetitive behavioral patterns. The processing of emotional stimuli, be it language or facial expressions is impaired in individuals with ASD (Dalton et al., 2005; Preissler and Carey, 2005; Monk et al., 2010; Lartseva et al., 2014; Neuhaus et al., 2016; Wang and Adolphs, 2017). Therefore, deficits in social communication, together with emotional processing, and a lack of social interest in communication can result in language delay, and a proportion of children at the severe end of the spectrum will not develop language abilities (Landry and Loveland, 1988).

The heritability of ASD is estimated at between 64 and 91% (Tick et al., 2016), and genes that encode proteins for synaptic formation, microglial function, transcriptional regulation and chromatin-remodeling pathways are implicated (De Rubeis et al., 2014; Parikshak et al., 2016). New mutations contribute to the risk, and a recent large scale study, showed that approximately one third of spontaneous, non-inherited genetic mutations found in people with ASD were also found in the general population (Kosmicki et al., 2017). A recent study suggests that those ASD children with de novo mutations show relative strengths in verbal and language abilities, including a smaller discrepancy between non-verbal and verbal IQ and a greater likelihood of having achieved fluent language, relative to those with no identified genetic abnormalities (Bishop et al., 2017). Taken together, these genetic studies in ASD highlight the neurodiversity of the disorder (Baron-Cohen, 2017; Vorstman et al., 2017; Yuen et al., 2017).

The origins of ASD are likely to occur during the prenatal timeframe, a time window during which important connections are formed (Willsey et al., 2013). A study, using a high-resolution transcriptional atlas in primates, showed that many ASD-related genes are activated in new-born neurons during prenatal development, while schizophrenia related genes are activated from infancy through adulthood (Bakken et al., 2016). Maternal infections during pregnancy are associated with the development of neurodevelopmental disorders (Atladottir et al., 2010; Jiang et al., 2016; Careaga et al., 2017). Certain subtypes of ASD are associated with increased levels of maternal peripheral chemokines and cytokines during gestation (Goines et al., 2011; Jones et al., 2017; Graham et al., in press). Moreover, subgroups of children diagnosed with ASD have elevated levels of peripheral cytokines (Ashwood et al., 2011), and microglial activation in young adults with ASD has been demonstrated using positron emission tomography (PET) imaging (Suzuki et al., 2013). Progress is being made in diagnosing infants at high risk of developing ASD, by utilizing imaging techniques such as fMRI (Hazlett et al., 2017; Shen et al., 2017). A recent structural and diffusion MRI study of 3 year old infants diagnosed with Neurodevelopmental Disorders (32 ASD and 16 other developmental disorders, including intellectual disability and language disorder) reported an over-connectivity pattern in ASD in networks primarily involving the fronto-temporal nodes, known to be crucial for social-skill development (Conti et al., 2017).

Risk factors such as advanced parental age (Durkin et al., 2008; Sandin et al., 2016), low birth weight (Schendel and Bhasin, 2008) and multiple births (Croen et al., 2002) have been identified, while others such as mode of birth have been advanced. However, epidemiological data suggests that C-section mode of delivery, currently far in excess of WHO recommendations (WHO, 2015) and known to alter microbiome signatures (see below), is associated only with a slightly increased risk of ASD and that this may be due to familial confounds (Curran et al., 2014, 2015, 2016; O'Neill et al., 2015). Identifying additional modifiable environmental factors that play a causal role in ASD, particularly during the prenatal and early post-natal period, is of vital importance.

Schizophrenia spectrum disorders (SSD)

Schizophrenia is a heterogeneous neurodevelopmental disorder, with a general population lifetime prevalence of approximately 0.87% (Perala et al., 2007), and an annual incidence of approximately 0.20/1,000/year (Messias et al., 2007). There is a slightly greater risk for males (Aleman et al., 2003) and psychotic symptoms usually manifest clinically during the adolescent period. This disorder can have a major detrimental impact on functioning, and is associated with a reduced life expectancy (Laursen et al., 2014; Schoenbaum et al., 2017; Strati et al., 2017) and a suicide rate of 5% (Hor and Taylor, 2010). schizophrenia is classically characterized by positive (delusions, hallucinations), negative (affective flattening, alogia, and avolition), and cognitive symptoms (Aleman et al., 1999; Kahn and Keefe, 2013; Schaefer et al., 2013). Social interaction and communication deficiencies, including disorganized speech, can be prominent, even early in the course of this disorder (Sullivan et al., 2003; Roche et al., 2016; Morgan et al., 2017).

Similar to ASD, the precise cause of schizophrenia is unknown. A complex and dynamic bidirectional interaction of genomic and environmental factors converge to shape the trajectory of schizophrenia (O'Tuathaigh et al., 2017). Prenatal and early post-natal environmental factors sensitize the vulnerable brain. Although psychotic symptoms usually manifest during the adolescent period, it has been established that schizophrenia is associated with poor premorbid functioning, cognitive impairment, and social deficits prior to the onset of psychotic symptoms (Schenkel and Silverstein, 2004). Indeed, previously considered distinct forms of psychopathology may in fact have characteristics in common, and exhibit age adjusted variations of common underlying dispositions (Casey et al., 2014; Hommer and Swedo, 2015).

The immune system is an important player in the pathophysiology of schizophrenia (Benros et al., 2012; Feigenson et al., 2014; Muller, 2014). At the genetic level, genes related to B-lymphocyte lineages involved in acquired immunity (CD19 and CD20 lines) and major histocompatibility complex locus have been linked to schizophrenia (Corvin and Morris, 2014; Schizophrenia Working Group of the Psychiatric Genomics Consortium., 2014). A recent translational study implicated excessive complement activity, particularly the role of C4 in mediating synapse elimination during post-natal development (Sekar et al., 2016). Neuro-immune signaling also changes during the adolescent period, regulating changes in synaptic pruning, neurite outgrowth, and neurotransmitter release via Blood Brain Barrier (BBB) dynamics and glial activity (Brenhouse and Schwarz, 2016). It is established that subgroups of patients with schizophrenia have elevated levels of peripheral cytokines, including subgroups of medication free first-episode psychosis individuals (Miller et al., 2011; Di Nicola et al., 2013; de Witte et al., 2014; Upthegrove et al., 2014). There is also some suggestion, though not well established, that schizophrenia is associated with altered intestinal (Severance et al., 2013) and blood brain barrier function (Pollak et al., 2017). This, taken together with altered microglial activation in psychosis patients (Bloomfield et al., 2016), highlights the key role of the immune system, in at least subgroups of individuals with psychosis (Al-Diwani et al., 2017).

Infections at different stages of brain development result in varying degrees of lifelong changes in behavior and cognition (Spencer and Meyer, 2017). Certain infections are known to increase the risk of schizophrenia (Meyer et al., 2009; Brown, 2012). A large epidemiological study (n = 1,015,447), showed that treatment with anti-infective agents (primarily driven by infections treated with antibiotics), were associated with an increased risk of schizophrenia by a hazard rate ratio of 1.37 (Kohler et al., 2017). However, an earlier study found an increased risk for mood and anxiety disorders for antibiotic exposure, but no change in risk for psychosis with any antibiotic group (Lurie et al., 2015). An infection with a robust link to psychosis is the protozoan Toxoplasma gondii (Torrey and Yolken, 2003; Severance et al., 2016b). A meta-analysis of 16 studies demonstrated increased T. gondii IgM levels in patients with acute psychosis (Monroe et al., 2015). The mechanism is not completely understood, but a putative role of attenuated CD8 T-cell response in T. gondii seropositive individuals has been suggested (Bhadra et al., 2013). It is known that T. gondii induces the production of a variety of cytokines by microglia, astrocytes, and neurons (Carruthers and Suzuki, 2007). Monocytes and dendritic cells are the most important candidates for the transport of T. gondii from the periphery to the immunologically privileged sites of the brain (Feustel et al., 2012).

Indeed, latent T. gondii infection is associated with an upregulation of cerebral complement factor C1q (Xiao et al., 2016). Furthermore, T. gondii infection can alter dopamine metabolism (Prandovszky et al., 2011) and latent T. gondii is associated with reduced psychomotor performance (Havlicek et al., 2001). More recently, T. gondii has been shown to lead to deficits in goal-directed behavior in healthy elderly individuals (Beste et al., 2014). Interestingly, acute T. gondii infection can affect the gut microbiota in mice (Molloy et al., 2013). Although only a minor subset of T. gondii seropositive individuals develop serious mental impairments, taken together, the example of T. gondii, suggests that microbial agents contribute to the vulnerability to the development of subgroups of schizophrenia (Yolken and Torrey, 2008). Although we have focussed on T. gondii, it is noteworthy that other infections, such as Human Herpesvirus 2, Borna Disease Virus Human Endogenous Retrovirus W, Chlamydophila pneumoniae, and Chlamydophila psittaci are also associated with the disorder (Arias et al., 2012). It remains an open question whether there is a common mechanism through which these microbes exert their influence, albeit, that one shared general feature in most examples cited is an intracellular life stage.

Interestingly, urbanicity, known to affect microbial diversity and impact the overall functionality of the gut microbiome (Mancabelli et al., 2017), is also a risk factor for the development of schizophrenia (Pedersen and Mortensen, 2001; Krabbendam and van Os, 2005; Peen et al., 2010; Vassos et al., 2012; Newbury et al., 2016). In healthy individuals, a negative correlation was found between early-life urbanicity and gray matter volume in the right dorsolateral prefrontal cortex in males and females, and in perigenual anterior cingulate cortex volumes, a key region for regulation of amygdala, in men only (Haddad et al., 2015). Using fMRI, city living was associated with increased amygdala activity (Lederbogen et al., 2011), known to be associated with schizophrenia (Aleman and Kahn, 2005; Rasetti et al., 2009). Stamper and colleagues postulate that differential exposure to microbes in the urban compared to the rural environment interact with differences in social stressors to alter social stress neural circuitry (Stamper et al., 2016).

ASD and microbiota

GI symptoms are a common comorbidity in ASD (Molloy and Manning-Courtney, 2003; Buie et al., 2010; Berding and Donovan, 2016). However, the underlying mechanism is not fully known (Mayer et al., 2014b). The vast majority of human studies show that ASD is associated with altered microbial profiles (see Table 1). A systematic review of gut microbiota alterations in ASD, verified alterations in gut microbiota, but highlighted the heterogeneity of findings, and the limited quantity and quality of studies (Cao et al., 2013). Studies investigating ASD, the gut microbiota and SCFAs, showed significantly higher levels of Desulfovibrio species and Bacteroides vulgatus and higher levels of SCFA's in the stools of autistic children compared to controls (Finegold et al., 2010; Wang et al., 2012). Clostridium Bolteae, another species that is reported to be over-represented in the gut microbiota in ASD, and its capsular polysaccharide consisting of rhamnose and mannose units, has been proposed as a viable potential vaccine to reduce C. bolteae colonization of the intestinal tract in autistic patients (Pequegnat et al., 2013).

Most studies conducted in ASD are non-interventional, and many do not adequately record detailed dietary information or medication use. Indeed, it is well established that ASD is highly associated with atypical eating patterns (Cermak et al., 2010). The interventional studies are few, and of small sample size. An open labeled trial (n = 11), with no control group, using the poorly absorbed oral antibiotic, vancomycin for 12 weeks, reportedly resulted in a short-term improvement in ASD related behavioral symptomatology in a group of children with regressive-onset autism (Sandler et al., 2000). Follow-up which occurred between 2 and 8 months, showed that the improvement was not sustained. More recently, a small (n = 18) open label study of Fecal Microbiota Transfer (FMT) in children with ASD reported an improvement in both GI symptoms and behavioral symptoms after 8 weeks (Kang et al., 2017). In this study, the abundance of Bifidobacterium, Prevotella, and Desulfovibrio increased following the 8 weeks of FMT treatment (see Table 1). Interestingly, in a cross sectional study, in healthy prepubertal children (n = 65) dietary fiber was associated with a better performance on a task measuring attentional inhibition (Khan et al., 2015). Moreover, a study investigating microbial composition at 1 year of age showed that a higher alpha diversity was associated with lower scores on the Mullen scale, the visual reception scale, and the expressive language scale at 2 years of age (Carlson et al., in press).

Schizophrenia spectrum disorder and the microbiota

As discussed below, data from pre-clinical studies indicate that certain domains related to schizophrenia, such as social cognition, are under the partial influence of the gut microbiota (Dinan et al., 2014). However, pre-clinical models have many limitations and translating promising pre-clinical findings into discernible clinical benefits for patients can be challenging, particularly for complex disorders such as schizophrenia. Moreover, it is important to highlight that there are considerable interpersonal differences in the gut microbiota profiles of healthy individuals (Backhed et al., 2012; Falony et al., 2016; Zhernakova et al., 2016). Consequently, there are multiple possible configurations for a healthy gut microbiota and it is also likely that some stable configurations are associated with disorders (Relman, 2012). It is important also to appreciate that the functional output of multiple microbiota configurations may in fact be equivalent, given that concepts of redundancy and pleiotropy can also be applied to specific microbial members of the overall consortium (Falony et al., 2016).

Despite the significant challenges, several pilot clinical studies investigating the microbiome in schizophrenia have emerged (see Table 2). A recent study investigating the gut microbiota in schizophrenia was conducted in First Episode Psychosis (FEP) patients (n = 28) compared to healthy controls (n = 16) (Schwarz et al., in press). There were five significant differences between the groups at the family level; Lactobacillaceae, Halothiobacillaceae, Brucellaceae, and Micrococcineae were increased, whereas Veillonellaceae were decreased in FEP patients. At the genus level, Lactobacillus, Tropheryma, Halothiobacillus, Saccharophagus, Ochrobactrum, Deferribacter, and Halorubrum were increased, and Anabaena, Nitrosospira, and Gallionella were decreased in FEP. Lactobacillus group bacterial numbers correlated positively with severity of psychotic symptoms measured using the Brief Psychiatric Rating Scale, and negatively with global assessment of functioning (GAF) scale. A subgroup analysis of those classified as less physically active, confirmed significant increases in Lactobacillaceae and significant decreases in Veillonellaceae in FEP. It is noteworthy that the vast majority of FEP patients were prescribed antipsychotic medication, which can impact gut microbiota composition (Davey et al., 2012, 2013; Bahra et al., 2015; Bahr et al., 2015). A small study (n = 32) of the oropharyngeal microbiome in schizophrenia also showed an increased abundance of Lactobacillus in schizophrenia patients, in addition to, Bifidobacterium and Ascomycota, compared to healthy controls (Castro-Nallar et al., 2015). Another study of the oral pharynx of 41 individuals with schizophrenia and 33 controls demonstrated that one bacteriophage genome Lactobacillus phage phiadh, was significantly more abundant in schizophrenia patients than in controls after adjustment for multiple comparisons and demographic covariates (Yolken et al., 2015).

Studies investigating the fungal composition of the human gut—the Mycobiome—are also emerging (Suhr and Hallen-Adams, 2015). A case-control cohort study that included 261 individuals with schizophrenia, 270 with bipolar disorder, and 277 non-psychiatric controls, found no differences in C. albicans exposure when analyzed at the group level. However, when stratified by sex, there was a reported increase in the odds for schizophrenia in males (Severance et al., 2016a). The same group conducted a randomized, double-blind, placebo-controlled, probiotic trial over a 14-week period, and showed that probiotic treatment significantly reduced C. albicans antibodies in males only, and a trend toward improvement in positive psychiatric symptoms in seronegative males (Severance et al., 2017). Both groups were prescribed antipsychotic medication, but antipsychotic regimes were not different between probiotic and placebo groups.

Communication pathways of brain-gut-microbiota axis

The human body contains as many bacterial cells as human cells (Sender and Fuchs, 2016), the majority of which reside in the gut, with bacterial concentrations ranging from 10¹ to 10³ cells per gram in the upper intestines to 10¹¹–10¹² bacteria per gram in the colon (O'Hara and Shanahan, 2006; Derrien and van Hylckama Vlieg, 2015). With over 1,000 species and 7,000 strains the microbiota is an ecosystem dominated by bacteria, mainly strict anaerobes, but also includes viruses and bacteriophages, protozoa, archaea and fungi (Lankelma et al., 2015). In terms of bacterial phyla found in the gut, Firmicutes (species such as Lactobacillus, Clostridium, Enterococcus) and Bacteroidetes (species such as Bacteroides) account for the majority (Dethlefsen et al., 2007), though the other phyla such as Actinobacteria (Bifidobacteria), Proteobacteria (Escherichia coli), Fusobacteria, Verrucomicrobia, and Cyanobacteria are also present in relatively low abundance (Eckburg et al., 2005; Qin et al., 2010; Lankelma et al., 2015).

Although the functional significance of the gut microbiota has yet to be fully determined (Franzosa et al., 2014; Cani, 2017), it is clear that an intricate and interlinked symbiotic relationship exists between host and microbe (Ley et al., 2008), and there are a number of bidirectional signaling pathways by which the gut microbiota, acting via the brain-gut axis, can impact the brain. A key signaling pathway involves modulation of the immune system (Erny et al., 2015), though other pathways include the hypothalamic-pituitary-adrenal (HPA) axis (Sudo et al., 2004; Mudd et al., 2017), tryptophan metabolism (O'Mahony et al., 2015), the production of bacterial metabolites, such as SCFA (Tan et al., 2014) and via the vagus nerve (Bravo et al., 2011). Although much progress has been made, the precise signaling pathways mediating the influence of microbial products derived from gut microbiota on the brain remain largely unknown. Epigenetic factors may also play a role (Dalton et al., 2014; Stilling et al., 2014a,b; Thaiss et al., 2016). Recently, a novel signaling pathway has been advanced, that involves bacterial peptidoglycan (PGN) derived from the commensal gut microbiota (Arentsen et al., 2017). PGN was shown to translocate into the brain to activate specific pattern-recognition receptors (PRRs) of the innate immune system, and this could occur in both physiological and pathological conditions (Arentsen et al., 2017).

In addition, pre-clinical evidence from germ-free (GF) mice suggests that the microbiota can modulate the Blood Brain Barrier (BBB). Exposure of GF adult mice to the fecal microbiota from pathogen-free donors decreased BBB permeability (Braniste et al., 2014). Moreover, monocolonization of the intestine of GF adult mice with SCFA-producing bacterial strains normalized BBB permeability, whilst sodium butyrate was associated with increased expression of the tight junction protein occludin in the frontal cortex and hippocampus (Braniste et al., 2014). Together with a study that showed antibiotic-induced gut dysbiosis reduced the expression of tight junction proteins (claudin and occludin) mRNA in the hippocampus, and increased the expression of tight junction protein 1 and occludin mRNA in the amygdala (Frohlich et al., 2016), suggests that the BBB may be partially modulated by changes in the gut microbiota.

Microbiota and the immune system

A bidirectional communication system exists between the immune system and the CNS. Neuroimmune signaling during the prenatal or early post-natal developmental stages can have long lasting effects on the brain, and is an important determinant of cognitive function and emotional behavior (Dantzer et al., 2008; Bilbo et al., 2012; Filiano et al., 2017; Freytag et al., 2017). Peripheral cytokine signaling can modulate astrocytes, microglia and neurons in the CNS (Kohman and Rhodes, 2013). This occurs through leaky regions in the BBB such as circumventricular organs, active transport through transport molecules, activation of cells lining the cerebral vasculature (endothelial cells and perivascular macrophages), binding to cytokine receptors associated with the vagus nerve, stimulating the HPA axis at the anterior pituitary or hypothalamus and recruitment of activated cells such as monocytes/macrophages from the periphery to the brain (Haroon et al., 2012). In addition, functional lymphatic vessels lining the dural sinuses have been discovered, which serve as a route by which immune cells can communicate with the CNS (Louveau et al., 2015). Consequently, peripheral cytokines can modulate neurogenesis, synapse formation and plasticity (Hodes et al., 2015). It is established that cytokines can impact cognition and mood (Dowlati et al., 2010; Udina et al., 2012; Valkanova et al., 2013; Khandaker et al., 2014). Brain regions affected by administration of inflammatory stimuli include the basal ganglia and the dorsal anterior cingulate cortex (dACC), part of the limbic system, involved in cognitive and emotional processing (Harrison et al., 2009; Slavich et al., 2010; Capuron et al., 2012; Felger and Miller, 2012; Felger et al., 2013; Miller et al., 2013).

A critical function of the gut microbiota is to prime the development of the neuroimmune system (Round and Mazmanian, 2009; Olszak et al., 2012; Chistiakov et al., 2014; Francino, 2014). Alterations in the gut microbiota signature early in life can predispose to immune disorders (Penders et al., 2007; Fujimura et al., 2016) and the luminal surface of the gut is a key interface in this process (O'Hara and Shanahan, 2006). Indeed, the hygiene hypothesis first proposed in the late 1980's (Strachan, 1989; Patel and Gruchalla, 2017) and reconceptualized as the “old friends hypothesis” (Rook et al., 2003; Williamson et al., 2015) proposes that encountering less microbial biodiversity may contribute to the increase in chronic inflammatory disorders (Klerman and Weissman, 1989; Guarner et al., 2006; Rook and Lowry, 2008; Turnbaugh et al., 2009; Hidaka, 2012; Rook et al., 2013, 2014; Kostic et al., 2015; Stein et al., 2016). An intriguing strategy of “reintroducing” old friends has been suggested by a pre-clinical study using heat-killed Mycobacterium vaccae, an immunoregulatory environmental microorganism. Mice given this vaccine exhibited reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1–2 weeks following the final immunization, compared to the control group (Reber et al., 2016). Depletion of regulatory T cells negated the protective effects of immunization with M. vaccae on anxiety-like or fear behaviors.

