The role of the microbiota-gut-brain axis in schizophrenia: an immunological perspective

Abstract

Schizophrenia (SZ) is a severe neuropsychiatric disorder arising from complex interactions between genetic susceptibility and environmental factors. There is growing evidence that immune dysregulation and neuroinflammation are central to its pathogenesis, with the microbiota-gut-brain (MGB) axis playing a critical role. This review synthesizes clinical and preclinical findings to elucidate the relationship between gut microbiota dysbiosis and aberrant inflammatory signaling in the periphery and central nervous system in schizophrenia. We detail how alterations in gut microbiota metabolites, following dysbiosis disrupt blood-brain barrier (BBB) integrity and exacerbate neuroinflammation, ultimately leading to the neuropathology of SZ. The review further explores how gut dysbiosis activates innate immune pathways, including the complement system (e.g., C4) and Toll-like receptors (e.g., TLR4), and examines the bidirectional relationship between cytokine imbalances and gut microbiota. A key focus is placed on the dysregulation of the kynurenine pathway of tryptophan metabolism, which mechanistically links immune activation to neurotransmitter imbalances. Collectively, these findings demonstrate that gut microbiota dysbiosis contributes to the pathophysiology of schizophrenia through multifaceted immune-neuro-endocrine pathways, highlighting the MGB axis as a promising target for novel therapeutic strategies.

1 Introduction

Schizophrenia (SZ) is a chronic brain disorder characterized by genetic heterogeneity and neuropathological alterations, with high mortality rates (1). It impairs higher-order brain functions, leading to multifaceted disabilities and incoordination of mental activities. Its clinical symptoms primarily include positive symptoms, negative symptoms, and cognitive deficits (2, 3). Evidence supports the interplay between genetic and environmental factors plays a crucial role in the pathogenesis of schizophrenia (4–6).

Current evidence from genetics, molecular neuropathology, and clinical studies underscores the importance of immune factors in both the pathogenesis and treatment of schizophrenia (7–9). Notably, genetic data from multiple large-scale patient cohorts and genome-wide association studies have shown that single nucleotide polymorphisms located within the major immune-related region on chromosome 6 are associated with schizophrenia (10–12). This finding provides strong genetic support for the immune hypothesis of schizophrenia. Furthermore, immune dysfunction may indirectly increase the risk of developing schizophrenia (see Figure 1). This dysfunction can be triggered by intrinsic host factors, such as autoimmune diseases (13–15), as well as extrinsic environmental factors, such as maternal infection and environmental exposures to infections during early life, childhood, and around the first episode of psychosis (16, 17).

Figure 1

Among these risk factors, infectious pathogens play a significant role as environmental risk factors in SZ. Clinical evidence (see Table 1) and meta-analyses (30) show a significant association between schizophrenia and a history of infection with various pathogens (for example, Chlamydophila psittaci, Chlamydia pneumoniae, Human Herpesvirus 2, Borna disease virus, and Human Endogenous Retrovirus W). Exposure to these infectious pathogens and inflammatory stimuli can profoundly affect the brain and behavior (31). A prominent example is Toxoplasma gondii infection, which, in animal models, alters behavior and increases the release of neurotransmitters such as dopamine, and the amount of dopamine release is correlated with the number of infected cells (32). In humans, it is associated with symptoms similar to those observed in schizophrenia (33). Notably, such infections can induce a complex neuroimmune response involving cytokine production by microglia, astrocytes, and neurons (34). Furthermore, they can dysregulate key immune components; for example, CD8⁺T cells, which are crucial for sustaining lasting immunity, have been found to be downregulated in schizophrenia patients (35). It is noteworthy that Toxoplasma gondii infection has been shown to affect the gut microbiome in mice (36). This suggests that the immune and neurochemical disruptions may be partially mediated through gut-related pathways. This interplay highlights the intricate interactions between genetic and environmental factors in disease development (37).

In fact, the total number of non-redundant genes encoded by the microbiota far exceeds that of the human host, and the composition and function of the microbiota are significantly influenced by environmental factors (38, 39). This genomic feature highlights the potentially critical role of the microbiome in mediating gene-environment interactions in humans.

A growing number of studies indicate that levels of natural antibodies against Gram-negative bacteria and lipopolysaccharide (LPS), such as IgA, IgM, and IgG, are elevated in patients with SZ. The production of these antibodies may be related to gut microbiota dysbiosis and increased intestinal permeability (40). Recent research has shown that gut microbes and their metabolites can enter the systemic circulation and affect the central nervous system, which may be closely related to the mechanisms underlying the symptoms of schizophrenia. Together, this evidence positions the Microbiota-Gut-Brain (MGB) axis as a key pathway through which environmental and immune factors contribute to the pathophysiology of schizophrenia, a premise we will explore in detail throughout this review.