Mechanistic influences of microbiota on brain function and development

Toll-like receptors (TLRs)

Structural components of bacteria interact with the immune system via TLRs (McCusker and Kelley, 2013). Different TLRs recognize specific bacterial structures, for example; TLR2 recognizes structures from Gram positive bacteria whereas TLR4 mediates responses to structures such as lipopolysaccharide (LPS) primarily from Gram negative bacteria (Marteau and Shanahan, 2003). In the CNS, neurons and glial cells can express various TLRs (Bsibsi et al., 2002; Kielian, 2006; Trudler et al., 2010). Activation of TLRs trigger the induction of pro and anti-inflammatory cytokines (Takeda and Akira, 2005) and, as mentioned above, there are a number of routes by which peripheral cytokines can impact the brain (Haroon et al., 2012; Miller et al., 2013; Louveau et al., 2015). Dysregulation of this process, or excessive TLR activation, can result in chronic inflammatory and over-exuberant repair responses. Consequently, TLRs may serve as molecular communication channels between gut microbiota alterations and immune system homeostasis (Rogier et al., 2015). Indeed, TLR2 and TLR4 knockout mice showed subtle impairments in behavior and cognitive functions (Park et al., 2015; Too et al., 2016). A clinical study in subjects diagnosed with psychotic disorders showed specific alterations in TLR agonist-mediated cytokine release compared to healthy controls (McKernan et al., 2011), and more recently it has been shown that abnormal expression of TLRs can be modulated by antipsychotics (Kéri et al., 2017). Moreover, in post-mortem prefrontal cortex samples from subjects diagnosed with psychosis, alterations in TLR4 have been shown, which were dependent on antipsychotic treatment status at time of death (García-Bueno et al., 2016).

Microbiota and microglia

Microglia, central to the inflammatory process (Facci et al., 2014) are emerging as playing key roles in brain development, plasticity and cognition (Tay et al., 2017). These phagocytic innate immune cells account for approximately 10% of cells in the brain (Prinz et al., 2014), contribute to the plasticity of neural circuits by modulating synaptic architecture and function (Graeber and Streit, 2010) and can be modulated by glutamatergic and GABAergic neurotransmission (Fontainhas et al., 2011). Pre-clinical studies have shown that acute stress results in microglia activation and increased levels of proinflammatory cytokines in areas such as the hippocampus (Frank et al., 2007) and hypothalamus (Blandino et al., 2009; Sugama et al., 2011). Most studies show increases in activated microglia in response to chronic stress (Tynan et al., 2010; Hinwood et al., 2011, 2012; Bollinger et al., 2016).

Preliminary changes in the microenvironment of the microglia may result in a susceptibility to a secondary inflammatory stimulus (Perry and Holmes, 2014). This concept of microglia priming may be of relevance to neurodevelopmental disorders, such as ASD and schizophrenia, which often require multiple environmental “hits” (Feigenson et al., 2014; Fenn et al., 2014). In an environmental two-hit rodent model in which the first experimental manipulation targeted pregnant dams, and the second manipulation was given to the resulting offspring, exposure to prenatal immune challenge and peripubertal stress synergistically induced pathological effects on adult behavioral functions and neurochemistry (Giovanoli et al., 2013, 2015). Thus, early-life stress may prime microglia, leading to a potentiated response to subsequent stress (Calcia et al., 2016).

In human studies, microglial dysregulation has been demonstrated in several psychiatric disorders. In medication free depressed patients, microglial activation has been demonstrated in the prefrontal cortex, ACC, and insula, using translocator protein density measured by distribution volume in a PET study positron emission tomography (PET) study (Setiawan et al., 2015). Using a different tracer, (11)[C]PBR28, subjects at high risk of psychosis, and those with schizophrenia also showed evidence of altered microglial activation compared to healthy controls (van Berckel et al., 2008; Bloomfield et al., 2016). However, not all studies are consistent and no clear consensus exists (Holmes et al., 2016; Narendran and Frankle, 2016; Collste et al., 2017; Notter and Meyer, 2017).

The gut microbiota, emerging as an important neuroimmunomodulator (Foster, 2016; Rea et al., 2016), is also involved in the maturation and activation of microglia (Cryan and Dinan, 2015; Erny et al., 2015). Interestingly, GF mice display underdeveloped and immature microglia in the cortex, corpus callosum, hippocampus, olfactory bulb, and cerebellum (Erny et al., 2015). There was an upregulation of microglia transcription and survival factors, and downregulation of cell activation genes and genes for type 1 IFN receptor signaling compared with those isolated from conventionally colonized control mice. These defects were partially restored by recolonization with a complex microbiota, and SCFAs reversed the defective microglia in the absence of complex microbiota (Erny et al., 2015). Collectively, these studies suggest that subtle alterations in gut microbiota acquisition and development, by regulating neuro-inflammatory processes, may act as additional vulnerability factors that predispose to neurodevelopmental disorders such as ASD and schizophrenia.

Microbiota and neurochemistry

At the cellular level, brain development and function requires a complex and coordinated birth, migration and differentiation of both neurons and glia, followed by synaptic integration and neural circuit formation. Both ASD and schizophrenia are associated with dysregulation of synaptic function and structure (McGlashan and Hoffman, 2000; Faludi and Mirnics, 2011; Spooren et al., 2012; Habela et al., 2016). The gut microbiota plays a role in developmental programming of the brain, specifically, synapse maturation and synaptogenesis (Diaz Heijtz et al., 2011) Figure 2. Synaptophysin, a marker of synaptogenesis, and PSD 95, a marker of excitatory synapse maturation, were decreased in the striatum in GF animals compared to specific-pathogen-free (SPF) animals. This suggests that the gut microbiota may programme certain brain circuits when colonized by maternal microbiota. However, the authors point out that exposure to gut microbiota metabolites during embryogenesis may also be a possible mechanism. Interestingly, reduced levels of synaptophysin have been demonstrated in the cerebral cortex of post-mortem samples from schizophrenia subjects (Hu et al., 2015).

Figure 2

Brain-derived neurotrophic factor (BDNF)

A key regulator of synaptic plasticity and neurogenesis in the brain, throughout life, is the neurotrophin, BDNF (Monteggia et al., 2004). Given the role of BDNF in the regulation of synaptic strengthening and pruning, maintaining appropriate levels of BDNF and other neurotrophins, especially during critical neurodevelopmental windows is vital for both ASD and schizophrenia (Nieto et al., 2013). Meta-analysis showed reduced blood levels in both medication naïve and medicated adult individuals diagnosed with schizophrenia (Green et al., 2011). Conversely, children with ASD have increased levels of blood BDNF (Qin et al., 2016; Saghazadeh and Rezaei, 2017). In GF rodents, levels of BDNF were reduced in the cortex and hippocampus in GF mice (Sudo et al., 2004). In a study by Clarke et al. this finding was replicated, but in male mice only (Clarke et al., 2013). However, not all studies are consistent; Neufeld et al. (2011) confirmed a decreased level of anxiety like behavior in GF animals, but found an increase in BDNF mRNA in the hippocampus in female mice. Prebiotics can alter BDNF levels (Savignac et al., 2013) and increase BDNF gene expression in the hippocampus (Burokas et al., in press). Collectively, these pre-clinical studies suggest that certain neurotransmitters and neuromodulators of relevance to the pathophysiology of ASD and schizophrenia are under the influence of the gut microbiota Figure 2.

γ-aminobutyric acid (GABA) and glutamate

At the neurotransmitter level, several signaling pathways have been shown to be dysfunctional in ASD and schizophrenia. Glutamatergic and GABAergic dysfunction and the consequences on excitatory to inhibitory cortical activity is one hypothesis to account for the similarities in the social and cognitive disturbances in ASD and schizophrenia (Canitano and Pallagrosi, 2017). GABA is an important inhibitory neurotransmitter in the brain, and GABA dysfunction has been implicated in ASD and schizophrenia (Schmidt and Mirnics, 2015). Although not a central source, it is interesting to note that certain bacteria can produce neuroactive metabolites (Wikoff et al., 2009; Lyte, 2011, 2013), for example specific strains of Lactobacillus and Bifidobacteria can produce GABA by metabolizing dietary glutamate (Barrett et al., 2012). Indeed, L. rhamnosus (JB-1) was shown to reduce anxiety and depression related behavior in mice and increase GABA receptor levels in the hippocampus (Bravo et al., 2011). Interestingly, in vagotomized mice, these effects were not found, further supporting the concept that the vagus nerve is an important neural signaling pathway between the microbiota and brain. A pre-clinical magnetic resonance spectroscopy study adds further evidence to support the concept that oral L. rhamnosus can increase central GABA levels (Janik et al., 2016). In a recent study, prebiotics, fructo-oligosaccharide (FOS) and galacto-oligosaccharide (GOS), increased GABA-B1 and GABA-B2 receptor gene expression in the hippocampus (Burokas et al., in press).

The glutamate hypothesis of schizophrenia, has suggested that hypofunction of signaling through NMDA receptors (NMDARs) plays a causal role in schizophrenia (Gonzalez-Burgos and Lewis, 2012). The glutamatergic system appears to contribute to certain cognitive deficits in schizophrenia (Thomas et al., 2017). Similarly, glutamatergic dysfunction has been implicated in ASD (Rojas, 2014). In GF mice Neufeld and colleagues demonstrated a decrease in the NMDAR subunit NR2B mRNA expression in the amygdala (Neufeld et al., 2011) Figure 2. Although a review of post-mortem studies of subjects with schizophrenia found consistent evidence of morphological alterations of dendrites of glutamatergic neurons in the cerebral cortex, there were no consistent alterations of mRNA expression of glutamate receptors (Hu et al., 2015).

Serotonin

Serotonin (5-HT) has a wide range of physiological functions, and is involved in the modulation of anxiety, conditioned fear, stress responses, reward, and social behavior (Lucki, 1998; Dayan and Huys, 2008; Asan et al., 2013). A meta-analysis of post-mortem studies found an elevation in prefrontal 5-HT1A receptors and a reduction in prefrontal 5-HT2A receptors in schizophrenia (Selvaraj et al., 2014). Serotonin, and its pre-cursor tryptophan, are critical signaling molecules in the brain-gut-microbiota axis (O'Mahony et al., 2015). In GF mice decreased 5-HT1A in hippocampus has been shown (Neufeld et al., 2011). In the gastrointestinal tract (GI), 5-HT plays an important role in secretion, sensing and signaling (Mawe and Hoffman, 2013). The largest reserve of 5-HT is located in enterochromaffin cells (Berger et al., 2009). Emerging evidence also suggests that the serotonergic system may be under the influence of gut microbiota, especially, but not limited to, periods prior to the emergence of a stable adult-like gut microbiota (Desbonnet et al., 2008; El Aidy et al., 2012; Clarke et al., 2013). A metabolomics study demonstrated that the gut microbiota has a significant impact on blood metabolites and showed an almost three-fold increase in plasma serotonin levels when GF mice are colonized by gut microbiota (Wikoff et al., 2009). The gut microbiota itself is also an important regulator of 5-HT synthesis and secretion. For example, colonic tryptophan hydroxylase 1 (Tph1) mRNA and protein were increased in humanized GF and conventionally raised mice. Bacterial metabolites have also been demonstrated to influence Tph1 transcription in a human enterochromaffin cell model (Reigstad et al., 2015). Others have demonstrated that distinct microbial metabolites produced by spore forming bacteria increase colonic and blood 5-HT in chromaffin cell cultures (Yano et al., 2015).

Kynurenine

The regulation of circulating tryptophan availability, and the distribution and subsequent kynurenine pathway metabolism, in the periphery and CNS, is tightly regulated during all stages of life (Ruddick et al., 2006; Badawy, 2017). The enzyme indoleamine 2,3-dioxygenase (IDO) found in macrophages and microglia cells is the first and rate limiting step in the kynurenine pathway of tryptophan catabolism. The expression of tryptophan-2,3-dioxygenase (TDO) can be induced by circulating glucocorticoids (O'Connor et al., 2009) and has been reported to be regulated by the gut microbiota during colonization (El Aidy et al., 2014). Under normal physiological conditions, approximately 99% of tryptophan is metabolized to kynurenine in the liver by TDO. However, proinflammatory cytokines such as IFN-γ, CRP, IL-1, IL-6, and TNF-α can induce IDO resulting in the metabolism of tryptophan along the kynurenine pathway (Schwarcz et al., 2012). Kynurenine, tryptophan and 3-hydroxykynurenine (3-HK) can cross the BBB and tryptophan's conversion to kynurenine and 3-HK in the peripheral circulation can therefore contribute to CNS levels (Schwarcz et al., 2012; Myint and Kim, 2014). In the brain, kynurenine metabolism occurs in all cells, though the two kynurenine pathway branches are physically segregated into distinct cell types. Astrocytes contain kynurenine aminotransferases (KATs), not kynurenine 3-monooxygenase (KMO) and therefore cannot produce 3-hydroxykynurenine (3-HK) from Kynurenine (Guidetti et al., 2007). The end result of the metabolic pathway in astrocytes is the neuroprotective Kynurenic acid (KYNA) (Gramsbergen et al., 1997), whereas, in microglia, it is the neurotoxic metabolite quinolinic acid (Alberati-Giani et al., 1996).

As mentioned above, regulation of the kynurenine pathway is important throughout life, but especially during sensitive periods of early neurodevelopment. KYNA is an NMDA and alpha7 nicotinic (α7nACh) receptor antagonist, both important in modulating brain development (Myint and Kim, 2014). Administration of kynurenine, starting during embryogenesis, reduced the expression of α7nACh receptor and mGluR2 expression, and induced deficits in prefrontal cortex mediated cognition in adult rats (Pershing et al., 2015). Indeed, prenatal, but not adolescent, kynurenine treatment caused significant impairments in hippocampal-mediated behavioral tasks (Pocivavsek et al., 2014). Combining perinatal choline-supplementation, with embryonic kynurenine manipulation, to potentially increase activation of α7nACh receptors during development, can attenuate cognitive impairments in adult rat offspring (Notarangelo and Pocivavsek, 2017). Furthermore, prenatal kynurenine induces age-dependent changes in NMDA receptor expression (NR2A, NR1) (Pershing et al., 2016). This study also showed that juvenile rats that were given kynurenine performed better in a trace fear conditioning task, whereas the adults showed deficits. Prenatal inhibition of kynurenine pathway, using the kynurenine-3-monoxygenase inhibitor (Ro61-8048), results in altered synaptic transmission and protein expression in the brains of adult offspring (Forrest et al., 2013; Khalil et al., 2014; Pisar et al., 2014), and also changes hippocampal plasticity (Forrest et al., 2015). Using a kynurenine 3-monooxygenase knockout mouse model (Kmo−/−), which increased brain KYNA levels, showed impairments in contextual memory, social behavior, and increased anxiety-like behavior (Erhardt et al., in press). Interestingly, administering D-amphetamine to Kmo−/− mice showed potentiated horizontal activity in the open field paradigm.

In schizophrenia, increased KYNA levels in CSF, including in drug naïve patients (Nilsson et al., 2005), and in post-mortem brain samples have been shown (Erhardt et al., 2001; Plitman et al., 2017). In a clinical study, patients with schizophrenia (n = 64) were more intolerant to a psychological stress challenge than healthy controls, and while salivary KYNA levels increased significantly between baseline and 20 min following the stressor in both patients and controls, patients who were unable to tolerate the stressful tasks showed significantly higher levels of KYNA than patients who tolerated the psychological stressor or healthy controls (Chiappelli et al., 2014). A recent pre-clinical study showed that restraint stress in pregnant mice caused significant elevations of KYNA levels in the maternal plasma, placenta, and fetal brain (Notarangelo and Schwarcz, 2017). Furthermore, the kynurenine/tryptophan ratio was significantly higher in patients diagnosed with psychotic disorder (Barry et al., 2009). Collectively, these pre-clinical and clinical studies highlight the importance of the kynurenine pathway during neurodevelopment, and there is a growing appreciation that integrating these important insights with the emerging importance of microbial regulation of this pathway will be an important research objective (Kennedy et al., 2017).

Zinc signaling

The essential micronutrient Zinc plays an important role in immune function and GI development and function (Kau et al., 2011; Vela et al., 2015). Multiple independent factors affect Zinc status, including diet, prenatal and early life stress, immune system dysregulation, and impaired GI function (Vela et al., 2015). Zinc deficiency, particularly during the prenatal phase, has been proposed as an environmental risk factor for ASD. Indeed, in rats, acute Zinc deficiency can result in hyperactivity and over-responsivity, whereas prenatal deficiency can impair vocalizations and social behavior (Grabrucker et al., 2014). It has been suggested that the post-synaptic protein Shank3, which is localized at synapses in the brain and is associated with neuro-developmental disorders such as ASD and schizophrenia, is an important component of zinc-sensitive signaling system that regulates excitatory synaptic transmission, and may lead to cognitive and behavioral abnormalities in infants with ASD (Grabrucker et al., 2014; Arons and Lee, 2016). In clinical studies, Zinc deficiency has been reported in infants with ASD (Yorbik et al., 2004; Yasuda et al., 2011; Li et al., 2014). However, studies investigating Zinc levels in schizophrenia have yielded inconsistent results (Cai et al., 2015). The impact of micronutrient imbalances on the gut microbiota are beginning to emerge (Hibberd et al., 2017). In a study using chicks, Zinc deficiency induced gut microbiota alterations and decreased species richness and diversity (Reed et al., 2015). Excess dietary Zinc significantly altered the gut microbiota and in turn reduced the threshold of antibiotics needed to confer susceptibility to C. difficile infection in mice (Zackular et al., 2016).

Epigenetic influences

Dietary factors can result in epigenetic alterations that lead to disease susceptibility (Jirtle and Skinner, 2007). It has been established that prenatal malnutrition increases the risk of schizophrenia (Susser and Lin, 1992; St Clair et al., 2005; Xu et al., 2009). Furthermore, it has been suggested that the microbiota is an important mediator of gene–environment interactions (Stilling et al., 2014b). SCFAs (butyrate, acetate and propionate) are neurohormonal signaling molecules produced by certain classes of bacteria such as Bacteroides, Bifidobacterium, Propionibacterium, Eubacterium, Lactobacillus, Clostridium, Roseburia, and Prevotella (Macfarlane and Macfarlane, 2012). SCFAs are transported by monocarboxylate transporters, which notably are expressed at the BBB (Steele, 1986; Vijay and Morris, 2014). A pre-clinical imaging study demonstrated that microbiota-derived acetate can cross the BBB where it can subsequently alter hypothalamic gene expression (Frost et al., 2014). Butyrate has been shown to be associated with increased expression of the tight junction protein occludin in the frontal cortex and hippocampus (Braniste et al., 2014). Butyrate, which acts as a potent inhibitor of Histone deacetylase (HDAC), is also a ligand for a subset of G protein-coupled receptors (Bourassa et al., 2016). It is clear that supra-physiological levels do have marked behavioral consequences (MacFabe et al., 2007; Macfabe, 2012; Thomas et al., 2012). However, the ability of physiological levels of SCFAs to substantially effect behavior via central mechanism are likely to be subtle, though cumulative chronic delivery may produce long-lasting stable effects on gene expression.

Microbiota and social behavior and cognition

Neuronal activity in the amygdala is altered in GF mice (Stilling et al., 2015). In these mice, expression of immediate early response genes such as Fos, Fosb, Egr2, or Nr4a1 were increased in the amygdala, in conjunction with increased signaling of the transcription factor CREB (Stilling et al., 2015). Differential expression and recoding of several genes involved in fundamental brain processes ranging from neuronal plasticity, metabolism, neurotransmission and morphology were identified and a significant downregulation was noted for immune system-related genes (Stilling et al., 2015). In addition to an altered transcriptional profile in the amygdala, GF mice have recently been shown to exhibit reduced freezing behavior during a cued memory retention test, while colonized GF mice were behaviorally comparable to conventionally raised mice during the retention test (Hoban et al., 2017). Furthermore, adult GF mice have distinct dendritic morphological changes in the amygdala and hippocampus (Luczynski et al., 2016) and myelination of the prefrontal cortex has also been shown to be under the influence of the gut microbiota (Hoban et al., 2016b). Using GF mice, Desbonnet et al. (2014) showed that the microbiota is crucial for the development of normal social behaviors, including social motivation and preference for social novelty, while also being an important regulator of repetitive behaviors (Arentsen et al., 2015; Buffington et al., 2016). This decreased sociability has also been demonstrated in rats (Crumeyrolle-Arias et al., 2014). Interestingly, the peptidoglycan (PGN)-sensing molecule, Pglyrp2, has been shown to modulate the development of social behavior in mice and alterations in the expression of the ASD risk gene c-Met (Arentsen et al., 2017).

Oxytocin, a neuropeptide produced in the paraventricular nucleus (PVN) of the hypothalamus, is important for sociability (Teng et al., 2013). Offspring of mothers fed a high-fat diet showed reduced levels of oxytocin PVN neurons, in addition to behavioral and gut microbiota alterations (Buffington et al., 2016). L. reuteri treatment restored oxytocin levels and social behaviors. A recent study, using low dose penicillin, administered to dams in late pregnancy and early post-natal life showed that this antibiotic induced gut microbiota alterations, increased cytokine expression in frontal cortex, modified BBB integrity and decreased anxiety-like and social behaviors, in offspring (Leclercq et al., 2017). Interestingly, concurrent supplementation with L. rhamnosus (JB-1) attenuated the penicillin induced decrease in social novelty.

The maternal immune activation (MIA) model serves as a useful model for neurodevelopmental disorders such as ASD and schizophrenia, and it is well established that prenatal infection can act as “neurodevelopmental disease primer,” the consequences of which are dependent on precise timing of MIA (Meyer et al., 2006; Smith et al., 2007; Knuesel et al., 2014; Meyer, 2014; Coiro et al., 2015; Meehan et al., 2016; Pendyala et al., 2017). MIA rodents display all three of the core features of human ASD, including limited social interactions, a tendency toward repetitive behavior and reduced communication (Patterson, 2011). A recent study showed that MIA induces dysregulation of fetal brain transcriptome by downregulating genes related to ASD (Lombardo et al., 2017). MIA has been associated with altered gut microbiota. Furthermore, the commensal Bacteroides fragilis reversed the deficits in communicative, stereotypic, anxiety-like and sensorimotor behaviors (Hsiao et al., 2013).

Autistic like behavior and neurochemical alterations have also been demonstrated in a mouse model of food allergy (de Theije et al., 2014b). The same author showed an altered gut microbiota profile in an autism model, using valproic acid (VPA) (de Theije et al., 2014a). Interestingly, VPA, a medication used as a mood stabilizer in bipolar affective disorder and as an antiepileptic, functions as a HDAC inhibitor and has a similar structure to the SCFA propionic acid. It is well established that VPA acid use during pregnancy increases the risk of autism (Jacob et al., 2013), and propionic acid can also modulate mitochondrial function in autism and control cell lines (Frye et al., 2016).

As indicated above, multiple cognitive domains are impacted in ASD and schizophrenia and the gut microbiota has been implicated in a number of relevant cognitive functions. The combination of acute stress and infection can impact cognition. Citrobacter rodentium infected C57BL/6 mice that were exposed to acute stress exhibited memory dysfunction (Gareau et al., 2011). Moreover, GF Swiss-Webster mice displayed memory impairment at baseline, in the absence of acute stress (Gareau et al., 2011). In male C57BL/6 mice, higher percentages of Clostridiales and lower levels of Bacteroidales in high-energy diets were related to poorer cognitive flexibility (Magnusson et al., 2015). In BALB/c mice, treatment with B. Longum resulted in an improvement in stress related behavior and cognition (Savignac et al., 2015). Hippocampal neurogenesis, a pivotal process in learning and memory consolidation (Deng et al., 2010; Levone et al., 2015; Anacker and Hen, 2017; Hueston et al., 2017) has been shown to be regulated by the gut microbiota. GF mice exhibit increased adult hippocampal neurogenesis in the dorsal hippocampus, and post-weaning microbial colonization failed to reverse the changes in adult hippocampal neurogenesis (Ogbonnaya et al., 2015). Furthermore, exercise or probiotics were able to ameliorate deficits in neurogenesis and behavior in antibiotic-treated mice (Mohle et al., 2016). A recent study showed that L. johnsonii CJLJ103 attenuated colitis and memory impairment in mice by inhibiting gut microbiota lipopolysaccharide production and NF-κB activation (Lim et al., 2017).

Using an antibiotic (ampicillin, metronidazole, vancomycin, ciprofloxacin, imipenem) treated rat model, gut microbiota depletion during adulthood resulted in deficits in spatial memory as measured by Morris water maze (Hoban et al., 2016a). In another pre-clinical study, that used ampicillin, bacitracin, meropenem, neomycin, and vancomycin, novel object recognition, but not spatial memory, was impaired in antibiotic-treated mice and this cognitive deficit was associated with brain region-specific changes in the expression of cognition-relevant signaling molecules, notably BDNF, N-methyl-D-aspartate receptor subunit 2B, serotonin transporter and neuropeptide Y system. The authors concluded that circulating metabolites and the cerebral neuropeptide Y system play an important role in the cognitive impairment and dysregulation of cerebral signaling molecules due to antibiotic-induced gut alterations (Frohlich et al., 2016). Furthermore, in a pre-clinical rodent model of diabetes, L. acidophilus, B. lactis, and L. fermentum, improved diabetes-induced impairment of cognitive function in the Morris water maze and synaptic activity in rats (Davari et al., 2013). The N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine causes hyperlocomotion, social withdrawal, and cognitive impairment in rodents, and serves as a useful pharmacological rodent model of schizophrenia (Jones et al., 2011). A study investigating the effect of subchronic phencyclidine (subPCP) treatment on cognition and gut microbiota, found that the microbiota altered immediately after subPCP washout. Administration of ampicillin abolished the subPCP-induced memory deficit (Pyndt Jorgensen et al., 2015).

Microbiota and stress

The brain interprets perceived stressors to determine physiological and behavioral responses. This process can promote adaptation (allostasis), but when responses are exaggerated or overused (allostatic overload), pathology can ensue (McEwen, 2017). The immune system and HPA axis are pivotal to the stress response and act as mediators to alter neural circuitry and function, particularly in the hippocampus, amygdala, and prefrontal cortex (McEwen et al., 2016). Stressful life events can precipitate psychotic symptoms (Day et al., 1987), and increased sensitivity to minor stressful events are associated with more intense psychotic experiences in first episode psychosis (FEP) (Reininghaus et al., 2016b). In addition early life event stressors, such as childhood trauma (Varese et al., 2012) and social adversity/defeat stressors, such as migration/ethnic minority status can increase the risk of psychosis (Elizabeth Cantor-Graae and Jean-Paul Selten, 2005; Selten and Cantor-Graae, 2005; Fusar-Poli et al., 2017). As mentioned above, schizophrenia is a highly heterogenous disorder, and commonly co-morbid with anxiety and depressive disorders (Buckley et al., 2009; Achim et al., 2011). Similarly, approximately 40% of young people with ASD have at least one comorbid DSM-IV anxiety disorder (van Steensel et al., 2011) and there are higher levels of depression (Ghaziuddin et al., 2002; Magnuson and Constantino, 2011; Strang et al., 2012).

Stress can reshape gut microbiota composition (Wang and Wu, 2005; O'Mahony et al., 2009; Galley et al., 2014a,b; Golubeva et al., 2015; Frohlich et al., 2016). For example, early life maternal separation resulted in a significant decrease in fecal Lactobacillus numbers on day 3 post-separation which was correlated with stress related behaviors in rhesus monkeys (Bailey and Coe, 1999). In a mouse model of social disruption, stress altered the gut microbial profile and increased the levels of the pro-inflammatory cytokine IL-6 (Bailey et al., 2011). Interestingly, it was possible to transfer an anxious behavioral phenotype between two strains of mice via fecal microbiota transfer (Bercik et al., 2011). More recently, it has been shown that mice that received an obesity associated microbiota exhibit more anxiety-like behaviors associated with increased evidence of neuroinflammation compared to controls (Bruce-Keller et al., 2015).

As previously mentioned, the developmental trajectory of the gut microbiota is compatible with concepts of the early-life period as a vulnerable phase for the subsequent emergence of neurodevelopmental disorders (O'Mahony et al., 2009, 2017; Borre et al., 2014). Pre-clinical evidence suggests that the gut microbiota signature acquired and maintained during these pivotal stages may also affect stress reactivity. GF rodents demonstrate abnormal behavioral and neuroendocrine responses to stress (Sudo et al., 2004; Nishino et al., 2013; Crumeyrolle-Arias et al., 2014; Moloney et al., 2014) and the normal development of the HPA axis is contingent on microbiota colonization at specific neurodevelopmental time points (Sudo et al., 2004).

Furthermore, the expression of anxiety like behavior in a mouse model of early life stress is partially dependent on the gut microbiota (De Palma et al., 2015). Evidence suggests that prenatal stress also impacts the gut microbiota with implications for physiological outcomes in the offspring (Golubeva et al., 2015). In a mouse model of prenatal stress, maternal stress decreased the abundance of vaginal Lactobacillus, resulting in decreased transmission of this bacterium to offspring, which corresponded with changes in metabolite profiles involved in energy balance, and with disruptions of amino acid profiles in the developing brain (Jasarevic et al., 2015). Human infants of mothers with high self-reported stress and high salivary cortisol concentrations during pregnancy had significantly higher relative abundances of Proteobacterial groups known to contain pathogens and lower relative abundances of lactic acid bacteria (Lactobacillus) and Bifidobacteria (Zijlmans et al., 2015). In addition, those infants with altered microbiota composition exhibited a higher level of maternally reported infant GI symptoms and allergic reactions, highlighting the functional consequences of aberrant colonization patterns.

The stress related disorder, depression, commonly co-morbid with ASD and schizophrenia, has been associated with alterations in gut microbiota profiles (Naseribafrouei et al., 2014; Jiang et al., 2015) and altered metabolomic output (Yu et al., 2017). Fecal Microbiota Transfer (FMT) from depressed patients to GF mice (Zheng et al., 2016) and antibiotic treated rats (Kelly, 2016; Kelly et al., 2016a) resulted in the transfer of certain depressive and anxiety like behaviors in the recipient rodents. The first study investigating the gut microbiota in bipolar affective disorder patients (n = 115), showed levels of Faecalibacterium were decreased, after adjusting for age, sex, and BMI, compared to healthy control subjects (n = 64). Moreover, Faecalibacterium was associated with better self-reported health outcomes based on the Short Form Health Survey, the Patient Health Questionnaire, the Pittsburg Sleep Quality Index, the Generalized Anxiety Disorder scale, and the Altman Mania Rating Scale (Evans et al., 2017). Interestingly, reduced levels of Faecalibacterium were reported in the study by Jiang and colleagues, which negatively correlated with severity of depressive symptoms (Jiang et al., 2015).

Fecal microbiota signatures in patients with diarrhea-predominant Irritable Bowel Syndrome (IBS), a stress related GI disorder, were shown to be similar to those patients with depression (Liu et al., 2016). Moreover, FMT from IBS patients to rats, induced anxiety related behaviors in the rats (De Palma and Lynch, 2017). In a double blind RCT of IBS patients, 6 weeks of B. longum NCC3001 reduced depression scores as measured by the Hospital Anxiety and Depression scale, and responses to negative emotional stimuli in amygdala and fronto-limbic regions, using fMRI, compared to placebo (Pinto-Sanchez et al., 2017). A recent study, using structural MRI, showed that gut microbial composition correlated with sensory and salience-related brain regions (Labus et al., 2017).

Translational approaches

In pre-clinical studies, both prebiotic (Burokas et al., in press) and probiotic treatment can reduce stress related behaviors (Abildgaard et al., 2017; Moya-Pérez et al., 2017). In a recent study, L. reuteri was reported to reduce despair like behavior in mice by inhibition of intestinal Indoleamine 2,3-dioxygenase (IDO1) and decrease peripheral levels of kynurenine (Marin et al., 2017). The profusion of pre-clinical data indicating a role for the brain-gut-microbiota axis in brain development, function and behavior, prompted the growing need to translate these findings into human populations (Kelly et al., 2015). “Psychobiotics,” originally defined as live bacteria that when ingested in adequate amounts could produce a positive mental health benefit, in terms of anxiety, mood and cognition (Dinan et al., 2013), has more recently been expanded to encompass “any substance that exerts a microbiome-mediated psychological effect” (Sarkar et al., 2016; Allen et al., 2017).

The process of translating psychobiotics from bench to bedside is not without significant challenges (Arrieta et al., 2016; Kelly, 2016; Kelly et al., 2016b; Cani, 2017), but a growing number of small studies with healthy individuals suggest that prolonged pre- and probiotic consumption can positively affect aspects of mood and anxiety in healthy controls (Messaoudi et al., 2011; Mohammadi et al., 2015; Steenbergen et al., 2015; Allen et al., 2016) and modulate HPA axis function (Messaoudi et al., 2011; Schmidt et al., 2015; Allen et al., 2016). Importantly, a fermented milk containing B. animalis, Streptococcus thermophiles, L. bulgaricus, and L. lactis, administered for 4 weeks to healthy women, reduced the task-related response of a distributed functional network containing affective, viscerosensory and somatosensory cortices, independent of self-reposted GI symptoms (Tillisch et al., 2013).

In humans, studies investigating the potential cognitive enhancing effects of microbial based therapies are starting to emerge (Allen et al., 2016). In this study, 4 weeks of treatment with the probiotic B. longum 1714 modestly improved performance in a hippocampal dependent memory task in healthy volunteers. However, this effect is likely strain specific since this subtle cognitive enhancing effect was not evident following administration of L. rhamnosus (JB-1) (Kelly et al., 2017a). In a randomized, double-blind, placebo-controlled trial involving healthy human participants (n = 76), the tetracycline antibiotic doxycycline (200 mg), a matrix metalloproteinase inhibitor, resulted in reduced fear memory retention, measured with fear-potentiated startle, 7 days post-acquisition compared to participants that received placebo (Bach et al., 2017). Doxycycline can alter the composition of the gut microbiota and its metabolomic output (Angelakis et al., 2014; Behr et al., 2017). Considering the recent pre-clinical data suggesting a role for the gut microbiota in the behavioral response during amygdala-dependent memory retention (Hoban et al., 2017), it would be a compelling prospect to ascertain if alterations in gut microbiota played a physiological role in this antibiotic human study. A cross sectional MRI study comparing 20 obese individuals to 19 age and sex matched non-obese controls, reported that the relative abundance of Actinobacteria phylum was associated with magnetic diffusion tensor imaging variables in the thalamus, hypothalamus, and amygdala and also with to cognitive test scores related to speed, attention, and cognitive flexibility (Fernandez-Real et al., 2015). Although preliminary, these studies, and others (Pinto-Sanchez et al., 2017), are beginning to merge microbiome research with neuroimaging to further delineate the role of the gut microbiota on cognition and neural circuitry.

To date, there are two interventional studies investigating potential psychobiotics in clinical depression, with conflicting results. In the first study, 8 weeks of a multispecies probiotic containing L. acidophilus, L. casei, and B. bifidum, added to an SSRI, reportedly reduced depressive symptoms in moderately depressed patients compared to placebo (Akkasheh et al., 2016). The other study, conducted in antidepressant free depressed subjects, failed to show superiority of L. helveticus and B. longum over placebo, in an 8-week double blind randomized controlled trial (Romijn et al., 2017). A Mediterranean diet, suggested as protective for depression, has been associated with beneficial microbiome-related metabolomic profiles (De Filippis et al., 2015) and there is increasing awareness of the role of a healthy diet in reducing the risk of depression (Jacka et al., 2010, 2017; Opie et al., 2017). Collectively, these studies suggest that the gut microbiota may play a pathophysiological role in stress-related disorders. However, given the small sample sizes and lack of a standardized approach in these studies, a robust and consistent gut microbiota signature in stress-related disorders, remains elusive. Moreover, a systematic review found very limited evidence for the efficacy of psychobiotics in psychological outcomes (Romijn and Rucklidge, 2015). Similarly, even in GI disorders, gut microbiota analysis as a diagnostic or prognostic tool has not transitioned into routine clinical practice (Quigley, 2017).

There has been one clinical interventional study investigating probiotics in patients diagnosed with schizophrenia. This randomized, double-blind, placebo-controlled trial (n = 65), used Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12, improved GI symptoms, but failed to impact positive or negative symptoms (Dickerson et al., 2014). A number of small studies have shown that the antibiotic minocycline, notwithstanding a complex mechanism of action, is known to modulate the brain-gut-microbiota axis, (Wong et al., 2016), and may improve negative and cognitive symptoms in schizophrenia (Miyaoka et al., 2008; Levkovitz et al., 2010; Jhamnani et al., 2013; Khodaie-Ardakani et al., 2014). This raises the question of whether microbiome based therapies could play a role in the amelioration of cognitive or negative symptoms in subgroups of psychosis spectrum disorder.

Schizophrenia spectrum disorder and stratified psychiatry

The full neuropsychiatric implications of specific aberrations in the gut microbiota at early developmental stages or during adolescence have not been fully explored. It is an intriguing prospect that these aberrations may serve as additional risk factors or mediators for the development of psychotic disorders. It remains an unanswered question whether the gut microbiota is a state or trait marker and whether it plays a role, in conjunction with for example, stress, as a trigger factor for a psychotic relapse. The role of psychobiotics in schizophrenia remains under investigated (see Table 2). It would be interesting to explore whether a microbial based therapy could be a useful preventative strategy, or as an adjunctive agent in subgroups or whether it could reduce conversion to psychosis in subgroups at risk of developing the disorder. Well powered, longitudinal studies, encompassing neuroimaging markers would be required to definitively answer these questions.

In recent years, the categorical diagnostic system in clinical psychiatry has been challenged. Even the term schizophrenia has been disputed (van Os, 2016), with evidence showing that renaming the disorder can reduce stigma and benefit communication between clinicians, patients and families (George and Klijn, 2013; Lasalvia et al., 2015). There is growing momentum toward a more precise, dimensional approach, designed to uncover the biological mechanisms of these complex disorders. Functional dimensional constructs grouped into domains such as negative valance (acute threat (fear), potential threat (anxiety), sustained threat, loss, frustrative non-reward), positive valence (approach motivation, initial responsiveness to reward attainment, sustained/longer term responsiveness to reward attainment, reward learning, habit), cognitive (attention, perception, declarative memory, language, cognitive control, working memory), social processing (affiliation and attachment, social communication, perception, and understanding of self/others), and arousal/regulatory systems (arousal, circadian rhythms, sleep-wakefulness) examined across units of analysis from genes, molecules, cells, circuits, physiology, neuroimaging, behavior and self-report have been proposed (Insel et al., 2010). This dimensional approach is more difficult in disorders such as psychosis, compared to mood disorders, but this exciting process has begun (Reininghaus et al., 2016a; Cohen et al., 2017; Joyce et al., 2017). By deconstructing heterogenous systems-disorders (Öngür, 2017; Silbersweig and Loscalzo, 2017), such as schizophrenia into transdiagnostic constructs, and stratifying subgroups of patients based on similar pathophysiology, such as microbiome alterations and related signaling pathways, this opens up the possibility to advance personalized and precision treatments options (Kaiser and Feng, 2015).

Additionally, by removing the constraints of classical psychiatric disease diagnosis it has the potential to better align pre-clinical and clinical studies to build a common framework of comparable neurobiological abnormalities. Clearly, it is impossible to fully mimic a complex neuropsychiatric disorder such as schizophrenia or ASD in non-human animals. Hallucinations, delusions, thought disorder, and language impairments cannot be modeled. Thus, rather than modeling an entire disorder, the focus should be aimed at more precise constructs such those mentioned above, with the addition of the gut microbiota. Most currently used behavioral models do not include the gut microbiota as a factor. Clearly demonstrating causality in microbiome research is challenging (Hanage, 2014; Cani, 2017). The humanized FMT model is an integral component to demonstrate cause and effect in gut microbiota studies involving neurodevelopmental disorders such as schizophrenia, and provided a reliable and reproducible model can be developed, the precise temporal dynamics of the emergence and possible persistence of the behavioral alterations post FMT could be further delineated.

Furthermore, whether different human donor symptom profiles can be transferred via FMT may further disentangle the contribution of the gut microbiota to the pathophysiology of aspects of psychosis, by attempting to transfer sub-categories of psychotic subjects, including medication free subjects, with different constructs such as negative valance, positive valence, cognitive, social processing and arousal/regulatory systems. While it must be acknowledged that significant neuroscientific advances have frequently been lost in translation and not had appreciable benefits for psychiatric patients as yet, an evolving dimensional framework, consolidating multiple disciplines, and encompassing the gut microbiota as an additional environmental construct linked to other constructs, offers potential to identify sub-groups of patients that may be more likely to respond to a microbiome-based therapeutic approach at specific neurodevelopmental time points (Kelly, 2016; Severance et al., 2016c; Kelly et al., 2017b).

Conclusions and perspectives

Highly complex neurodevelopmental disorders such as ASD and schizophrenia require a systems level approach. The human brain develops and functions within the context of a complex network of lifelong microbial signaling pathways from gut to brain. Pre-clinical studies are beginning to provide mechanistic insights into these signaling pathways as they relate to the social, emotional and cognitive domains of the brain. Furthermore, they suggest that psychobiotics can ameliorate certain defects. However, translating these promising pre-clinical benefits to human neurodevelopment disorders is challenging. The majority of clinical studies investigating the gut microbiota in ASD are cross sectional and underpowered, and there is insufficient evidence of solid clinical relevance. In schizophrenia, there is emerging preliminary evidence of an altered gut microbiota. An intriguing prospect would be to focus on different neurodevelopmental time points, for example during adolescence, in subgroups at risk of developing neuropsychiatric symptoms, and to encompass a dimensional construct approach. Larger prospective interventional clinical studies, with central markers of brain function, utilizing therapeutic modulation of the gut microbiota or its metabolites are required. Furthermore, exploration of the interaction of the gut microbiota and nutritional modification, at different neurodevelopmental stages, including pre-conception, warrants exploration as a preventative strategy for neurodevelopmental disorders in addition to stress-related disorders (Jacka, 2017). Although it is premature to draw firm conclusions about the clinical utility of microbiome based treatment strategies in neurodevelopmental disorders at this point, it is an exciting frontier in psychiatry research.