2 The microbiota-gut-brain axis and schizophrenia: evidence from clinical and preclinical studies

During fetal development, microbial communities are already present in the maternal placenta, amniotic fluid, and umbilical cord (41–43). The perinatal period represents a critical window for the development of both the gut microbiota and the brain. Factors such as perinatal maternal stress, mode of delivery, environmental exposures, and genetic factors significantly influence the composition of the offspring’s gut microbiota and can alter behavior and Central nervous system (CNS) structure (41–50). Historically, a complex bidirectional communication system between the gastrointestinal tract, its microbiota, and the CNS—comprising neural, hormonal, and immune pathways—has been recognized and termed the MGB axis (51).

In recent years, numerous clinical studies have demonstrated that patients with schizophrenia exhibit characteristic gut dysbiosis, manifested as significant disruptions in microbial relative abundance and reduced α-diversity (52–57). Specifically, these alterations include an increased abundance of Proteobacteria and Lactobacillus, along with decreased levels of anti-inflammatory commensals such as Prevotella (58). This dysbiosis reflects a pro-inflammatory state within the gastrointestinal tract, characterized by an elevated abundance of Lachnoclostridium and reduced levels of short-chain fatty acid-producing Blautia spp. and Ruminococcus spp. (59). These microbial changes correlate with higher lipopolysaccharide (LPS) and lower superoxide dismutase-1 levels (59, 60), which can lead to microbial translocation, systemic inflammation, and increased permeability of both the intestinal and blood-brain barriers (BBB), creating a vicious cycle (61–65). These alterations are associated with specific SZ phenotypes, symptom severity, and treatment response (39, 66–68). For instance, a meta-analysis by Murray et al. indicated that abnormal proliferation of specific microbial taxa (e.g., Bifidobacterium and Lactobacillus) is significantly correlated with core clinical features, including worsened negative symptoms, metabolic pathway disturbances, and reduced cortical gray matter volume (57).

3 Microbial metabolites in SZ pathology: BBB disruption and neuroinflammation

The alterations in microbial composition described above are closely linked to functional disturbances in the gut ecosystem of patients with schizophrenia. Influenced by the altered gut microbiota composition, SZ patients show an increased incidence of gastrointestinal barrier dysfunction, food antigen sensitivity, inflammation, and metabolic syndrome (56, 69, 70). This may result from severe disruption of functional capacity in the gut microbiota of SZ patients, leading to a marked increase in pro-inflammatory metabolites and a significant decrease in anti-inflammatory metabolites (71). In preclinical and clinical metabolomics studies, approximately 10 metabolites have been identified to exhibit significant alterations in patients with SZ. These include N-acetylaspartate, lactate, tryptophan, kynurenine, glutamate, creatine, linoleic acid, D-serine, glutathione, and 3-hydroxybutyrate, among others (72). A recent study found that elevated levels of lactate and cortisol in the peripheral blood of SZ patients were significantly correlated with decreased immune parameters (such as reactive lymphocytes) and altered concentrations of cerebral metabolites like glutamate and N-acetylaspartate (73). Another study further identified correlations between specific gut bacteria (e.g., Streptococcus-Sobrinus) and metabolites (such as 7-aminomethyl-7-carbaguanine and vitamin D2), and discovered that these microbial features were closely associated with patients’ cognitive function (74). Furthermore, the gut microbiome is associated with changes in brain structure and function in SZ patients, as evidenced by neuroimaging studies linking microbial α-diversity to alterations in gray matter volume and regional homogeneity (75). These alterations in brain structure may facilitate the entry of toxic substances and peripheral inflammatory mediators into the brain, thereby triggering neuroinflammation. This process can involve gut microbiota metabolites crossing the blood-brain barrier, modulating the microbiota-gut-brain axis, and regulating microglial activity and cytokine release.