References

• 1

  AbildgaardA.ElfvingB.HoklandM.WegenerG.LundS. (2017). Probiotic treatment reduces depressive-like behaviour in rats independently of diet. Psychoneuroendocrinology79, 40–48. 10.1016/j.psyneuen.2017.02.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  AchimA. M.MaziadeM.RaymondÉ.OlivierD.MéretteC.RoyM.-A. (2011). How prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a significant association. Schizophr. Bull.37, 811–821. 10.1093/schbul/sbp148

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  AdamsJ. B.JohansenL. J.PowellL. D.QuigD.RubinR. A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC Gastroenterol.11:22. 10.1186/1471-230X-11-22

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  AdolphsR. (2001). The neurobiology of social cognition. Curr. Opin. Neurobiol.11, 231–239. 10.1016/S0959-4388(00)00202-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  AkkashehG.Kashani-PoorZ.Tajabadi-EbrahimiM.JafariP.AkbariH.TaghizadehM.et al. (2016). Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. Nutrition32, 315–320. 10.1016/j.nut.2015.09.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  Alberati-GianiD.Ricciardi-CastagnoliP.KohlerC.CesuraA. M. (1996). Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells. J. Neurochem.66, 996–1004. 10.1046/j.1471-4159.1996.66030996.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  Al-DiwaniA. A. J.PollakT. A.IraniS. R.LennoxB. R. (2017). Psychosis: an autoimmune disease?Immunology. [Epub ahead of print]. 10.1111/imm.12795

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  AlemanA.HijmanR.de HaanE. H.KahnR. S. (1999). Memory impairment in schizophrenia: a meta-analysis. Am. J. Psychiatry156, 1358–1366.

  • Pubmed Abstract
  • Google Scholar

• 9

  AlemanA.KahnR. S. (2005). Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia?Prog. Neurobiol.77, 283–298. 10.1016/j.pneurobio.2005.11.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  AlemanA.KahnR. S.SeltenJ. (2003). Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch. Gen. Psychiatry60, 565–571. 10.1001/archpsyc.60.6.565

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  AllenA. P.DinanT. G.ClarkeG.CryanJ. F. (2017). A psychology of the human brain-gut-microbiome axis. Soc. Pers. Psychol. Compass11, e12309. 10.1111/spc3.12309

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  AllenA. P.HutchW.BorreY. E.KennedyP. J.TemkoA.BoylanG.et al. (2016). Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl. Psychiatry6:e939. 10.1038/tp.2016.191

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  AnackerC.HenR. (2017). Adult hippocampal neurogenesis and cognitive flexibility [mdash] linking memory and mood. Nat. Rev. Neurosci.18, 335–346. 10.1038/nrn.2017.45

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  AngelakisE.MillionM.KankoeS.LagierJ. C.ArmougomF.GiorgiR.et al. (2014). Abnormal weight gain and gut microbiota modifications are side effects of long-term doxycycline and hydroxychloroquine treatment. Antimicrob. Agents Chemother.58, 3342–3347. 10.1128/AAC.02437-14

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  ArentsenT.QianY.GkotzisS.FemeniaT.WangT.UdekwuK.et al. (2017). The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior. Mol. Psychiatry22, 257–266. 10.1038/mp.2016.182

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  ArentsenT.RaithH.QianY.ForssbergH.HeijtzR. D. (2015). Host microbiota modulates development of social preference in mice. Microb. Ecol. Health Dis.26:29719. 10.3402/mehd.v26.29719

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  AriasI.SorlozanoA.VillegasE.LunaJ. D. D.McKenneyK.CervillaJ.et al. (2012). Infectious agents associated with schizophrenia: a meta-analysis. Schizophr. Res.136, 128–136. 10.1016/j.schres.2011.10.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  AronsM. H.LeeK. (2016). Shank3 is part of a zinc-sensitive signaling system that regulates excitatory synaptic strength. J. Neurosci.36, 9124–9134. 10.1523/JNEUROSCI.0116-16.2016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  ArrietaM.-C.StiemsmaL. T.AmenyogbeN.BrownE. M.FinlayB. (2014). The intestinal microbiome in early life: health and disease. Front. Immunol.5:427. 10.3389/fimmu.2014.00427

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  ArrietaM. C.WalterJ.FinlayB. B. (2016). Human microbiota-associated mice: a model with challenges. Cell Host Microbe19, 575–578. 10.1016/j.chom.2016.04.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  AsanE.SteinkeM.LeschK. P. (2013). Serotonergic innervation of the amygdala: targets, receptors, and implications for stress and anxiety. Histochem. Cell Biol.139, 785–813. 10.1007/s00418-013-1081-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  AshwoodP.KrakowiakP.Hertz-PicciottoI.HansenR.PessahI.Van de WaterJ. (2011). Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav. Immun.25, 40–45. 10.1016/j.bbi.2010.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  AtladottirH. O.ThorsenP.OstergaardL.SchendelD. E.LemckeS.AbdallahM.et al. (2010). Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J. Autism Dev. Disord.40, 1423–1430. 10.1007/s10803-010-1006-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  AverbeckB. B.CostaV. D. (2017). Motivational neural circuits underlying reinforcement learning. Nat. Neurosci.20, 505–512. 10.1038/nn.4506

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  AzevedoF. A.CarvalhoL. R.GrinbergL. T.FarfelJ. M.FerrettiR. E.LeiteR. E.et al. (2009). Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol.513, 532–541. 10.1002/cne.21974

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  BachD. R.TzovaraA.VunderJ. (2017). Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline. Mol. Psychiatry. [Epub ahead of print]. 10.1038/mp.2017.65

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  BackhedF.FraserC. M.RingelY.SandersM. E.SartorR. B.ShermanP. M.et al. (2012). Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe12, 611–622. 10.1016/j.chom.2012.10.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  BadawyA. A. B. (2017). Tryptophan availability for kynurenine pathway metabolism across the life span: control mechanisms and focus on aging, exercise, diet and nutritional supplements. Neuropharmacology112(Pt B), 248–263. 10.1016/j.neuropharm.2015.11.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  BahrS. M.TylerB. C.WooldridgeN.ButcherB. D.BurnsT. L.TeeschL. M.et al. (2015). Use of the second-generation antipsychotic, risperidone, and secondary weight gain are associated with an altered gut microbiota in children. Transl. Psychiatry5:e652. 10.1038/tp.2015.135

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  BahraS. M.WeidemannB. J.CastroA. N.WalshJ. W.deLeonO.BurnettC. M.et al. (2015). Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure. EBioMedicine2, 1725–1734. 10.1016/j.ebiom.2015.10.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  BaileyM. T.CoeC. L. (1999). Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev. Psychobiol.35, 146–155.

  • Pubmed Abstract
  • Google Scholar

• 32

  BaileyM. T.DowdS. E.GalleyJ. D.HufnagleA. R.AllenR. G.LyteM. (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav. Immun.25, 397–407. 10.1016/j.bbi.2010.10.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  BakkenT. E.MillerJ. A.DingS. L.SunkinS. M.SmithK. A.NgL.et al. (2016). A comprehensive transcriptional map of primate brain development. Nature535, 367–375. 10.1038/nature18637

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  Baron-CohenS. (2017). Editorial perspective: neurodiversity - a revolutionary concept for autism and psychiatry. J. Child Psychol. Psychiatry58, 744–747. 10.1111/jcpp.12703

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  BarrettE.RossR. P.O'TooleP. W.FitzgeraldG. F.StantonC. (2012). gamma-Aminobutyric acid production by culturable bacteria from the human intestine. J. Appl. Microbiol.113, 411–417. 10.1111/j.1365-2672.2012.05344.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  BarryS.ClarkeG.ScullyP.DinanT. (2009). Kynurenine pathway in psychosis: evidence of increased tryptophan degradation. J. Psychopharmacol.23, 287–294. 10.1177/0269881108089583

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  BassettD. S.SpornsO. (2017). Network neuroscience. Nat. Neurosci.20, 353–364. 10.1038/nn.4502

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  BehrC.KampH.FabianE.KrennrichG.MellertW.PeterE.et al. (2017). Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats. Arch. Toxicol. [Epub ahead of print]. 10.1007/s00204-017-1949-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  BenrosM. E.MortensenP. B.EatonW. W. (2012). Autoimmune diseases and infections as risk factors for schizophrenia. Ann. N.Y. Acad. Sci.1262, 56–66. 10.1111/j.1749-6632.2012.06638.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  BercikP.DenouE.CollinsJ.JacksonW.LuJ.JuryJ.et al. (2011). The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology141, 599–609, 609.e1–3. 10.1053/j.gastro.2011.04.052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  BerdingK.DonovanS. M. (2016). Microbiome and nutrition in autism spectrum disorder: current knowledge and research needs. Nutr. Rev.74, 723–736. 10.1093/nutrit/nuw048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  BergerM.GrayJ. A.RothB. L. (2009). The expanded biology of serotonin. Annu. Rev. Med.60, 355–366. 10.1146/annurev.med.60.042307.110802

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  BesteC.GetzmannS.GajewskiP. D.GolkaK.FalkensteinM. (2014). Latent Toxoplasma gondii infection leads to deficits in goal-directed behavior in healthy elderly. Neurobiol. Aging35, 1037–1044. 10.1016/j.neurobiolaging.2013.11.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  BhadraR.CobbD. A.WeissL. M.KhanI. A. (2013). Psychiatric disorders in toxoplasma seropositive patients–the CD8 connection. Schizophr. Bull.39, 485–489. 10.1093/schbul/sbt006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  BilboS. D.SmithS. H.SchwarzJ. M. (2012). A lifespan approach to neuroinflammatory and cognitive disorders: a critical role for glia. J. Neuroimmun. Pharmacol.7, 24–41. 10.1007/s11481-011-9299-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  BishopS. L.FarmerC.BalV.RobinsonE. B.WillseyA. J.WerlingD. M.et al. (2017). Identification of developmental and behavioral markers associated with genetic abnormalities in autism spectrum disorder. Am. J. Psychiatry174, 576–585. 10.1176/appi.ajp.2017.16101115

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  BlandinoP.Jr.BarnumC. J.SolomonL. G.LarishY.LankowB. S.DeakT. (2009). Gene expression changes in the hypothalamus provide evidence for regionally-selective changes in IL-1 and microglial markers after acute stress. Brain Behav. Immun.23, 958–968. 10.1016/j.bbi.2009.04.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  BloomfieldP. S.SelvarajS.VeroneseM.RizzoG.BertoldoA.OwenD. R.et al. (2016). Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [(11)C]PBR28 PET brain imaging study. Am. J. Psychiatry173, 44–52. 10.1176/appi.ajp.2015.14101358

  • CrossRef
  • Google Scholar

• 49

  BollingerJ. L.Bergeon BurnsC. M.WellmanC. L. (2016). Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. Brain Behav. Immun.52, 88–97. 10.1016/j.bbi.2015.10.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  BordensteinS. R.TheisK. R. (2015). Host biology in light of the microbiome: ten principles of holobionts and hologenomes. PLoS Biol.13:e1002226. 10.1371/journal.pbio.1002226

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  BorreY. E.O'KeeffeG. W.ClarkeG.StantonC.DinanT. G.CryanJ. F. (2014). Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol. Med.20, 509–518. 10.1016/j.molmed.2014.05.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  BourassaM. W.AlimI.BultmanS. J.RatanR. R. (2016). Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health?Neurosci. Lett.625, 56–63. 10.1016/j.neulet.2016.02.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  BranisteV.Al-AsmakhM.KowalC.AnuarF.AbbaspourA.TothM.et al. (2014). The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med.6:263ra158. 10.1126/scitranslmed.3009759

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  BravoJ. A.ForsytheP.ChewM. V.EscaravageE.SavignacH. M.DinanT. G.et al. (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl. Acad. Sci. U.S.A.108, 16050–16055. 10.1073/pnas.1102999108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  BrenhouseH. C.SchwarzJ. M. (2016). Immunoadolescence: neuroimmune development and adolescent behavior. Neurosci. Biobehav. Rev.70, 288–299. 10.1016/j.neubiorev.2016.05.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  BrownA. S. (2012). Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev. Neurobiol.72, 1272–1276. 10.1002/dneu.22024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  Bruce-KellerA. J.SalbaumJ. M.LuoM.BlanchardE. T.TaylorC. M.WelshD. A.et al. (2015). Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biol. Psychiatry77, 607–615. 10.1016/j.biopsych.2014.07.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  BsibsiM.RavidR.GvericD.van NoortJ. M. (2002). Broad expression of Toll-like receptors in the human central nervous system. J. Neuropathol. Exp. Neurol.61, 1013–1021. 10.1093/jnen/61.11.1013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  BuckleyP. F.MillerB. J.LehrerD. S.CastleD. J. (2009). Psychiatric Comorbidities and Schizophrenia. Schizophr. Bull.35, 383–402. 10.1093/schbul/sbn135

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  BuffingtonS. A.Di PriscoG. V.AuchtungT. A.AjamiN. J.PetrosinoJ. F.Costa-MattioliM. (2016). Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell165, 1762–1775. 10.1016/j.cell.2016.06.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  BuieT.FuchsG. J.III.FurutaG. T.KoorosK.LevyJ.LewisJ. D.et al. (2010). Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics125(Suppl. 1), S19–29. 10.1542/peds.2009-1878D

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  BurokasA.ArboleyaS.MoloneyR. D.PetersonV. L.MurphyK.ClarkeG.et al. (in press). Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic antidepressant-like effects reverse the impact of chronic stress in mice. Biol. Psychiatry.10.1016/j.biopsych.2016.12.031

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  CaiL.ChenT.YangJ.ZhouK.YanX.ChenW.et al. (2015). Serum trace element differences between Schizophrenia patients and controls in the Han Chinese population. Sci. Rep.5:15013. 10.1038/srep15013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  CalciaM. A.BonsallD. R.BloomfieldP. S.SelvarajS.BarichelloT.HowesO. D. (2016). Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology233, 1637–1650. 10.1007/s00213-016-4218-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  CaniP. D. (2017). Gut microbiota—at the intersection of everything?Nat. Rev. Gastroenterol. Hepatol.14, 321–322. 10.1038/nrgastro.2017.54

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  CanitanoR.PallagrosiM. (2017). Autism spectrum disorders and schizophrenia spectrum disorders: excitation/inhibition imbalance and developmental trajectories. Front. Psychiatry8:69. 10.3389/fpsyt.2017.00069

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  CaoX.LinP.JiangP.LiC. (2013). Characteristics of the gastrointestinal microbiome in children with autism spectrum disorder: a systematic review. Shanghai Arch. Psychiatry25, 342–353. 10.3969/j.issn.1002-0829.2013.06.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  CapuronL.PagnoniG.DrakeD. F.WoolwineB. J.SpiveyJ. R.CroweR. J.et al. (2012). Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch. Gen. Psychiatry69, 1044–1053. 10.1001/archgenpsychiatry.2011.2094

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  CareagaM.MuraiT.BaumanM. D. (2017). Maternal immune activation and autism spectrum disorder: from rodents to nonhuman and human primates. Biol. Psychiatry81, 391–401. 10.1016/j.biopsych.2016.10.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  CarlsonA. L.XiaK.Azcarate-PerilM. A.GoldmanB. D.AhnM.StynerM. A.et al. (in press). Infant gut microbiome associated with cognitive development. Biol. Psychiatry.10.1016/j.biopsych.2017.06.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  CarruthersV. B.SuzukiY. (2007). Effects of Toxoplasma gondii infection on the brain. Schizophr. Bull.33, 745–751. 10.1093/schbul/sbm008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  CaseyB. J.OliveriM. E.InselT. (2014). A neurodevelopmental perspective on the research domain criteria (RDoC) framework. Biol. Psychiatry76, 350–353. 10.1016/j.biopsych.2014.01.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  Castro-NallarE.BendallM. L.Perez-LosadaM.SabuncyanS.SeveranceE. G.DickersonF. B.et al. (2015). Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls. PeerJ3:e1140. 10.7717/peerj.1140

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  CermakS. A.CurtinC.BandiniL. G. (2010). Food selectivity and sensory sensitivity in children with autism spectrum disorders. J. Am. Diet. Assoc.110, 238–246. 10.1016/j.jada.2009.10.032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  ChenX.D'SouzaR.HongS. T. (2013). The role of gut microbiota in the gut-brain axis: current challenges and perspectives. Protein Cell4, 403–414. 10.1007/s13238-013-3017-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  ChiappelliJ.PocivavsekA.NugentK. L.NotarangeloF. M.KochunovP.RowlandL. M.et al. (2014). Stress-induced increase in kynurenic acid as a potential biomarker for patients with schizophrenia and distress intolerance. JAMA Psychiatry71, 761–768. 10.1001/jamapsychiatry.2014.243

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  ChistiakovD. A.BobryshevY. V.KozarovE.SobeninI. A.OrekhovA. N. (2014). Intestinal mucosal tolerance and impact of gut microbiota to mucosal tolerance. Front. Microbiol.5:781. 10.3389/fmicb.2014.00781

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  ChristensenD. L.BaioJ.Van Naarden BraunK.BilderD.CharlesJ.ConstantinoJ. N.et al. (2016). Prevalence and characteristics of autism spectrum disorder among children aged 8 years–autism and developmental disabilities monitoring network, 11 sites, United States, 2012. MMWR. Surveill. Summ.65, 1–23. 10.15585/mmwr.ss6503a1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  ChristianL. M.GalleyJ. D.HadeE. M.Schoppe-SullivanS.Kamp DushC.BaileyM. T. (2015). Gut microbiome composition is associated with temperament during early childhood. Brain Behav. Immun.45, 118–127. 10.1016/j.bbi.2014.10.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  ChuD. M.MaJ.PrinceA. L.AntonyK. M.SeferovicM. D.AagaardK. M. (2017). Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat. Med.23, 314–326. 10.1038/nm.4272

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  ClarkeG.GrenhamS.ScullyP.FitzgeraldP.MoloneyR. D.ShanahanF.et al. (2013). The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry18, 666–673. 10.1038/mp.2012.77

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  CohenA. S.LeT. P.FedechkoT. L.ElvevagB. (2017). Can RDoC help find order in thought disorder?Schizophr. Bull.43, 503–508. 10.1093/schbul/sbx030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  CoiroP.PadmashriR.SureshA.SpartzE.PendyalaG.ChouS.et al. (2015). Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders. Brain Behav. Immun.50, 249–258. 10.1016/j.bbi.2015.07.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  CollsteK.Plaven-SigrayP.Fatouros-BergmanH.VictorssonP.SchainM.ForsbergA.et al. (2017). Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [lsqb]11C[rsqb]PBR28. Mol. Psychiatry22, 850–856. 10.1038/mp.2016.247

  • CrossRef
  • Google Scholar

• 85

  ContiE.MitraJ.CalderoniS.PannekK.ShenK. K.PagnozziA.et al. (2017). Network over-connectivity differentiates autism spectrum disorder from other developmental disorders in toddlers: a diffusion MRI study. Hum. Brain Mapp.38, 2333–2344. 10.1002/hbm.23520

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  CorvinA.MorrisD. W. (2014). Genome-wide association studies: findings at the major histocompatibility complex locus in psychosis. Biol. Psychiatry75, 276–283. 10.1016/j.biopsych.2013.09.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  CroenL. A.GretherJ. K.SelvinS. (2002). Descriptive epidemiology of autism in a California population: who is at risk?J. Autism Dev. Disord.32, 217–224. 10.1023/A:1015405914950

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  Crumeyrolle-AriasM.JaglinM.BruneauA.VancasselS.CardonaA.DaugeV.et al. (2014). Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology42, 207–217. 10.1016/j.psyneuen.2014.01.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  CryanJ. F.DinanT. G. (2015). Gut microbiota: microbiota and neuroimmune signalling-Metchnikoff to microglia. Nat. Rev. Gastroenterol. Hepatol.12, 494–496. 10.1038/nrgastro.2015.127

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  CurranE. A.CryanJ. F.KennyL. C.DinanT. G.KearneyP. M.KhashanA. S. (2016). Obstetrical mode of delivery and childhood behavior and psychological development in a British Cohort. J. Autism Dev. Disord.46, 603–614. 10.1007/s10803-015-2616-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  CurranE. A.DalmanC.KearneyP. M.KennyL. C.CryanJ. F.DinanT. G.et al. (2015). Association Between obstetric mode of delivery and autism spectrum disorder: a population-based sibling design study. JAMA Psychiatry72, 935–942. 10.1001/jamapsychiatry.2015.0846

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  CurranE. A.O'NeillS. M.CryanJ. F.KennyL. C.DinanT. G.KhashanA. S.et al. (2014). Research Review: birth by caesarean section and development of autism spectrum disorder and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. J Child Psychol Psychiatry.56, 500–508. 10.1111/jcpp.12351

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  DaltonK. M.NacewiczB. M.JohnstoneT.SchaeferH. S.GernsbacherM. A.GoldsmithH. H.et al. (2005). Gaze fixation and the neural circuitry of face processing in autism. Nat. Neurosci.8, 519–526. 10.1038/nn1421

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  DaltonV. S.KolshusE.McLoughlinD. M. (2014). Epigenetics and depression: return of the repressed. J. Affect. Disord.155, 1–12. 10.1016/j.jad.2013.10.028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  DantzerR.O'ConnorJ. C.FreundG. G.JohnsonR. W.KelleyK. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci.9, 46–56. 10.1038/nrn2297

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  DavariS.TalaeiS. A.AlaeiH.SalamiM. (2013). Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome-gut-brain axis. Neuroscience240, 287–296. 10.1016/j.neuroscience.2013.02.055

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  DaveyK. J.CotterP. D.O'SullivanO.CrispieF.DinanT. G.CryanJ. F.et al. (2013). Antipsychotics and the gut microbiome: olanzapine-induced metabolic dysfunction is attenuated by antibiotic administration in the rat. Transl. Psychiatry3:e309. 10.1038/tp.2013.83

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  DaveyK. J.O'MahonyS. M.SchellekensH.O'SullivanO.BienenstockJ.CotterP. D.et al. (2012). Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters. Psychopharmacology221, 155–169. 10.1007/s00213-011-2555-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  DayR.NielsenJ. A.KortenA.ErnbergG.DubeK. C.GebhartJ.et al. (1987). Stressful life events preceding the acute onset of schizophrenia: a cross-national study from the World Health Organization. Cult. Med. Psychiatry11, 123–205. 10.1007/BF00122563

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  DayanP.HuysQ. J. (2008). Serotonin, inhibition, and negative mood. PLoS Comput. Biol.4:e4. 10.1371/journal.pcbi.0040004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  De AngelisM.PiccoloM.VanniniL.SiragusaS.De GiacomoA.SerrazzanettiD. I.et al. (2013). Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS ONE8:e76993. 10.1371/journal.pone.0076993

  • CrossRef
  • Google Scholar

• 102

  De FilippisF.PellegriniN.VanniniL.JefferyI. B.La StoriaA.LaghiL.et al. (2015). High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut65, 1812–1821. 10.1136/gutjnl-2015-309957

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  DengW.AimoneJ. B.GageF. H. (2010). New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?Nat. Rev. Neurosci.11, 339–350. 10.1038/nrn2822

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  De PalmaG.BlennerhassettP.LuJ.DengY.ParkA. J.GreenW.et al. (2015). Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat. Commun.6:7735. 10.1038/ncomms8735

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  De PalmaG.LynchM. D. (2017). Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci. Transl. Med.9:eaaf6397 9. 10.1126/scitranslmed.aaf6397

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  DerrienM.van Hylckama VliegJ. E. (2015). Fate, activity, and impact of ingested bacteria within the human gut microbiota. Trends Microbiol.23, 354–366. 10.1016/j.tim.2015.03.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  De RubeisS.HeX.GoldbergA. P.PoultneyC. S.SamochaK.CicekA. E.et al. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature515, 209–215. 10.1038/nature13772

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  DesbonnetL.ClarkeG.ShanahanF.DinanT. G.CryanJ. F. (2014). Microbiota is essential for social development in the mouse. Mol. Psychiatry19, 146–148. 10.1038/mp.2013.65

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  DesbonnetL.GarrettL.ClarkeG.BienenstockJ.DinanT. G. (2008). The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J. Psychiatr. Res.43, 164–174. 10.1016/j.jpsychires.2008.03.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  de TheijeC. G.WopereisH.RamadanM.van EijndthovenT.LambertJ.KnolJ.et al. (2014a). Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav. Immun.37, 197–206. 10.1016/j.bbi.2013.12.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  de TheijeC. G.WuJ.KoelinkP. J.Korte-BouwsG. A.BorreY.KasM. J.et al. (2014b). Autistic-like behavioural and neurochemical changes in a mouse model of food allergy. Behav. Brain Res.261, 265–274. 10.1016/j.bbr.2013.12.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  DethlefsenL.McFall-NgaiM.RelmanD. A. (2007). An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature449, 811–818. 10.1038/nature06245

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  de WitteL.TomasikJ.SchwarzE.GuestP. C.RahmouneH.KahnR. S.et al. (2014). Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophr. Res.154, 23–29. 10.1016/j.schres.2014.02.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  Diaz HeijtzR.WangS.AnuarF.QianY.BjorkholmB.SamuelssonA.et al. (2011). Normal gut microbiota modulates brain development and behavior. Proc. Natl. Acad. Sci. U.S.A.108, 3047–3052. 10.1073/pnas.1010529108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  DickersonF. B.StallingsC.OrigoniA.KatsafanasE.SavageC. L.SchweinfurthL. A.et al. (2014). Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim. Care Companion CNS Disord.16:13m01579. 10.4088/PCC.13m01579

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  DinanT. G.BorreY. E.CryanJ. F. (2014). Genomics of schizophrenia: time to consider the gut microbiome?Mol. Psychiatry19, 1252–1257. 10.1038/mp.2014.93

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  DinanT. G.CryanJ. F. (2017). Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. J. Physiol.595, 489–503. 10.1113/JP273106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  DinanT. G.StantonC.CryanJ. F. (2013). Psychobiotics: a novel class of psychotropic. Biol. Psychiatry74, 720–726. 10.1016/j.biopsych.2013.05.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  DinanT. G.StillingR. M.StantonC.CryanJ. F. (2015). Collective unconscious: how gut microbes shape human behavior. J. Psychiatr. Res.63, 1–9. 10.1016/j.jpsychires.2015.02.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  Di NicolaM.CattaneoA.HepgulN.Di FortiM.AitchisonK. J.JaniriL.et al. (2013). Serum and gene expression profile of cytokines in first-episode psychosis. Brain Behav. Immun.31, 90–95. 10.1016/j.bbi.2012.06.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  DouglasA. E.WerrenJ. H. (2016). Holes in the hologenome: why host-microbe symbioses are not holobionts. MBio7:e02099. 10.1128/mBio.02099-15

  • CrossRef
  • Google Scholar

• 122

  DowlatiY.HerrmannN.SwardfagerW.LiuH.ShamL.ReimE. K.et al. (2010). A meta-analysis of cytokines in major depression. Biol. Psychiatry67, 446–457. 10.1016/j.biopsych.2009.09.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  DunbarR. I. (2012). The social brain meets neuroimaging. Trends Cogn. Sci.16, 101–102. 10.1016/j.tics.2011.11.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  DurkinM. S.MaennerM. J.NewschafferC. J.LeeL. C.CunniffC. M.DanielsJ. L.et al. (2008). Advanced parental age and the risk of autism spectrum disorder. Am. J. Epidemiol.168, 1268–1276. 10.1093/aje/kwn250

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  EckburgP. B.BikE. M.BernsteinC. N.PurdomE.DethlefsenL.SargentM.et al. (2005). Diversity of the human intestinal microbial flora. Science308, 1635–1638. 10.1126/science.1110591

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  El AidyS.DerrienM.AardemaR.HooiveldG.RichardsS. E.DaneA.et al. (2014). Transient inflammatory-like state and microbial dysbiosis are pivotal in establishment of mucosal homeostasis during colonisation of germ-free mice. Benef. Microbes5, 67–77. 10.3920/BM2013.0018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  El AidyS.KunzeW.BienenstockJ.KleerebezemM. (2012). The microbiota and the gut-brain axis: insights from the temporal and spatial mucosal alterations during colonisation of the germfree mouse intestine. Benef. Microbes3, 251–259. 10.3920/BM2012.0042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  Cantor-GraaeElizabetSeltenJean-Paul (2005). Schizophrenia and Migration: a meta-analysis and review. Am. J. Psychiatry162, 12–24. 10.1176/appi.ajp.162.1.12

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  ErhardtS.BlennowK.NordinC.SkoghE.LindstromL. H.EngbergG. (2001). Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci. Lett.313, 96–98. 10.1016/S0304-3940(01)02242-X

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  ErhardtS.PocivavsekA.RepiciM.LiuX.-C.ImbeaultS.MaddisonD. C.et al. (in press). Adaptive behavioral changes in kynurenine 3-monooxygenase knockout mice: relevance to psychotic disorders. Biol. Psychiatry.10.1016/j.biopsych.2016.12.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  ErnyD.Hrabe de AngelisA. L.JaitinD.WieghoferP.StaszewskiO.DavidE.et al. (2015). Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci.18, 965–977. 10.1038/nn.4030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  EvansS. J.BassisC. M.HeinR.AssariS.FlowersS. A.KellyM. B.et al. (2017). The gut microbiome composition associates with bipolar disorder and illness severity. J. Psychiatr. Res.87, 23–29. 10.1016/j.jpsychires.2016.12.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  FacciL.BarbieratoM.MarinelliC.ArgentiniC.SkaperS. D.GiustiP. (2014). Toll-like receptors 2, -3 and -4 prime microglia but not astrocytes across central nervous system regions for ATP-dependent interleukin-1beta release. Sci. Rep.4:6824. 10.1038/srep06824

  • CrossRef
  • Google Scholar

• 134

  FalonyG.JoossensM.Vieira-SilvaS.WangJ.DarziY.FaustK.et al. (2016). Population-level analysis of gut microbiome variation. Science352, 560–564. 10.1126/science.aad3503

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  FaludiG.MirnicsK. (2011). Synaptic changes in the brain of subjects with schizophrenia. Int. J. Dev. Neurosci.29, 305–309. 10.1016/j.ijdevneu.2011.02.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  FeigensonK. A.KusnecovA. W.SilversteinS. M. (2014). Inflammation and the two-hit hypothesis of Schizophrenia. Neurosci. Biobehav. Rev.38, 72–93. 10.1016/j.neubiorev.2013.11.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  FelgerJ. C.MillerA. H. (2012). Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front. Neuroendocrinol.33, 315–327. 10.1016/j.yfrne.2012.09.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  FelgerJ. C.MunJ.KimmelH. L.NyeJ. A.DrakeD. F.HernandezC. R.et al. (2013). Chronic interferon-alpha decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology38, 2179–2187. 10.1038/npp.2013.115

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  FennA. M.GenselJ. C.HuangY.PopovichP. G.LifshitzJ.GodboutJ. P. (2014). Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol. Psychiatry76, 575–584. 10.1016/j.biopsych.2013.10.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  Fernandez-RealJ. M.SerinoM.BlascoG.PuigJ.Daunis-i-EstadellaJ.RicartW.et al. (2015). Gut microbiota interacts with brain microstructure and function. j. Clin. Endocrinol. Metab.100, 4505–4513. 10.1210/jc.2015-3076

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  FeustelS. M.MeissnerM.LiesenfeldO. (2012). Toxoplasma gondii and the blood-brain barrier. Virulence3, 182–192. 10.4161/viru.19004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  FilianoA. J.GadaniS. P.KipnisJ. (2017). How and why do T cells and their derived cytokines affect the injured and healthy brain?Nat. Rev. Neurosci.18, 375–384. 10.1038/nrn.2017.39

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  FinegoldS. M.DowdS. E.GontcharovaV.LiuC.HenleyK. E.WolcottR. D. (2010). Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe16, 444–453. 10.1016/j.anaerobe.2010.06.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  FinegoldS. M.MolitorisD.SongY.LiuC.VaisanenM. L.BolteE.et al. (2002). Gastrointestinal microflora studies in late-onset autism. Clin. Infect. Dis.35, S6–S16. 10.1086/341914

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  FontainhasA. M.WangM.LiangK. J.ChenS.MettuP.DamaniM.et al. (2011). Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLoS ONE6:e15973. 10.1371/journal.pone.0015973

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  ForrestC. M.KhalilO. S.PisarM.McNairK.KornisiukE.SnitcofskyM.et al. (2013). Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway. Neuroscience254, 241–259. 10.1016/j.neuroscience.2013.09.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  ForrestC. M.McNairK.PisarM.KhalilO. S.DarlingtonL. G.StoneT. W. (2015). Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine. Neuroscience310, 91–105. 10.1016/j.neuroscience.2015.09.022

  • CrossRef
  • Google Scholar

• 148

  FosterJ. A. (2016). Gut Microbiome and behavior: focus on neuroimmune interactions. Int. Rev. Neurobiol.131, 49–65. 10.1016/bs.irn.2016.07.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  FrancinoM. P. (2014). Early development of the gut microbiota and immune health. Pathogens3, 769–790. 10.3390/pathogens3030769

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  FrankM. G.BarattaM. V.SprungerD. B.WatkinsL. R.MaierS. F. (2007). Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav. Immun.21, 47–59. 10.1016/j.bbi.2006.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  FranzosaE. A.MorganX. C.SegataN.WaldronL.ReyesJ.EarlA. M.et al. (2014). Relating the metatranscriptome and metagenome of the human gut. Proc. Natl. Acad. Sci. U.S.A.111, E2329–E2338. 10.1073/pnas.1319284111

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  FreytagV.Carrillo-RoaT.MilnikA. (2017). A peripheral epigenetic signature of immune system genes is linked to neocortical thickness and Memory8:15193. 10.1038/ncomms15193

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  FrohlichE. E.FarziA.MayerhoferR.ReichmannF.JacanA.WagnerB.et al. (2016). Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication. Brain Behav. Immun.56, 140–155. 10.1016/j.bbi.2016.02.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  FrostG.SleethM. L.Sahuri-ArisoyluM.LizarbeB.CerdanS.BrodyL.et al. (2014). The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun.5:3611. 10.1038/ncomms4611

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  FryeR. E.RoseS.ChackoJ.WynneR.BennuriS. C.SlatteryJ. C.et al. (2016). Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. Transl. Psychiatry6:e927. 10.1038/tp.2016.189

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  FujimuraK. E.SitarikA. R.HavstadS.LinD. L.LevanS.FadroshD.et al. (2016). Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat. Med.22, 1187–1191. 10.1038/nm.4176

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  Fusar-PoliP.TantardiniM.De SimoneS.Ramella-CravaroV.OliverD.KingdonJ.et al. (2017). Deconstructing vulnerability for psychosis: meta-analysis of environmental risk factors for psychosis in subjects at ultra high-risk. Eur. Psychiatry40, 65–75. 10.1016/j.eurpsy.2016.09.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  GalleyJ. D.NelsonM. C.YuZ.DowdS. E.WalterJ.KumarP. S.et al. (2014a). Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota. BMC Microbiol.14:189. 10.1186/1471-2180-14-189

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  GalleyJ. D.YuZ.KumarP.DowdS. E.LyteM.BaileyM. T. (2014b). The structures of the colonic mucosa-associated and luminal microbial communities are distinct and differentially affected by a prolonged murine stressor. Gut Microbes5, 748–760. 10.4161/19490976.2014.972241

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  García-BuenoB.Gass,óP.MacDowellK. S.CalladoL. F.MasS.BernardoM.et al. (2016). Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia. J. Psychiatry Neurosci.41, E46–E55. 10.1503/jpn.150195

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  GareauM. G.WineE.RodriguesD. M.ChoJ. H.WharyM. T.PhilpottD. J.et al. (2011). Bacterial infection causes stress-induced memory dysfunction in mice. Gut60, 307–317. 10.1136/gut.2009.202515

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  GeorgeB.KlijnA. (2013). A modern name for schizophrenia (PSS) would diminish self-stigma. Psychol. Med.43, 1555–1557. 10.1017/S0033291713000895

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  GhaziuddinM.GhaziuddinN.GredenJ. (2002). Depression in persons with autism: implications for research and clinical care. J. Autism Dev. Disord.32, 299–306. 10.1023/A:1016330802348

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  GiovanoliS.EnglerH.EnglerA.RichettoJ.VogetM.WilliR.et al. (2013). Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science339, 1095–1099. 10.1126/science.1228261

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  GiovanoliS.NotterT.RichettoJ.LabouesseM. A.VuillermotS.RivaM. A.et al. (2015). Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging. J. Neuroinflammation12:221. 10.1186/s12974-015-0437-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  GoinesP. E.CroenL. A.BraunschweigD.YoshidaC. K.GretherJ.HansenR.et al. (2011). Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: a case-control study. Mol. Autism2:13. 10.1186/2040-2392-2-13

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  GolubevaA. V.CramptonS.DesbonnetL.EdgeD.O'SullivanO.LomasneyK. W.et al. (2015). Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood. Psychoneuroendocrinology60, 58–74. 10.1016/j.psyneuen.2015.06.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  GondaliaS. V.PalomboE. A.KnowlesS. R.CoxS. B.MeyerD.AustinD. W. (2012). Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res.5, 419–427. 10.1002/aur.1253

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  Gonzalez-BurgosG.LewisD. A. (2012). NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia. Schizophr. Bull.38, 950–957. 10.1093/schbul/sbs010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  GrabruckerS.JannettiL.EckertM.GaubS.ChhabraR.PfaenderS.et al. (2014). Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain137, 137–152. 10.1093/brain/awt303

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  GraeberM. B.StreitW. J. (2010). Microglia: biology and pathology. Acta Neuropathol.119, 89–105. 10.1007/s00401-009-0622-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  GrahamA. M.RasmussenJ. M.RudolphM. D.HeimC. M.GilmoreJ. H.StynerM.et al. (in press). Maternal Systemic interleukin-6 during pregnancy is associated with newborn amygdala phenotypes subsequent behavior at 2 years of age. Biol. Psychiatry.10.1016/j.biopsych.2017.05.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  GramsbergenJ. B.HodgkinsP. S.RassoulpourA.TurskiW. A.GuidettiP.SchwarczR. (1997). Brain-specific modulation of kynurenic acid synthesis in the rat. J. Neurochem.69, 290–298. 10.1046/j.1471-4159.1997.69010290.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  GreenM. J.MathesonS. L.ShepherdA.WeickertC. S.CarrV. J. (2011). Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol. Psychiatry16, 960–972. 10.1038/mp.2010.88

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  Grosse WiesmannC.SchreiberJ.SingerT.SteinbeisN.FriedericiA. D. (2017). White matter maturation is associated with the emergence of Theory of Mind in early childhood. Nat. Commun.8:14692. 10.1038/ncomms14692

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  GuarnerF.Bourdet-SicardR.BrandtzaegP.GillH. S.McGuirkP.van EdenW. (2006). Mechanisms of disease: the hygiene hypothesis revisited. Nat. Clin. Pract. Gastroenterol. Hepatol.3, 275–284. 10.1038/ncpgasthep0471

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  GuidettiP.HoffmanG. E.Melendez-FerroM.AlbuquerqueE. X.SchwarczR. (2007). Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry. Glia55, 78–92. 10.1002/glia.20432

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  HabelaC. W.SongH.MingG. L. (2016). Modeling synaptogenesis in schizophrenia and autism using human iPSC derived neurons. Mol. Cell. Neurosci.73, 52–62. 10.1016/j.mcn.2015.12.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  HaddadL.SchäferA.StreitF.LederbogenF.GrimmO.WüstS.et al. (2015). Brain structure correlates of urban upbringing, an environmental risk factor for Schizophrenia. Schizophr. Bull.41, 115–122. 10.1093/schbul/sbu072

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  HanageW. P. (2014). Microbiology: microbiome science needs a healthy dose of scepticism. Nature512, 247–248. 10.1038/512247a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  HaroonE.RaisonC. L.MillerA. H. (2012). Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology37, 137–162. 10.1038/npp.2011.205

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  HarrisonN. A.BrydonL.WalkerC.GrayM. A.SteptoeA.CritchleyH. D. (2009). Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol. Psychiatry66, 407–414. 10.1016/j.biopsych.2009.03.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  HavlicekJ.GasovaZ. G.SmithA. P.ZvaraK.FlegrJ. (2001). Decrease of psychomotor performance in subjects with latent ‘asymptomatic’ toxoplasmosis. Parasitology122, 515–520. 10.1017/S0031182001007624

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  HazlettH. C.GuH.MunsellB. C.KimS. H.StynerM.WolffJ. J.et al. (2017). Early brain development in infants at high risk for autism spectrum disorder. Nature542, 348–351. 10.1038/nature21369

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  HibberdM. C.WuM.RodionovD. A.LiX.ChengJ.GriffinN. W.et al. (2017). The effects of micronutrient deficiencies on bacterial species from the human gut microbiota. Sci. Transl. Med.9:eaal4069. 10.1126/scitranslmed.aal4069

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  HidakaB. H. (2012). Depression as a disease of modernity: explanations for increasing prevalence. J. Affect. Disord.140, 205–214. 10.1016/j.jad.2011.12.036

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  HinwoodM.MorandiniJ.DayT. A.WalkerF. R. (2011). Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb. Cortex22, 1442–1454. 10.1093/cercor/bhr229

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  HinwoodM.TynanR. J.CharnleyJ. L.BeynonS. B.DayT. A.WalkerF. R. (2012). Chronic stress induced remodeling of the prefrontal cortex: structural re-organization of microglia and the inhibitory effect of minocycline. Cereb. Cortex23, 1784–1797. 10.1093/cercor/bhs151

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  HobanA. E.MoloneyR. D.GolubevaA. V.McVey NeufeldK. A.O'SullivanO.PattersonE.et al. (2016a). Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat. Neuroscience339, 463–477. 10.1016/j.neuroscience.2016.10.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  HobanA. E.StillingR. M.MoloneyG.ShanahanF.DinanT. G.ClarkeG.et al. (2017). The microbiome regulates amygdala-dependent fear recall. Mol. Psychiatry. [Epub ahead of print]. 10.1038/mp.2017.100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  HobanA. E.StillingR. M.RyanF. J.ShanahanF.DinanT. G.ClaessonM. J.et al. (2016b). Regulation of prefrontal cortex myelination by the microbiota. Transl. Psychiatry6:e774. 10.1038/tp.2016.42

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  HodesG. E.KanaV.MenardC. (2015). Neuroimmune mechanisms of Depression18, 1386–1393. 10.1038/nn.4113

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  HolmesS. E.HinzR.DrakeR. J.GregoryC. J.ConenS.MatthewsJ. C.et al. (2016). In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study. Mol. Psychiatry21, 1672–1679. 10.1038/mp.2016.180