3.1 Bile acids

The potential role of bile acids (BAs) metabolism dysregulation in SZ is likely mediated through interactions with the gut-brain axis (76). Clinical studies have confirmed significant alterations in both the gut microbiota composition and BAs profiles in SZ patients (77), highlighting a potential correlation between BAs dysregulation and the disorder. A metagenome-wide association study further identified gut bacteria unique to SZ patients, including Alkalibacterium, Enterococcus faecium, and Lactobacillus fermentum (78). Cross-sectional studies found that certain gut microbes such as Collinsella, Corynebacterium, Lactobacillus, and Succinivibrio (67); Lachnospiraceae (79); and Veillonella (75) were positively correlated with the severity of SZ. This association between gut microbiota dysbiosis and SZ severity might be mediated through abnormalities in the BAs decoupling process. Metabolomic analysis of serum BAss in SZ patients revealed significantly altered BAs profiles compared to healthy controls (80). Notably, levels of primary Bas, such as CDCA, were generally elevated in patients, whereas levels of secondary Bas (e.g., DCA and LCA) were reduced (80). These altered BAs profiles may subsequently affect the composition of the gut microbiota, thereby interfering with neural function and contributing to the development and progression of SZ. A recent case report described a 39-year-old Persian male with treatment-resistant SZ who, after receiving 300 mg UDCA daily for 12 weeks, showed significant improvement in both positive and negative symptoms, along with enhanced cognitive abilities. Importantly, UDCA treatment was not only effective but also well-tolerated, with no adverse reactions reported during the treatment period, underscoring the safety and efficacy of UDCA supplementation (81). Animal studies have revealed that secondary bile acids may impair the integrity of the BBB. Among these, DCA has been demonstrated to damage endothelial tight junctions, leading to increased BBB permeability (82). This disruption allows toxic substances and peripheral inflammatory mediators to enter the brain, triggering neuroinflammation.

3.2 Polyamines

Polyamines (PAs) are important metabolites produced by gut bacteria. Research has confirmed that the gut microbiota is a significant source of polyamine synthesis, with its production of putrescine, spermidine, and spermine playing a key role in maintaining intestinal polyamine homeostasis (83). Historically, PAs were implicated in the etiology of schizophrenia because certain antipsychotic and antimalarial drugs contain structural components resembling spermidine and were associated with extrapyramidal symptoms and psychosis (84). A multi-omics analysis revealed significant disturbances in the polyamine biosynthesis pathway (85). Currently, elevated blood concentrations of PAs (primarily spermine and/or spermidine) have been observed in cases across various subtypes of schizophrenia (86–88). However, data on PA concentrations in the brain remain limited. One study on human brain tissue found no difference in polyamine levels in the frontal cortex or hippocampus of schizophrenia patients compared to control subjects (89). Another study reported significantly elevated agmatine concentrations in both the plasma and postmortem frontal cortex tissue of first-episode and chronic schizophrenia patients (90–93), and found that antipsychotic treatment could reduce blood agmatine levels (94). Elevated spermidine and total PA concentrations were also detected in fibroblasts obtained from SZ patients (95). Furthermore, studies on serum from SZ patients showed elevated levels of polyamine oxidase (the enzyme responsible for degrading PAs) (96, 97), while the activities of three enzymes involved in PA synthesis—ornithine aminotransferase, antizyme inhibitor 1 (AZIN1), and ornithine cyclodeaminase —were found to be reduced in the prefrontal cortex of both treated and untreated patients (98), ultimately potentially leading to disrupted polyamine homeostasis. A translational convergent functional genomics study identified the gene AZIN1, which encodes AZIN1, as a candidate gene for schizophrenia (99), providing genetic support for these findings. The pathophysiological role of PAs in SZ is primarily thought to be mediated through the dopamine pathway and by altering the function of the N-methyl-D-aspartate receptor (100), although the precise mechanisms remain unclear.

Under pathological conditions such as cerebral ischemia and trauma, stress states can induce significant disruption in polyamine metabolism, particularly the abnormal accumulation of putrescine. This alteration is closely associated with vasogenic edema and the disruption of the BBB (101). Research has confirmed that inhibiting polyamine biosynthesis with the ornithine decarboxylase inhibitor α-difluoromethylornithine significantly mitigates increased BBB permeability, Evans blue extravasation, and brain tissue water content in models of cerebral ischemia (102). Notably, this protective effect can be reversed by the administration of exogenous putrescine. This indicates that upregulation of endogenous polyamines, especially putrescine, serves as a critical mediator in BBB injury.

3.3 Short-chain fatty acids

The structural integrity of the BBB is maintained by tightly joined brain endothelial cells, astrocytic end-feet, pericytes, and various transport proteins, which stringently regulate the penetration of substances from the blood into the brain tissue (103). SCFAs—such as acetate, propionate, and butyrate—produced by gut microbial fermentation, can enter the systemic circulation, reach the brain, and are present in considerable concentrations in the cerebrospinal fluid (104).