  • CrossRef
  • Google Scholar

• 194

  HommerR. E.SwedoS. E. (2015). Schizophrenia and autism—related disorders. Schizophr. Bull.41, 313–314. 10.1093/schbul/sbu188

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  HorK.TaylorM. (2010). Suicide and schizophrenia: a systematic review of rates and risk factors. J. Psychopharmacol.24, 81–90. 10.1177/1359786810385490

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  HsiaoE. Y.McBrideS. W.HsienS.SharonG.HydeE. R.McCueT.et al. (2013). Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopment disorders. Cell155, 1451–1463. 10.1016/j.cell.2013.11.024

  • CrossRef
  • Google Scholar

• 197

  HuW.MacDonaldM. L.ElswickD. E.SweetR. A. (2015). The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann. N.Y. Acad. Sci.1338, 38–57. 10.1111/nyas.12547

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  HuestonC. M.CryanJ. F.NolanY. M. (2017). Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators. Transl. Psychiatry7:e1081. 10.1038/tp.2017.48

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  InselT.CuthbertB.GarveyM.HeinssenR.PineD. S.QuinnK.et al. (2010). Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry167, 748–751. 10.1176/appi.ajp.2010.09091379

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  JackaF. N. (2017). Nutritional psychiatry: where to next?EBioMedicine17, 24–29. 10.1016/j.ebiom.2017.02.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  JackaF. N.O'NeilA.OpieR.ItsiopoulosC.CottonS.MohebbiM.et al. (2017). A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial). BMC Med.15:23. 10.1186/s12916-017-0791-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  JackaF. N.PascoJ. A.MykletunA.WilliamsL. J.HodgeA. M.O'ReillyS. L.et al. (2010). Association of Western and traditional diets with depression and anxiety in women. Am. J. Psychiatry167, 305–311. 10.1176/appi.ajp.2009.09060881

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  JacobJ.VanessaR.SteveM.SeanC.DavidW.JamesB. (2013). A chemical-genetics approach to study the molecular pathology of central serotonin abnormalities in fetal valproate syndrome. J. Neurol. Neurosurg. Psychiatr.84:e2. 10.1136/jnnp-2013-306573.34

  • CrossRef
  • Google Scholar

• 204

  JanakP. H.TyeK. M. (2015). From circuits to behaviour in the amygdala. Nature517, 284–292. 10.1038/nature14188

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  JanikR.ThomasonL. A. M.StaniszA. M.ForsytheP.BienenstockJ.StaniszG. J. (2016). Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate. Neuroimage125, 988–995. 10.1016/j.neuroimage.2015.11.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  JasarevicE.HowertonC. L.HowardC. D.BaleT. L. (2015). Alterations in the Vaginal Microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinology156, 3265–3276. 10.1210/en.2015-1177

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  JhamnaniK.ShivakumarV.KalmadyS.RaoN. P.VenkatasubramanianG. (2013). Successful use of add-on minocycline for treatment of persistent negative symptoms in schizophrenia. J. Neuropsychiatry Clin. Neurosci.25, E06–E07. 10.1176/appi.neuropsych.11120376

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  JiangH.LingZ.ZhangY.MaoH.MaZ.YinY.et al. (2015). Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav. Immun.48, 186–194. 10.1016/j.bbi.2015.03.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  JiangH. Y.XuL. L.ShaoL.XiaR. M.YuZ. H.LingZ. X.et al. (2016). Maternal infection during pregnancy and risk of autism spectrum disorders: a systematic review and meta-analysis. Brain Behav. Immun.58, 165–172. 10.1016/j.bbi.2016.06.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  JirtleR. L.SkinnerM. K. (2007). Environmental epigenomics and disease susceptibility. Nat. Rev. Genet.8, 253–262. 10.1038/nrg2045

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  JonesC. A.WatsonD. J. G.FoneK. C. F. (2011). Animal models of schizophrenia. Br. J. Pharmacol.164, 1162–1194. 10.1111/j.1476-5381.2011.01386.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  JonesK. L.CroenL. A.YoshidaC. K.HeuerL.HansenR.ZerboO.et al. (2017). Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol. Psychiatry22, 273–279. 10.1038/mp.2016.77

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  JoyceD. W.KehagiaA. A.TracyD. K.ProctorJ.ShergillS. S. (2017). Realising stratified psychiatry using multidimensional signatures and trajectories. J. Transl. Med.15:15. 10.1186/s12967-016-1116-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  KahnR. S.KeefeR. S. (2013). Schizophrenia is a cognitive illness: time for a change in focus. JAMA Psychiatry70, 1107–1112. 10.1001/jamapsychiatry.2013.155

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  KaiserT.FengG. (2015). Modeling psychiatric disorders for developing effective treatments. Nat. Med.21, 979–988. 10.1038/nm.3935

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  KangD.-W.AdamsJ. B.GregoryA. C.BorodyT.ChittickL.FasanoA.et al. (2017). Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome5:10. 10.1186/s40168-016-0225-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  KangD. W.ParkJ. G.IlhanZ. E.WallstromG.LabaerJ.AdamsJ. B.et al. (2013). Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS ONE8:e68322. 10.1371/journal.pone.0068322

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  KauA. L.AhernP. P.GriffinN. W.GoodmanA. L.GordonJ. I. (2011). Human nutrition, the gut microbiome and the immune system. Nature474, 327–336. 10.1038/nature10213

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  KellyJ. R. (2016). The Gut Microbiota in Depression. Ph.D., thesis, University College Cork.

  • Pubmed Abstract
  • Google Scholar

• 220

  KellyJ. R.AllenA. P.TemkoA.HutchW.KennedyP. J.FaridN.et al. (2017a). Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain Behav. Immun.61, 50–59. 10.1016/j.bbi.2016.11.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  KellyJ. R.BorreY.CO. B.PattersonE.El AidyS.DeaneJ.et al. (2016a). Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J. Psychiatr. Res.82, 109–118. 10.1016/j.jpsychires.2016.07.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  KellyJ. R.ClarkeG.CryanJ. F.DinanT. G. (2016b). Brain-gut-microbiota axis: challenges for translation in psychiatry. Ann. Epidemiol.26, 366–372. 10.1016/j.annepidem.2016.02.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  KellyJ. R.ClarkeG.CryanJ. F.DinanT. G. (2017b). Dimensional thinking in psychiatry in the era of the Research Domain Criteria (RDoC). Irish J. Psychol. Med. [Epub ahead of print]. 10.1017/ipm.2017.7

  • CrossRef
  • Google Scholar

• 224

  KellyJ. R.KennedyP. J.CryanJ. F.DinanT. G.ClarkeG.HylandN. P. (2015). Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front. Cell. Neurosci.9:392. 10.3389/fncel.2015.00392

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  KennedyP. J.CryanJ. F.DinanT. G.ClarkeG. (2017). Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology112, 399–412. 10.1016/j.neuropharm.2016.07.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  KériS.Szab,óC.KelemenO. (2017). Antipsychotics influence Toll-like receptor (TLR) expression and its relationship with cognitive functions in schizophrenia. Brain Behav. Immun.62, 256–264. 10.1016/j.bbi.2016.12.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  KhalilO. S.PisarM.ForrestC. M.VincentenM. C.DarlingtonL. G.StoneT. W. (2014). Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring. Eur. J. Neurosci.39, 1558–1571. 10.1111/ejn.12535

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  KhanN. A.RaineL. B.DrolletteE. S.ScudderM. R.KramerA. F.HillmanC. H. (2015). Dietary fiber is positively associated with cognitive control among prepubertal children. J. Nutr.145, 143–149. 10.3945/jn.114.198457

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  KhandakerG. M.PearsonR. M.ZammitS.LewisG.JonesP. B. (2014). Association of serum interleukin 6 and c-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry71, 1121–1128. 10.1001/jamapsychiatry.2014.1332

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  Khodaie-ArdakaniM. R.MirshafieeO.FarokhniaM.TajdiniM.HosseiniS. M.ModabberniaA.et al. (2014). Minocycline add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study. Psychiatry Res.215, 540–546. 10.1016/j.psychres.2013.12.051

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  KielianT. (2006). Toll-like receptors in central nervous system glial inflammation and homeostasis. J. Neurosci. Res.83, 711–730. 10.1002/jnr.20767

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  KirschP.EsslingerC.ChenQ.MierD.LisS.SiddhantiS.et al. (2005). Oxytocin modulates neural circuitry for social cognition and fear in humans. J. Neurosci.25, 11489–11493. 10.1523/JNEUROSCI.3984-05.2005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  KlermanG. L.WeissmanM. M. (1989). INcreasing rates of depression. JAMA261, 2229–2235. 10.1001/jama.1989.03420150079041

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  KnueselI.ChichaL.BritschgiM.SchobelS. A.BodmerM.HellingsJ. A.et al. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol.10, 643–660. 10.1038/nrneurol.2014.187

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  KohlerO.PetersenL.MorsO.MortensenP. B.YolkenR. H.GasseC.et al. (2017). Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta Psychiatr. Scand.135, 97–105. 10.1111/acps.12671

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 236

  KohmanR. A.RhodesJ. S. (2013). Neurogenesis, inflammation and behavior. Brain Behav. Immun.27, 22–32. 10.1016/j.bbi.2012.09.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  KolbB.MychasiukR.MuhammadA.LiY.FrostD. O.GibbR. (2012). Experience and the developing prefrontal cortex. Proc. Natl. Acad. Sci. U.S.A.109, 17186–17193. 10.1073/pnas.1121251109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  KosmickiJ. A.SamochaK. E.HowriganD. P.SandersS. J. (2017). Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat. Genet.49, 504–510. 10.1038/ng.3789

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  KosticA. D.GeversD.SiljanderH.VatanenT.HyotylainenT.HamalainenA. M.et al. (2015). The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe17, 260–273. 10.1016/j.chom.2015.01.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  KrabbendamL.van OsJ. (2005). Schizophrenia and urbanicity: a major environmental influence–conditional on genetic risk. Schizophr. Bull.31, 795–799. 10.1093/schbul/sbi060

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  LabusJ. S.HollisterE. B.JacobsJ.KirbachK.OezguenN.GuptaA.et al. (2017). Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome. Microbiome5:49. 10.1186/s40168-017-0260-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  LandryS. H.LovelandK. A. (1988). Communication behaviors in autism and developmental language delay. J. Child Psychol. Psychiatry29, 621–634. 10.1111/j.1469-7610.1988.tb01884.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  LankelmaJ. M.NieuwdorpM.de VosW. M.WiersingaW. J. (2015). The gut microbiota in internal medicine: implications for health and disease. Neth. J. Med.73, 61–68.

  • Pubmed Abstract
  • Google Scholar

• 244

  LartsevaA.DijkstraT.BuitelaarJ. K. (2014). Emotional language processing in autism spectrum disorders: a systematic review. Front. Hum. Neurosci.8:991. 10.3389/fnhum.2014.00991

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  LasalviaA.PentaE.SartoriusN.HendersonS. (2015). Should the label “schizophrenia” be abandoned?Schizophr. Res.162, 276–284. 10.1016/j.schres.2015.01.031

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  LaursenT. M.NordentoftM.MortensenP. B. (2014). Excess early mortality in schizophrenia. Annu. Rev. Clin. Psychol.10, 425–448. 10.1146/annurev-clinpsy-032813-153657

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  LeclercqS.MianF. M.StaniszA. M.BindelsL. B.CambierE.Ben-AmramH.et al. (2017). Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat. Commun.8:15062. 10.1038/ncomms15062

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  LederbogenF.KirschP.HaddadL.StreitF.TostH.SchuchP.et al. (2011). City living and urban upbringing affect neural social stress processing in humans. Nature474, 498–501. 10.1038/nature10190

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  LevkovitzY.MendlovichS.RiwkesS.BrawY.Levkovitch-VerbinH.GalG.et al. (2010). A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J. Clin. Psychiatry71, 138–149. 10.4088/JCP.08m04666yel

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  LevoneB. R.CryanJ. F.O'LearyO. F. (2015). Role of adult hippocampal neurogenesis in stress resilience. Neurobiol. Stress1, 147–155. 10.1016/j.ynstr.2014.11.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  LeyR. E.LozuponeC. A.HamadyM.KnightR.GordonJ. I. (2008). Worlds within worlds: evolution of the vertebrate gut microbiota. Nat. Rev. Microbiol.6, 776–788. 10.1038/nrmicro1978

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  LiS.-O.WangJ.-L.BjørklundG.ZhaoW.-N.YinC.-H. (2014). Serum copper and zinc levels in individuals with autism spectrum disorders. Neuroreport25, 1216–1220. 10.1097/WNR.0000000000000251

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  LimS.-M.JangH.-M.JeongJ.-J.HanM. J.KimD.-H. (2017). Lactobacillus johnsonii CJLJ103 attenuates colitis and memory impairment in mice by inhibiting gut microbiota lipopolysaccharide production and NF-κB activation. J. Funct. Foods34, 359–368. 10.1016/j.jff.2017.05.016

  • CrossRef
  • Google Scholar

• 254

  LiuY.ZhangL.WangX.WangZ.ZhangJ.JiangR.et al. (2016). Similar fecal microbiota signatures in patients with diarrhea-predominant irritable bowel syndrome and patients with depression. Clin. Gastroenterol. Hepatol.14, 1602–1611.e5. 10.1016/j.cgh.2016.05.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  LombardoM. V.MoonH. M.SuJ.PalmerT. D.CourchesneE.PramparoT. (2017). Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol. Psychiatry. [Epub ahead of print]. 10.1038/mp.2017.15

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 256

  LouveauA.SmirnovI.KeyesT. J.EcclesJ. D.RouhaniS. J.PeskeJ. D.et al. (2015). Structural and functional features of central nervous system lymphatic vessels. Nature523, 337–341. 10.1038/nature14432

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 257

  LuckiI. (1998). The spectrum of behaviors influenced by serotonin. Biol. Psychiatry44, 151–162. 10.1016/S0006-3223(98)00139-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  LuczynskiP.WhelanS. O.O'SullivanC.ClarkeG.ShanahanF.DinanT. G.et al. (2016). Adult microbiota-deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus. Eur. J. Neurosci.44, 2654–2666. 10.1111/ejn.13291

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 259

  LurieI.YangY. X.HaynesK.MamtaniR.BoursiB. (2015). Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study. J. Clin. Psychiatry76, 1522–1528. 10.4088/JCP.15m09961

  • CrossRef
  • Google Scholar

• 260

  LyteM. (2011). Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Bioessays33, 574–581. 10.1002/bies.201100024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  LyteM. (2013). Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog.9:e1003726. 10.1371/journal.ppat.1003726

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 262

  MacfabeD. F. (2012). Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb. Ecol. Health Dis.23:19260. 10.3402/mehd.v23i0.19260

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 263

  MacFabeD. F.CainD. P.Rodriguez-CapoteK.FranklinA. E.HoffmanJ. E.BoonF.et al. (2007). Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav. Brain Res.176, 149–169. 10.1016/j.bbr.2006.07.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 264

  MacfarlaneG. T.MacfarlaneS. (2012). Bacteria, colonic fermentation, and gastrointestinal health. J. AOAC Int.95, 50–60. 10.5740/jaoacint.SGE_Macfarlane

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 265

  MagnusonK. M.ConstantinoJ. N. (2011). Characterization of depression in children with autism spectrum disorders. J. Dev. Behav. Pediatrics32, 332–340. 10.1097/DBP.0b013e318213f56c

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  MagnussonK. R.HauckL.JeffreyB. M.EliasV.HumphreyA.NathR.et al. (2015). Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience300, 128–140. 10.1016/j.neuroscience.2015.05.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 267

  MancabelliL.MilaniC.LugliG. A.TurroniF.FerrarioC.van SinderenD.et al. (2017). Meta-analysis of the human gut microbiome from urbanized and pre-agricultural populations. Environ. Microbiol.19, 1379–1390. 10.1111/1462-2920.13692

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  MarinI. A.GoertzJ. E.RenT.RichS. S.Onengut-GumuscuS.FarberE.et al. (2017). Microbiota alteration is associated with the development of stress-induced despair behavior. Sci. Rep.7:43859. 10.1038/srep43859

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  MarteauP.ShanahanF. (2003). Basic aspects and pharmacology of probiotics: an overview of pharmacokinetics, mechanisms of action and side-effects. Best Pract. Res. Clin. Gastroenterol.17, 725–740. 10.1016/S1521-6918(03)00055-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  MartinW. F.GargS.ZimorskiV. (2015). Endosymbiotic theories for eukaryote origin. Philos. Trans. R. Soc. Biol. Sci.370:20140330. 10.1098/rstb.2014.0330

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 271

  MaweG. M.HoffmanJ. M. (2013). Serotonin signalling in the gut–functions, dysfunctions and therapeutic targets. Nat. Rev. Gastroenterol. Hepatol.10, 473–486. 10.1038/nrgastro.2013.105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  MayerE. A.KnightR.MazmanianS. K.CryanJ. F. (2014a). Gut microbes and the brain: paradigm shift in Neuroscience. J. Neurosci.34, 15490–15496. 10.1523/JNEUROSCI.3299-14.2014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  MayerE. A.PaduaD.TillischK. (2014b). Altered brain-gut axis in autism: comorbidity or causative mechanisms?Bioessays36, 933–939. 10.1002/bies.201400075

  • CrossRef
  • Google Scholar

• 274

  McCuskerR. H.KelleyK. W. (2013). Immune-neural connections: how the immune system's response to infectious agents influences behavior. J. Exp. Biol.216, 84–98. 10.1242/jeb.073411

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  McEwenB. S. (2017). Allostasis and the epigenetics of brain and body health over the life course: the brain on stress. JAMA Psychiatry74, 551–552. 10.1001/jamapsychiatry.2017.0270

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 276

  McEwenB. S.NascaC.GrayJ. D. (2016). Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology41, 3–23. 10.1038/npp.2015.171

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  McFall-NgaiM.HadfieldM. G.BoschT. C.CareyH. V.Domazet-LosoT.DouglasA. E.et al. (2013). Animals in a bacterial world, a new imperative for the life sciences. Proc. Natl. Acad. Sci. U.S.A.110, 3229–3236. 10.1073/pnas.1218525110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  McGlashanT. H.HoffmanR. E. (2000). Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch. Gen. Psychiatry57, 637–648. 10.1001/archpsyc.57.7.637

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 279

  McKernanD. P.DennisonU.GasznerG.CryanJ. F.DinanT. G. (2011). Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. Transl. Psychiatry1:e36. 10.1038/tp.2011.37

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 280

  MeehanC.HarmsL.FrostJ. D.BarretoR.ToddJ.SchallU.et al. (2016). Effects of immune activation during early or late gestation on schizophrenia-related behaviour in adult rat offspring. Brain Behav. Immun.63, 8–20. 10.1016/j.bbi.2016.07.144

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  MessaoudiM.LalondeR.ViolleN.JavelotH.DesorD.NejdiA.et al. (2011). Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br. J. Nutr.105, 755–764. 10.1017/S0007114510004319

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  MessiasE.ChenC.-Y.EatonW. W. (2007). Epidemiology of Schizophrenia: review of Findings and Myths. Psychiatr. Clin. North Am.30, 323–338. 10.1016/j.psc.2007.04.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 283

  MeyerU. (2014). Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol. Psychiatry75, 307–315. 10.1016/j.biopsych.2013.07.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 284

  MeyerU.FeldonJ.YeeB. K. (2009). A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr. Bull.35, 959–972. 10.1093/schbul/sbn022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 285

  MeyerU.NyffelerM.EnglerA.UrwylerA.SchedlowskiM.KnueselI.et al. (2006). The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J. Neurosci.26, 4752–4762. 10.1523/JNEUROSCI.0099-06.2006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 286

  MillerA. H.HaroonE.RaisonC. L.FelgerJ. C. (2013). Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress. Anxiety30, 297–306. 10.1002/da.22084

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 287

  MillerB. J.BuckleyP.SeaboltW.MellorA.KirkpatrickB. (2011). Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol. Psychiatry70, 663–671. 10.1016/j.biopsych.2011.04.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 288

  MiyaokaT.YasukawaR.YasudaH.HayashidaM.InagakiT.HoriguchiJ. (2008). Minocycline as adjunctive therapy for schizophrenia: an open-label study. Clin. Neuropharmacol.31, 287–292. 10.1097/WNF.0b013e3181593d45

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 289

  MohammadiA. A.JazayeriS.Khosravi-DaraniK.SolatiZ.MohammadpourN.AsemiZ.et al. (2015). Effects of probiotics on biomarkers of oxidative stress and inflammatory factors in petrochemical workers: a randomized, double-blind, placebo-controlled trial. Int. J. Prev. Med.6:82. 10.4103/2008-7802.164146

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 290

  MohleL.MatteiD.HeimesaatM. M.BereswillS.FischerA.AlutisM.et al. (2016). Ly6C(hi) monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis. Cell Rep.15, 1945–1956. 10.1016/j.celrep.2016.04.074

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 291

  MolloyC. A.Manning-CourtneyP. (2003). Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders. Autism7, 165–171. 10.1177/1362361303007002004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 292

  MolloyM. J.GraingerJ. R.BouladouxN.HandT. W.KooL. Y.NaikS.et al. (2013). Intraluminal containment of commensal outgrowth in the gut during infection-induced dysbiosis. Cell Host Microbe14, 318–328. 10.1016/j.chom.2013.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 293

  MoloneyR. D.DesbonnetL.ClarkeG.DinanT. G.CryanJ. F. (2014). The microbiome: stress, health and disease. Mamm. Genome25, 49–74. 10.1007/s00335-013-9488-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 294

  MonkC. S.WengS.-J.WigginsJ. L.KurapatiN.LouroH. M. C.CarrascoM.et al. (2010). Neural circuitry of emotional face processing in autism spectrum disorders. J. Psychiatry Neurosci.35, 105–114. 10.1503/jpn.090085

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 295

  MonroeJ. M.BuckleyP. F.MillerB. J. (2015). Meta-analysis of anti-Toxoplasma gondii IgM antibodies in acute psychosis. Schizophr. Bull.41, 989–998. 10.1093/schbul/sbu159

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 296

  MonteggiaL. M.BarrotM.PowellC. M.BertonO.GalanisV.GemelliT.et al. (2004). Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc. Natl. Acad. Sci. U.S.A.101, 10827–10832. 10.1073/pnas.0402141101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 297

  MontielC.AugustoJ.BaezY.MarioG.Pacheco-LopezG. (2014). Social neuroeconomics: the influence of microbiota in partner-choice and sociality. Curr. Pharm. Des.20, 4774–4783. 10.2174/1381612820666140130210631

  • CrossRef
  • Google Scholar

• 298

  MorganC. J.ColemanM. J.UlgenA.BolingL.ColeJ. O.JohnsonF. V.et al. (2017). Thought disorder in schizophrenia and bipolar disorder probands, their relatives, and nonpsychiatric controls. Schizophr. Bull.43, 523–535. 10.1093/schbul/sbx016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 299

  Moya-PérezA.Perez-VillalbaA.Benítez-PáezA.CampilloI.SanzY. (2017). Bifidobacterium CECT 7765 modulates early stress-induced immune, neuroendocrine and behavioral alterations in mice. Brain Behav. Immun.65, 43–56. 10.1016/j.bbi.2017.05.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 300

  MuddA. T.BerdingK.WangM.DonovanS. M.DilgerR. N. (2017). Serum cortisol mediates the relationship between fecal Ruminococcus and brain N-acetylaspartate in the young pig. Gut. Microbes. [Epub ahead of print]. 10.1080/19490976.2017.1353849

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 301

  MullerN. (2014). Immunology of schizophrenia. Neuroimmunomodulation21, 109–116. 10.1159/000356538

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 302

  MyintA. M.KimY. K. (2014). Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis. Prog. Neuropsychopharmacol. Biol. Psychiatry48, 304–313. 10.1016/j.pnpbp.2013.08.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 303

  NarendranR.FrankleW. G. (2016). Comment on Analyses and conclusions of “microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [(11)C]PBR28 PET brain imaging study.”Am. J. Psychiatry173, 536–537. 10.1176/appi.ajp.2016.15111417

  • CrossRef
  • Google Scholar

• 304

  NaseribafroueiA.HestadK.AvershinaE.SekeljaM.LinlokkenA.WilsonR.et al. (2014). Correlation between the human fecal microbiota and depression. Neurogastroenterol. Motil.26, 1155–1162. 10.1111/nmo.12378

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 305

  NeufeldK. M.KangN.BienenstockJ.FosterJ. A. (2011). Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil.23:255-e119. 10.1111/j.1365-2982.2010.01620.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 306

  NeuhausE.JonesE. J.BarnesK.SterlingL.EstesA.MunsonJ.et al. (2016). The relationship between early neural responses to emotional faces at age 3 and later autism and anxiety symptoms in adolescents with autism. J. Autism Dev. Disord.46, 2450–2463. 10.1007/s10803-016-2780-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 307

  NewburyJ.ArseneaultL.CaspiA.MoffittT. E.OdgersC. L.FisherH. L. (2016). Why are children in urban neighborhoods at increased risk for psychotic symptoms? Findings from a UK longitudinal cohort study. Schizophr. Bull.42, 1372–1383. 10.1093/schbul/sbw052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 308

  NietoR.KukuljanM.SilvaH. (2013). BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory. Front. Psychiatry4:45. 10.3389/fpsyt.2013.00045

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 309

  NilssonL. K.LinderholmK. R.EngbergG.PaulsonL.BlennowK.LindstromL. H.et al. (2005). Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr. Res.80, 315–322. 10.1016/j.schres.2005.07.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 310

  NishinoR.MikamiK.TakahashiH.TomonagaS.FuruseM.HiramotoT.et al. (2013). Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods. Neurogastroenterol. Motil.25, 521–528. 10.1111/nmo.12110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 311

  NotarangeloF. M.PocivavsekA. (2017). Elevated kynurenine pathway metabolism during neurodevelopment: implications for brain and behavior. Neuropharmacology112, 275–285. 10.1016/j.neuropharm.2016.03.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 312

  NotarangeloF. M.SchwarczR. (2017). Restraint stress during pregnancy rapidly raises kynurenic acid levels in mouse placenta and fetal brain. Dev. Neurosci.38, 458–468. 10.1159/000455228

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 313

  NotterT.MeyerU. (2017). Microglia and schizophrenia: where next?Mol. Psychiatry22, 788–789. 10.1038/mp.2017.67

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 314

  O'TuathaighC. M. P.FumagalliF.DesbonnetL.Perez-BranguliF.MoloneyG.LoftusS.et al. (2017). Epistatic and independent effects on schizophrenia-related phenotypes following co-disruption of the risk factors neuregulin-1 × DISC1. Schizophr. Bull.43, 214–225. 10.1093/schbul/sbw120

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 315

  O'ConnorJ. C.LawsonM. A.AndreC.MoreauM.LestageJ.CastanonN.et al. (2009). Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiatry14, 511–522. 10.1038/sj.mp.4002148

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 316

  OgbonnayaE. S.ClarkeG.ShanahanF.DinanT. G.CryanJ. F.O'LearyO. F. (2015). Adult hippocampal neurogenesis is regulated by the microbiome. Biol. Psychiatry78, e7–e9. 10.1016/j.biopsych.2014.12.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 317

  O'HaraA. M.ShanahanF. (2006). The gut flora as a forgotten organ. EMBO Rep.7, 688–693. 10.1038/sj.embor.7400731

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 318

  OlszakT.AnD.ZeissigS.VeraM. P.RichterJ.FrankeA.et al. (2012). Microbial exposure during early life has persistent effects on natural killer T cell function. Science336, 489–493. 10.1126/science.1219328

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 319

  O'MahonyS. M.ClarkeG.BorreY. E.DinanT. G.CryanJ. F. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav. Brain Res.277, 32–48. 10.1016/j.bbr.2014.07.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 320

  O'MahonyS. M.ClarkeG.DinanT. G.CryanJ. F. (2017). Early-life adversity and brain development: is the microbiome a missing piece of the puzzle?Neuroscience342, 37–54. 10.1016/j.neuroscience.2015.09.068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 321

  O'MahonyS. M.MarchesiJ. R.ScullyP.CodlingC.CeolhoA. M.QuigleyE. M.et al. (2009). Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol. Psychiatry65, 263–267. 10.1016/j.biopsych.2008.06.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 322

  O'NeillS. M.CurranE. A.DalmanC.KennyL. C.KearneyP. M.ClarkeG.et al. (2015). Birth by caesarean section and the risk of adult psychosis: a population-based cohort study. Schizophr Bull.42, 633–641. 10.1093/schbul/sbv152

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 323

  ÖngürD. (2017). Systems research in psychiatric neuroscience. JAMA Psychiatry74, 553–554. 10.1001/jamapsychiatry.2017.0513

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 324

  OpieR. S.ItsiopoulosC.ParlettaN.Sanchez-VillegasA.AkbaralyT. N.RuusunenA.et al. (2017). Dietary recommendations for the prevention of depression. Nutr. Neurosci.20, 161–171. 10.1179/1476830515Y.0000000043

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 325

  ParikshakN. N.SwarupV.BelgardT. G.IrimiaM.RamaswamiG.GandalM. J.et al. (2016). Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature540, 423–427. 10.1038/nature20612

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 326

  ParkS. J.LeeJ. Y.KimS. J.ChoiS. Y.YuneT. Y.RyuJ. H. (2015). Toll-like receptor-2 deficiency induces schizophrenia-like behaviors in mice. Sci. Rep.5:8502. 10.1038/srep08502

  • CrossRef
  • Google Scholar

• 327

  ParrachoH. M.BinghamM. O.GibsonG. R.McCartneyA. L. (2005). Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J. Med. Microbiol.54, 987–991. 10.1099/jmm.0.46101-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 328

  PatelS.GruchallaR. (2017). Can we be too clean for our own good? The hygiene hypothesis reviewed. Tex. Med.113, 54–59.

  • Pubmed Abstract
  • Google Scholar

• 329

  PattersonP. H. (2011). Modeling autistic features in animals. Pediatr. Res.69, 34R–40R. 10.1203/PDR.0b013e318212b80f

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 330

  PedersenC. B.MortensenP. B. (2001). Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch. Gen. Psychiatry58, 1039–1046. 10.1001/archpsyc.58.11.1039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 331

  PeenJ.SchoeversR. A.BeekmanA. T.DekkerJ. (2010). The current status of urban-rural differences in psychiatric disorders. Acta Psychiatr. Scand.121, 84–93. 10.1111/j.1600-0447.2009.01438.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 332

  PendersJ.ThijsC.van den BrandtP. A.KummelingI.SnijdersB.StelmaF.et al. (2007). Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study. Gut56, 661–667. 10.1136/gut.2006.100164

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 333

  PendyalaG.ChouS.JungY.CoiroP.SpartzE.PadmashriR.et al. (2017). Maternal immune activation causes behavioral impairments and altered cerebellar cytokine and synaptic protein expression. Neuropsychopharmacology42, 1435–1446. 10.1038/npp.2017.7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 334

  PequegnatB.SagermannM.VallianiM.TohM.ChowH.Allen-VercoeE.et al. (2013). A vaccine and diagnostic target for Clostridium bolteae, an autism-associated bacterium. Vaccine31, 2787–2790. 10.1016/j.vaccine.2013.04.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 335

  PeralaJ.SuvisaariJ.SaarniS. I.KuoppasalmiK.IsometsaE.PirkolaS.et al. (2007). Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch. Gen. Psychiatry64, 19–28. 10.1001/archpsyc.64.1.19

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 336

  PerryV. H.HolmesC. (2014). Microglial priming in neurodegenerative disease. Nat. Rev. Neurol.10, 217–224. 10.1038/nrneurol.2014.38

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 337

  PershingM. L.BortzD. M.PocivavsekA.FredericksP. J.JorgensenC. V.VunckS. A.et al. (2015). Elevated levels of kynurenic acid during gestation produce neurochemical, morphological, and cognitive deficits in adulthood: implications for schizophrenia. Neuropharmacology90, 33–41. 10.1016/j.neuropharm.2014.10.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 338

  PershingM. L.PhenisD.ValentiniV.PocivavsekA.LindquistD. H.SchwarczR.et al. (2016). Prenatal kynurenine exposure in rats: age-dependent changes in NMDA receptor expression and conditioned fear responding. Psychopharmacology233, 3725–3735. 10.1007/s00213-016-4404-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 339

  Pinto-SanchezM. I.HallG. B.GhajarK.NardelliA.BolinoC.LauJ. T.et al. (2017). Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology153, 448–459.e8. 10.1053/j.gastro.2017.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 340

  PisarM.ForrestC. M.KhalilO. S.McNairK.VincentenM. C.QasemS.et al. (2014). Modified neocortical and cerebellar protein expression and morphology in adult rats following prenatal inhibition of the kynurenine pathway. Brain Res.1576, 1–17. 10.1016/j.brainres.2014.06.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 341

  PlitmanE.IwataY.CaravaggioF.NakajimaS.ChungJ. K.GerretsenP.et al. (2017). Kynurenic acid in schizophrenia: a systematic review and meta-analysis. Schizophr. Bull.43, 764–777. 10.1093/schbul/sbw221

  • CrossRef
  • Google Scholar

• 342

  PocivavsekA.ThomasM. A.ElmerG. I.BrunoJ. P.SchwarczR. (2014). Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats. Psychopharmacology231, 2799–2809. 10.1007/s00213-014-3452-2

  • CrossRef
  • Google Scholar

• 343

  PollakT. A.DrndarskiS.StoneJ. M.DavidA. S.McGuireP.AbbottN. J. (2017). The blood-brain barrier in psychosis. Lancet Psychiatry. [Epub ahead of print]. 10.1016/S2215-0366(17)30293-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 344

  PrandovszkyE.GaskellE.MartinH.DubeyJ. P.WebsterJ. P.McConkeyG. A. (2011). The neurotropic parasite Toxoplasma gondii increases dopamine metabolism. PLoS ONE6:e23866. 10.1371/journal.pone.0023866

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 345

  PreisslerM. A.CareyS. (2005). The role of inferences about referential intent in word learning: evidence from autism. Cognition97, B13–B23. 10.1016/j.cognition.2005.01.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 346

  PrinzM.TayT. L.WolfY.JungS. (2014). Microglia: unique and common features with other tissue macrophages. Acta Neuropathol.128, 319–331. 10.1007/s00401-014-1267-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 347

  Pyndt JorgensenB.KrychL.PedersenT. B.PlathN.RedrobeJ. P.HansenA. K.et al. (2015). Investigating the long-term effect of subchronic phencyclidine-treatment on novel object recognition and the association between the gut microbiota and behavior in the animal model of schizophrenia. Physiol. Behav.141, 32–39. 10.1016/j.physbeh.2014.12.042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 348

  QinJ.LiR.RaesJ.ArumugamM.BurgdorfK. S.ManichanhC. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature464, 59–65. 10.1038/nature08821

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 349

  QinX.FengJ.CaoC.WuH.LohY.ChengY. (2016). Association of peripheral blood levels of brain-derived neurotrophic factor with autism spectrum disorder in children: a systematic review and meta-analysis. JAMA Pediatr.170, 1079–1086. 10.1001/jamapediatrics.2016.1626

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 350

  QuigleyE. M. M. (2017). Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet?Nat. Rev. Gastroenterol. Hepatol.14, 315–320. 10.1038/nrgastro.2017.29

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 351

  RasettiR.MattayV. S.WiedholzL. M.KolachanaB. S.HaririA. R.CallicottJ. H.et al. (2009). Evidence that altered amygdala activity in schizophrenia is related to clinical state and not genetic risk. Am. J. Psychiatry166, 216–225. 10.1176/appi.ajp.2008.08020261

  • CrossRef
  • Google Scholar

• 352

  ReaK.DinanT. G.CryanJ. F. (2016). The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress4, 23–33. 10.1016/j.ynstr.2016.03.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 353

  ReberS. O.SieblerP. H.DonnerN. C.MortonJ. T.SmithD. G.KopelmanJ. M.et al. (2016). Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc. Natl. Acad.f Sci. U.S.A.113, E3130–E3139. 10.1073/pnas.1600324113

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 354

  ReedS.NeumanH.MoscovichS.GlahnR. P.KorenO.TakoE. (2015). Chronic zinc deficiency alters chick gut microbiota composition and function. Nutrients7, 9768–9784. 10.3390/nu7125497

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 355

  ReigstadC. S.SalmonsonC. E.RaineyJ. F.III.SzurszewskiJ. H.LindenD. R.SonnenburgJ. L.et al. (2015). Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J.29, 1395–1403. 10.1096/fj.14-259598

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 356

  ReininghausU.BohnkeJ. R.HosangG.FarmerA.BurnsT.McGuffinP.et al. (2016a). Evaluation of the validity and utility of a transdiagnostic psychosis dimension encompassing schizophrenia and bipolar disorder. Br. J. Psychiatry209, 107–113. 10.1192/bjp.bp.115.167882

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 357

  ReininghausU.KemptonM. J.ValmaggiaL.CraigT. K.GaretyP.OnyejiakaA.et al. (2016b). Stress sensitivity, aberrant salience, and threat anticipation in early psychosis: an experience sampling study. Schizophr. Bull.42, 712–722. 10.1093/schbul/sbv190

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 358

  RelmanD. A. (2012). The human microbiome: ecosystem resilience and health. Nutr. Rev.70(Suppl. 1), S2–S9. 10.1111/j.1753-4887.2012.00489.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 359

  RocheE.SeguradoR.RenwickL.McClenaghanA.SextonS.FrawleyT.et al. (2016). Language disturbance and functioning in first episode psychosis. Psychiatry Res.235, 29–37. 10.1016/j.psychres.2015.12.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 360

  RogierR.KoendersM. I.Abdollahi-RoodsazS. (2015). Toll-like receptor mediated modulation of T cell response by commensal intestinal microbiota as a trigger for autoimmune Arthritis2015:527696. 10.1155/2015/527696

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 361

  RojasD. C. (2014). The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J. Neural Transm.121, 891–905. 10.1007/s00702-014-1216-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 362

  RomijnA. R.RucklidgeJ. J. (2015). Systematic review of evidence to support the theory of psychobiotics. Nutr. Rev.73, 675–693. 10.1093/nutrit/nuv025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 363

  RomijnA. R.RucklidgeJ. J.KuijerR. G.FramptonC. (2017). A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Aust. N. Z. J. Psychiatry51, 810–821. 10.1177/0004867416686694

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 364

  RookG. A.LowryC. A. (2008). The hygiene hypothesis and psychiatric disorders. Trends Immunol.29, 150–158. 10.1016/j.it.2008.01.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 365

  RookG. A.LowryC. A.RaisonC. L. (2013). Microbial ‘Old Friends’, immunoregulation and stress resilience. Evol. Med. Public Health2013, 46–64. 10.1093/emph/eot004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 366

  RookG. A.MartinelliR.BrunetL. R. (2003). Innate immune responses to mycobacteria and the downregulation of atopic responses. Curr. Opin. Allergy Clin. Immunol.3, 337–342. 10.1097/00130832-200310000-00003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 367

  RookG. A.RaisonC. L.LowryC. A. (2014). Microbiota, immunoregulatory old friends and psychiatric disorders. Adv. Exp. Med. Biol.817, 319–356. 10.1007/978-1-4939-0897-4_15

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 368

  RosenbergE.KorenO.ReshefL.EfronyR.Zilber-RosenbergI. (2007). The role of microorganisms in coral health, disease and evolution. Nat. Rev. Microbiol.5, 355–362. 10.1038/nrmicro1635

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 369

  RoundJ. L.MazmanianS. K. (2009). The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol.9, 313–323. 10.1038/nri2515

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 370

  RuddickJ. P.EvansA. K.NuttD. J.LightmanS. L.RookG. A.LowryC. A. (2006). Tryptophan metabolism in the central nervous system: medical implications. Expert Rev. Mol. Med.8, 1–27. 10.1017/S1462399406000068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 371

  SaghazadehA.RezaeiN. (2017). Brain-derived neurotrophic factor levels in autism: a systematic review and meta-analysis. J. Autism Dev. Disord.47, 1018–1029. 10.1007/s10803-016-3024-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 372

  SandinS.SchendelD.MagnussonP.HultmanC.SurenP.SusserE.et al. (2016). Autism risk associated with parental age and with increasing difference in age between the parents. Mol. Psychiatry21, 693–700. 10.1038/mp.2015.70

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 373

  SandlerR. H.FinegoldS. M.BolteE. R.BuchananC. P.MaxwellA. P.VaisanenM. L.et al. (2000). Short-term benefit from oral vancomycin treatment of regressive-onset autism. J. Child Neurol.15, 429–435. 10.1177/088307380001500701

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 374

  SarkarA.LehtoS. M.HartyS.DinanT. G.CryanJ. F.BurnetP. W. J. (2016). Psychobiotics and the manipulation of bacteria–gut–brain signals. Trends Neurosci.39, 763–781. 10.1016/j.tins.2016.09.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 375

  SavignacH. M.CoronaG.MillsH.ChenL.SpencerJ. P.TzortzisG.et al. (2013). Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine. Neurochem. Int.63, 756–764. 10.1016/j.neuint.2013.10.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 376

  SavignacH. M.TramullasM.KielyB.DinanT. G.CryanJ. F. (2015). Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav. Brain Res.287, 59–72. 10.1016/j.bbr.2015.02.044

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 377

  SchaeferJ.GiangrandeE.WeinbergerD. R.DickinsonD. (2013). The global cognitive impairment in schizophrenia: consistent over decades and around the world. Schizophr. Res.150, 42–50. 10.1016/j.schres.2013.07.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 378

  SchendelD.BhasinT. K. (2008). Birth weight and gestational age characteristics of children with autism, including a comparison with other developmental disabilities. Pediatrics121, 1155–1164. 10.1542/peds.2007-1049

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 379

  SchenkelL. S.SilversteinS. M. (2004). Dimensions of premorbid functioning in schizophrenia: a review of neuromotor, cognitive, social, and behavioral domains. Genet. Soc. Gen. Psychol. Monogr.130, 241–270. 10.3200/MONO.130.3.241-272

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 380

  Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature511, 421–427. 10.1038/nature13595

  • CrossRef
  • Google Scholar

• 381

  SchmidtK.CowenP. J.HarmerC. J.TzortzisG.ErringtonS.BurnetP. W. (2015). Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology232, 1793–1801. 10.1007/s00213-014-3810-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 382

  SchmidtM. J.MirnicsK. (2015). Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology40, 190–206. 10.1038/npp.2014.95

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 383

  SchoenbaumM.SutherlandJ. M.ChappelA.AzrinS.GoldsteinA. B.RuppA.et al. (2017). Twelve-month health care use and mortality in commercially insured young people with incident psychosis in the United States. Schizophr. Bull. [Epub ahead of print]. 10.1093/schbul/sbx009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 384

  SchwarczR.BrunoJ. P.MuchowskiP. J.WuH. Q. (2012). Kynurenines in the mammalian brain: when physiology meets pathology. Nat. Rev. Neurosci.13, 465–477. 10.1038/nrn3257

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 385

  SchwarzE.MaukonenJ.HyytiainenT.KieseppaT.OrešičM.SabunciyanS.et al. (in press). Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity treatment response. Schizophr. Res.10.1016/j.schres.2017.04.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 386

  SekarA.BialasA. R.de RiveraH.DavisA.HammondT. R.KamitakiN.et al. (2016). Schizophrenia risk from complex variation of complement component 4. Nature530, 177–183. 10.1038/nature16549

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 387

  SeltenJ. P.Cantor-GraaeE. (2005). Social defeat: risk factor for schizophrenia?Br. J. Psychiatry187, 101–102. 10.1192/bjp.187.2.101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 388

  SelvarajS.ArnoneD.CappaiA.HowesO. (2014). Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci. Biobehav. Rev.45, 233–245. 10.1016/j.neubiorev.2014.06.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 389

  SempleB. D.BlomgrenK.GimlinK.FerrieroD. M.Noble-HaeussleinL. J. (2013). Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog. Neurobiol.106–107, 1–16. 10.1016/j.pneurobio.2013.04.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 390

  SenderR.FuchsS. (2016). Revised estimates for the number of human and bacteria cells in the body. PLoS Biol.14:e1002533. 10.1371/journal.pbio.1002533

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 391

  SetiawanE.WilsonA. A.MizrahiR.RusjanP. M.MilerL.RajkowskaG.et al. (2015). Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry72, 268–275. 10.1001/jamapsychiatry.2014.2427

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 392

  SeveranceE. G.GressittK. L.StallingsC. R.KatsafanasE.SchweinfurthL. A.SavageC. L.et al. (2016a). Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. NPJ Schizophr.2:16018. 10.1038/npjschz.2016.18

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 393

  SeveranceE. G.GressittK. L.StallingsC. R.KatsafanasE.SchweinfurthL. A.SavageC. L.et al. (2017). Probiotic normalization of Candida albicans in schizophrenia: a randomized, placebo-controlled, longitudinal pilot study. Brain Behav. Immun.62, 41–45. 10.1016/j.bbi.2016.11.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 394

  SeveranceE. G.GressittK. L.StallingsC. R.OrigoniA. E.KhushalaniS.LewekeF. M.et al. (2013). Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr. Res.148, 130–137. 10.1016/j.schres.2013.05.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 395

  SeveranceE. G.XiaoJ.Jones-BrandoL.SabunciyanS.LiY.PletnikovM.et al. (2016b). Chapter seven - Toxoplasma gondii—a gastrointestinal pathogen associated with human brain diseases, in International Review of Neurobiology, eds CryanJ. F.ClarkeG. (Academic Press), 143–163.