Recent research has shown that SCFAs play a crucial role in modulating the structure and function of the BBB. On the one hand, SCFAs can enhance BBB integrity by regulating the expression of tight junction proteins. For instance, studies in germ-free or antibiotic-treated mouse and rhesus monkey models have demonstrated reduced levels of BBB tight junction proteins (e.g., claudin-5, occludin) and increased BBB permeability; colonization with SCFA-producing strains (such as Clostridium tyrobutyricum and Bacteroides) reversed these effects (105–108). On the other hand, SCFAs can protect the BBB directly or indirectly through anti-inflammatory mechanisms. SCFAs can interact with free fatty acid receptor 3 present on brain endothelial cells (109), suppress inflammatory responses, and alleviate oxidative stress, thereby promoting BBB stability. For example, propionate exerts anti-inflammatory and antioxidant effects by reducing cell surface CD14 expression and influencing the translocation of Nuclear Factor Erythroid 2-Related Factor 2 (110). Peripherally, certain SCFAs (e.g., acetate, propionate, and butyrate) have also been identified to possess anti-inflammatory properties (111–113).

4 Gut microbiota dysbiosis and abnormal activation of the innate immune system

4.1 Evidence for the association between complement components and schizophrenia

Current studies have identified elevated transcript levels of complement components (C1qA, C3, C4, C5) in patients with schizophrenia (114) (see Table 2), suggesting, albeit not entirely consistently, that increased activation of the classical complement pathway may be associated with SZ.

4.2 Gut microbiota dysbiosis and abnormal activation of complement C4

Genetic susceptibility to schizophrenia is significantly associated with polymorphisms in genes related to the complement system, largely attributable to alleles of the complement C4 gene located within the major histocompatibility complex region on chromosome 6 (132). The C4 allele demonstrates the strongest association with SZ risk (132)and is closely linked to increased synaptic phagocytosis and elimination by microglia (8). Furthermore, recent research has found that C4 gene overexpression triggers impaired GluR1 trafficking through an intracellular mechanism involving the endosomal protein SNX27, leading to pathological synaptic loss.

Pathogen exposure has long been recognized as a risk factor for the development of schizophrenia (142). Immune-related environmental variables, such as pathogen infection and gut microbiota dysbiosis, may interact with complement system dysfunction (143). Particularly noteworthy is the finding that genetic polymorphisms of complement components C4A and C4B are significantly associated with various microbial environmental variables in schizophrenia patients, including a history of pathogen exposure and gut ecological imbalance (143). Among these, a negative correlation was observed between plasma lipopolysaccharide-binding protein (LBP) levels and C4A gene copy number was observed in patients with schizophrenia, but not in healthy controls (143). This discovery is significant because LBP, a marker of bacterial translocation, reflects the host’s response to gut microbial translocation and circulating bacterial LPS (144). Together, these results suggest that the complement system, particularly C4A, may play a key role in the gene-environment interactions of schizophrenia by modulating the gut microbiota and systemic immune activation status.

Furthermore, the negative correlation between C4A and C4B copy numbers in SZ patients may reflect a non-random association between these loci. Further analysis revealed that C4A and C4B haplotypes are significantly associated not only with the diagnosis of schizophrenia and environmental factors but also with psychiatric symptoms and cognitive function (143). While multiple previous studies have confirmed the association between the C4A gene and an increased risk of schizophrenia (132), the intrinsic mechanism underlying the negative correlation between C4B and schizophrenia risk remains unclear. It is currently unknown whether a lower C4B copy number has a protective effect against the disease or merely reflects an associated pathological protein deficiency. The negative correlations between C4A and C4B, as well as between C4L and C4S copy numbers, more likely indicate that these loci reside at opposing ends of a risk (C4A and C4L) and protective (C4B and C4S) spectrum, existing in a state of linkage disequilibrium (143). Biochemically, C4A exhibits higher affinity for amino groups, whereas C4B binds more readily to hydroxyl groups, suggesting that C4A may be more involved in binding immune complexes and protein antigens, while C4B plays a more important role in binding carbohydrate-rich microbial antigens (145). Consequently, a deficiency in C4B protein in patients may impair its ability to bind microbial antigens. Conversely, another possibility is that a lower C4B copy number might protect the stability of the host microbiome to some extent by reducing the excessive clearance of beneficial microbes mediated by C4B. A study on pediatric inflammatory bowel disease indicated that individuals with low C4B copy numbers had milder inflammation and higher gut microbial diversity compared to those with high C4B copy numbers (146).

As research on the gut microbiome in schizophrenia expands, integrating C4 genotyping with microbiome analysis is of great importance. Furthermore, these haplotype associations require further analysis to exclude nearby HLA gene variants—which may influence the observed immune phenotype due to linkage disequilibrium with specific C4 alleles (123).

5 Potential pathophysiological mechanisms of toll-like receptors and gut bacterial translocation in schizophrenia and psychiatric disorders

Toll-like receptors (TLRs) coordinate the activation of innate immune responses alongside the complement system and play a significant role in the neuroimmune mechanisms of schizophrenia. Studies indicate that activation of TLR2/3/4/5 triggers the NF-κB/NLRP3 pathway and the PI3K/Akt/mTORC1 signaling pathway, leading to microglial activation, neuroinflammation, and neuronal damage (147, 148). Furthermore, thickness changes in the limbic system and cortical brain regions of schizophrenia patients are correlated with abnormal expression of specific TLRs, suggesting their involvement in brain structural remodeling (149). Stimulation of whole blood cells from SZ patients with selective TLR agonists results in enhanced release of pro-inflammatory cytokines (including IL-1β, IL-6, IL-8, and TNF-α) (150), further supporting the role of TLRs in regulating neuroinflammation in schizophrenia.

TLR4, a key receptor for recognizing pathogen-associated molecular patterns such as LPS, activates downstream signaling through both MyD88-dependent and independent pathways, inducing the production of various cytokines and participating in the regulation of neuroinflammation and cellular function (151, 152). In recent years, studies on SZ bodily fluids have consistently reported increased numbers of TLR4-positive monocytes and elevated TLR4 expression in the peripheral blood of schizophrenia patients (149, 153–155), suggesting that TLR4 upregulation is a key factor in the immunopathological process of schizophrenia. Postmortem results show increased TLR4 protein expression in the prefrontal cortex of schizophrenia patients (152), which is associated with activation of the MyD88 and NF-κB pathways (156). Recent research has identified the TLR4/MyD88/NF-κB pathway as playing a central role in various neurological disease models, suggesting its relevance in schizophrenia pathogenesis. For instance, regulatory T cells modulate neuroinflammation and microglial pyroptosis in LPC-induced demyelination via this pathway, thereby alleviating myelin loss and cognitive dysfunction (157). Additionally, TLR4 regulates hippocampal neurogenesis and synaptic function through this pathway, and is involved in neuroinflammation and neuronal apoptosis (158). Conversely, inhibiting TLR4 can suppress microglial activation, alleviate neuroinflammation, improve cognitive function, and mitigate synaptic plasticity impairments and depression-like symptoms via this pathway (159, 160).

The pathological processes described above are often initiated in schizophrenia by a breach of the intestinal barrier, creating a conduit for gut-derived immune activation. Alterations in the microbial flora, gut inflammation, increased intestinal barrier permeability (forming a “leaky gut”), bacterial translocation, and exposure to stressful environments in schizophrenia (144, 152, 156), may trigger innate immunity via TLR4 stimulation. The specific mechanism may involve a compromised intestinal barrier allowing antigens from the gut microbiota to penetrate and contact IgG antibodies, forming immune complexes that circulate in the bloodstream, including to the choroid plexus of the CNS. The chronic accumulation of these complexes can initiate inflammation and contribute to the progression of chronic disease. When a “leaky gut” is present, intestinal barrier permeability is increased, pro-inflammatory substances like LPS may activate inflammatory pathways, be recognized and activated by the TLR4 receptor, and mediate inflammatory responses. This indirect influence of gut microbes on the innate immune system leads to changes in the circulating levels of pro- and anti-inflammatory cytokines, subsequently directly affecting brain function (161).

Exposure to microbial products such as LPS, which can translocate from a leaky gut, activates TLR4 signaling, which is closely intertwined with gut-brain axis interactions. This is corroborated by numerous animal models. Pretreatment with paliperidone (an atypical antipsychotic drug) inhibits TLR4 activation and neuroinflammatory responses in the prefrontal cortex of stressed rats. The mechanism involves modulating stress-induced gut inflammation and reducing plasma LPS levels, thereby influencing brain TLR4 signaling pathways. This result suggests that the therapeutic effects of paliperidone extend beyond its impact on dopamine and serotonin neurotransmission systems (162). Another rat study found that acute restraint stress can upregulate TLR4 gene expression in the frontal cortex by inducing gut microbiota translocation, while intervention with antibiotics or the TLR4 specific inhibitor TAK-242 effectively suppresses this process and reduces the accumulation of inflammatory and oxidative/nitrosative mediators (163). Furthermore, inhibiting TLR4 can also modulate gut microbiota homeostasis and the MyD88/NF-κB axis in ulcerative colitis (164), indicating that TLR4 