  • Google Scholar

• 396

  SeveranceE. G.YolkenR. H.EatonW. W. (2016c). Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr. Res.176, 23–35. 10.1016/j.schres.2014.06.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 397

  ShenM. D.KimS. H.McKinstryR. C.GuH.HazlettH. C.NordahlC. W.et al. (2017). Increased extra-axial cerebrospinal fluid in high-risk infants who later develop autism. Biol. Psychiatry82, 186–193. 10.1016/j.biopsych.2017.02.1095

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 398

  SherwinE.DinanT. G.CryanJ. F. (2017). Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann. N. Y. Acad. Sci. [Epub ahead of print]. 10.1111/nyas.13416

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 399

  SilbersweigD.LoscalzoJ. (2017). Precision psychiatry meets network medicine: network psychiatry. JAMA Psychiatry74, 665–666. 10.1001/jamapsychiatry.2017.0580

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 400

  SlavichG. M.WayB. M.EisenbergerN. I.TaylorS. E. (2010). Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc. Natl. Acad. Sci. U.S.A.107, 14817–14822. 10.1073/pnas.1009164107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 401

  SliwaJ.FreiwaldW. A. (2017). A dedicated network for social interaction processing in the primate brain. Science356, 745–749. 10.1126/science.aam6383

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 402

  SmithS. E. P.LiJ.GarbettK.MirnicsK.PattersonP. H. (2007). Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci.27, 10695–10702. 10.1523/JNEUROSCI.2178-07.2007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 403

  SonJ. S.ZhengL. J.RowehlL. M.TianX.ZhangY.ZhuW.et al. (2015). Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS ONE10:e0137725. 10.1371/journal.pone.0137725

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 404

  SongY.LiuC.FinegoldS. M. (2004). Real-time PCR quantitation of clostridia in feces of autistic children. Appl. Environ. Microbiol.70, 6459–6465. 10.1128/AEM.70.11.6459-6465.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 405

  SpencerS. J.MeyerU. (2017). Perinatal programming by inflammation. Brain Behav. Immun.63, 1–7. 10.1016/j.bbi.2017.02.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 406

  SpoorenW.LindemannL.GhoshA.SantarelliL. (2012). Synapse dysfunction in autism: a molecular medicine approach to drug discovery in neurodevelopmental disorders. Trends Pharmacol. Sci.33, 669–684. 10.1016/j.tips.2012.09.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 407

  StamperC. E.HoisingtonA. J.GomezO. M.Halweg-EdwardsA. L.SmithD. G.BatesK. L.et al. (2016). Chapter fourteen - the microbiome of the built environment and human behavior: implications for emotional health and well-being in postmodern western societies, in International Review of Neurobiology, eds CryanJ. F.ClarkeG. (Academic Press), 289–323.

  • Google Scholar

• 408

  St ClairD.XuM.WangP.YuY.FangY.ZhangF.et al. (2005). Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. JAMA294, 557–562. 10.1001/jama.294.5.557

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 409

  SteeleR. D. (1986). Blood-brain barrier transport of the alpha-keto acid analogs of amino acids. Fed. Proc.45, 2060–2064.

  • Pubmed Abstract
  • Google Scholar

• 410

  SteenbergenL.SellaroR.van HemertS.BoschJ. A.ColzatoL. S. (2015). A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav. Immun.48, 258–264. 10.1016/j.bbi.2015.04.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 411

  SteinM. M.HruschC. L.GozdzJ.IgartuaC.PivnioukV.MurrayS. E.et al. (2016). Innate immunity and asthma risk in amish and hutterite farm children. N. Engl. J. Med.375, 411–421. 10.1056/NEJMoa1508749

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 412

  StilesJ.JerniganT. L. (2010). The basics of brain development. Neuropsychol. Rev.20, 327–348. 10.1007/s11065-010-9148-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 413

  StillingR. M.BordensteinS. R.DinanT. G.CryanJ. F. (2014a). Friends with social benefits: host-microbe interactions as a driver of brain evolution and development?Front. Cell. Infect. Microbiol.4:147. 10.3389/fcimb.2014.00147

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 414

  StillingR. M.DinanT. G.CryanJ. F. (2014b). Microbial genes, brain and behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav.13, 69–86. 10.1111/gbb.12109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 415

  StillingR. M.RyanF. J.HobanA. E.ShanahanF.ClarkeG.ClaessonM. J.et al. (2015). Microbes and neurodevelopment–Absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav. Immun.50, 209–220. 10.1016/j.bbi.2015.07.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 416

  StrachanD. P. (1989). Hay fever, hygiene, and household size. BMJ299, 1259–1260. 10.1136/bmj.299.6710.1259

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 417

  StrangJ. F.KenworthyL.DaniolosP.CaseL.WillsM. C.MartinA.et al. (2012). Depression and anxiety symptoms in children and adolescents with autism spectrum disorders without intellectual disability. Res. Autism Spectr. Disord.6, 406–412. 10.1016/j.rasd.2011.06.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 418

  StratiF.CavalieriD.AlbaneseD.De FeliceC.DonatiC.HayekJ.et al. (2017). New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome5:24. 10.1186/s40168-017-0242-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 419

  SudoN.ChidaY.AibaY.SonodaJ.OyamaN.YuX. N.et al. (2004). Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol.558, 263–275. 10.1113/jphysiol.2004.063388

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 420

  SugamaS.TakenouchiT.FujitaM.KitaniH.HashimotoM. (2011). Cold stress induced morphological microglial activation and increased IL-1beta expression in astroglial cells in rat brain. J. Neuroimmunol.233, 29–36. 10.1016/j.jneuroim.2010.11.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 421

  SuhrM. J.Hallen-AdamsH. E. (2015). The human gut mycobiome: pitfalls and potentials–a mycologist's perspective. Mycologia107, 1057–1073. 10.3852/15-147

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 422

  SullivanP. F.KendlerK. S.NealeM. C. (2003). Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry60, 1187–1192. 10.1001/archpsyc.60.12.1187

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 423

  SusserE. S.LinS. P. (1992). Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945. Arch. Gen. Psychiatry49, 983–988. 10.1001/archpsyc.1992.01820120071010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 424

  SuzukiK.SugiharaG.OuchiY.NakamuraK.FutatsubashiM.TakebayashiK.et al. (2013). Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry70, 49–58. 10.1001/jamapsychiatry.2013.272

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 425

  TakedaK.AkiraS. (2005). Toll-like receptors in innate immunity. Int. Immunol.17, 1–14. 10.1093/intimm/dxh186

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 426

  TanJ.McKenzieC.PotamitisM.ThorburnA. N.MackayC. R.MaciaL. (2014). The role of short-chain fatty acids in health and disease. Adv. Immunol.121, 91–119. 10.1016/B978-0-12-800100-4.00003-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 427

  TayT. L.SavageJ. C.HuiC. W.BishtK.TremblayM.-È. (2017). Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J. Physiol.595, 1929–1945. 10.1113/JP272134

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 428

  TengB. L.NonnemanR. J.AgsterK. L.NikolovaV. D.DavisT. T.RiddickN. V.et al. (2013). Prosocial effects of oxytocin in two mouse models of autism spectrum disorders. Neuropharmacology72, 187–196. 10.1016/j.neuropharm.2013.04.038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 429

  ThaissC. A.LevyM.KoremT.Dohnalová,áL.ShapiroH.JaitinD. A.et al. (2016). microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell167, 1495–1510.e12. 10.1016/j.cell.2016.11.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 430

  ThomasE. H. X.BozaogluK.RossellS. L.GurvichC. (2017). The influence of the glutamatergic system on cognition in schizophrenia: a systematic review. Neurosci. Biobehav. Rev.77, 369–387. 10.1016/j.neubiorev.2017.04.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 431

  ThomasR. H.MeekingM. M.MephamJ. R.TichenoffL.PossmayerF.LiuS.et al. (2012). The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J. Neuroinflammation9:153. 10.1186/1742-2094-9-153

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 432

  TickB.BoltonP.HappeF.RutterM.RijsdijkF. (2016). Heritability of autism spectrum disorders: a meta-analysis of twin studies. J. Child Psychol. Psychiatry57, 585–595. 10.1111/jcpp.12499

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 433

  TillischK.LabusJ.KilpatrickL.JiangZ.StainsJ.EbratB.et al. (2013). Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology144, 1394–1401. 10.1053/j.gastro.2013.02.043

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 434

  TomovaA.HusarovaV.LakatosovaS.BakosJ.VlkovaB.BabinskaK.et al. (2015). Gastrointestinal microbiota in children with autism in Slovakia. Physiol. Behav.138, 179–187. 10.1016/j.physbeh.2014.10.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 435

  TooL. K.McGregorI. S.BaxterA. G.HuntN. H. (2016). Altered behaviour and cognitive function following combined deletion of Toll-like receptors 2 and 4 in mice. Behav. Brain Res.303, 1–8. 10.1016/j.bbr.2016.01.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 436

  TorreyE. F.YolkenR. H. (2003). Toxoplasma gondii and schizophrenia. Emerging Infect. Dis.9, 1375–1380. 10.3201/eid0911.030143

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 437

  TrudlerD.FarfaraD.FrenkelD. (2010). Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases: towards future therapeutic application. Mediators Inflamm.2010:497987. 10.1155/2010/497987

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 438

  TurnbaughP. J.HamadyM.YatsunenkoT.CantarelB. L.DuncanA.LeyR. E.et al. (2009). A core gut microbiome in obese and lean twins. Nature457, 480–484. 10.1038/nature07540

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 439

  TynanR. J.NaickerS.HinwoodM.NalivaikoE.BullerK. M.PowD. V.et al. (2010). Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav. Immun.24, 1058–1068. 10.1016/j.bbi.2010.02.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 440

  UdinaM.CastellviP.Moreno-EspanaJ.NavinesR.ValdesM.FornsX.et al. (2012). Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J. Clin. Psychiatry73, 1128–1138. 10.4088/JCP.12r07694

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 441

  UpthegroveR.Manzanares-TesonN.BarnesN. M. (2014). Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr. Res.155, 101–108. 10.1016/j.schres.2014.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 442

  ValkanovaV.EbmeierK. P.AllanC. L. (2013). CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J. Affect. Disord.150, 736–744. 10.1016/j.jad.2013.06.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 443

  van BerckelB. N.BossongM. G.BoellaardR.KloetR.SchuitemakerA.CaspersE.et al. (2008). Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol. Psychiatry64, 820–822. 10.1016/j.biopsych.2008.04.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 444

  van OsJ. (2016). “Schizophrenia” does not exist. BMJ352, i375. 10.1136/bmj.i375

  • CrossRef
  • Google Scholar

• 445

  van SteenselF. J. A.BögelsS. M.PerrinS. (2011). Anxiety disorders in children and adolescents with autistic spectrum disorders: a meta-analysis. Clin. Child Fam. Psychol. Rev.14:302. 10.1007/s10567-011-0097-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 446

  VareseF.SmeetsF.DrukkerM.LieverseR.LatasterT.ViechtbauerW.et al. (2012). Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr. Bull.38, 661–671. 10.1093/schbul/sbs050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 447

  VassosE.PedersenC. B.MurrayR. M.CollierD. A.LewisC. M. (2012). Meta-Analysis of the Association of Urbanicity With Schizophrenia. Schizophr. Bull.38, 1118–1123. 10.1093/schbul/sbs096

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 448

  VelaG.StarkP.SochaM.SauerA. K.HagmeyerS.GrabruckerA. M. (2015). Zinc in gut-brain interaction in autism and neurological disorders. Neural Plast.2015:15. 10.1155/2015/972791

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 449

  VijayN.MorrisM. E. (2014). Role of monocarboxylate transporters in drug delivery to the brain. Curr. Pharm. Des.20, 1487–1498. 10.2174/13816128113199990462

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 450

  VoreadesN.KozilA.WeirT. L. (2014). Diet and the development of the human intestinal microbiome. Front. Microbiol.5:494. 10.3389/fmicb.2014.00494

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 451

  VorstmanJ. A. S.ParrJ. R.Moreno-De-LucaD.AnneyR. J. L.NurnbergerJ. I.Jr.HallmayerJ. F. (2017). Autism genetics: opportunities and challenges for clinical translation. Nat. Rev. Genet.18, 362–376. 10.1038/nrg.2017.4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 452

  VuongH. E.HsiaoE. Y. (2017). Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry81, 411–423. 10.1016/j.biopsych.2016.08.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 453

  WangL.ChristophersenC. T.SorichM. J.GerberJ. P.AngleyM. T.ConlonM. A. (2011). Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl. Environ. Microbiol.77, 6718–6721. 10.1128/AEM.05212-11

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 454

  WangL.ChristophersenC. T.SorichM. J.GerberJ. P.AngleyM. T.ConlonM. A. (2012). Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig. Dis. Sci.57, 2096–2102. 10.1007/s10620-012-2167-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 455

  WangL.ChristophersenC. T.SorichM. J.GerberJ. P.AngleyM. T.ConlonM. A. (2013). Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol. Autism.4:42. 10.1186/2040-2392-4-42

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 456

  WangS.AdolphsR. (2017). Reduced specificity in emotion judgment in people with autism spectrum disorder. Neuropsychologia99, 286–295. 10.1016/j.neuropsychologia.2017.03.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 457

  WangS. X.WuW. C. (2005). Effects of psychological stress on small intestinal motility and bacteria and mucosa in mice. World J. Gastroenterol.11, 2016–2021. 10.3748/wjg.v11.i13.2016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 458

  Whitaker-AzmitiaP. M. (2001). Serotonin and brain development: role in human developmental diseases. Brain Res. Bull.56, 479–485. 10.1016/S0361-9230(01)00615-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 459

  WHO (2015). Statement on caesarean section rates. Reprod. Health Matt.23, 149–150. 10.1016/j.rhm.2015.07.007

  • CrossRef
  • Google Scholar

• 460

  WikoffW. R.AnforaA. T.LiuJ.SchultzP. G.LesleyS. A.PetersE. C.et al. (2009). Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. U.S.A.106, 3698–3703. 10.1073/pnas.0812874106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 461

  WilliamsB. L.HornigM.BuieT.BaumanM. L.Cho PaikM.WickI.et al. (2011). Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE6:e24585. 10.1371/journal.pone.0024585

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 462

  WilliamsonL. L.McKenneyE. A.HolzknechtZ. E.BelliveauC.RawlsJ. F.PoultonS.et al. (2015). Got worms? Perinatal exposure to helminths prevents persistent immune sensitization and cognitive dysfunction induced by early-life infection. Brain Behav. Immun.51, 14–28. 10.1016/j.bbi.2015.07.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 463

  WillseyA. J.SandersS. J.LiM.DongS.TebbenkampA. T.MuhleR. A.et al. (2013). Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell155, 997–1007. 10.1016/j.cell.2013.10.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 464

  WongM. L.InserraA.LewisM. D.MastronardiC. A.LeongL.ChooJ.et al. (2016). Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol. Psychiatry21, 797–805. 10.1038/mp.2016.46

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 465

  XiaoJ.LiY.GressittK. L.HeH.KannanG.SchultzT. L.et al. (2016). Cerebral complement C1q activation in chronic Toxoplasma infection. Brain Behav. Immun.58, 52–56. 10.1016/j.bbi.2016.04.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 466

  XuM.-Q.SunW.-S.LiuB.-X.FengG.-Y.YuL.YangL.et al. (2009). Prenatal malnutrition and adult schizophrenia: further evidence from the 1959-1961 chinese famine. Schizophr. Bull.35, 568–576. 10.1093/schbul/sbn168

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 467

  YanoJ. M.YuK.DonaldsonG. P.ShastriG. G.AnnP.MaL.et al. (2015). Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell161, 264–276. 10.1016/j.cell.2015.02.047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 468

  YasudaH.YoshidaK.YasudaY.TsutsuiT. (2011). Infantile zinc deficiency: association with autism spectrum disorders. Sci. Rep.1:129. 10.1038/srep00129

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 469

  YolkenR. H.SeveranceE. G.SabunciyanS.GressittK. L.ChenO.StallingsC.et al. (2015). Metagenomic sequencing indicates that the oropharyngeal phageome of individuals with schizophrenia differs from that of controls. Schizophr. Bull.41, 1153–1161. 10.1093/schbul/sbu197

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 470

  YolkenR. H.TorreyE. F. (2008). Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry13, 470–479. 10.1038/mp.2008.5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 471

  YorbikÖ.AkayC.SayalA.CanseverA.SöhmenT.O. ÇavdarA. (2004). Zinc status in autistic children. J. Trace Elements Exp. Med.17, 101–107. 10.1002/jtra.20002

  • CrossRef
  • Google Scholar

• 472

  YuM.JiaH.ZhouC.YangY.ZhaoY.YangM.et al. (2017). Variations in gut microbiota and fecal metabolic phenotype associated with depression by 16S rRNA gene sequencing and LC/MS-based metabolomics. J. Pharm. Biomed. Anal.138, 231–239. 10.1016/j.jpba.2017.02.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 473

  YuenR. K. C.MericoD.BookmanM.HoweJ. L.ThiruvahindrapuramB.PatelR. V.et al. (2017). Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat. Neurosci.20, 602–611. 10.1038/nn.4524

  • CrossRef
  • Google Scholar

• 474

  ZackularJ. P.MooreJ. L.JordanA. T.JuttukondaL. J.NotoM. J.NicholsonM. R.et al. (2016). Dietary zinc alters the microbiota and decreases resistance to clostridium difficile infection. Nat. Med.22, 1330–1334. 10.1038/nm.4174

  • CrossRef
  • Google Scholar

• 475

  ZhengP.ZengB.ZhouC.LiuM.FangZ.XuX.et al. (2016). Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol. Psychiatry.21, 786–79610.1038/mp.2016.44

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 476

  ZhernakovaA.KurilshikovA.BonderM. J.TigchelaarE. F.SchirmerM.VatanenT.et al. (2016). Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science352, 565–569. 10.1126/science.aad3369

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 477

  ZijlmansM. A. C.KorpelaK.Riksen-WalravenJ. M.de VosW. M.de WeerthC. (2015). Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology53, 233–245. 10.1016/j.psyneuen.2015.01.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 478

  Zilber-RosenbergI.RosenbergE. (2008). Role of microorganisms in the evolution of animals and plants: the hologenome theory of evolution. FEMS Microbiol. Rev.32, 723–735. 10.1111/j.1574-6976.2008.00123.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar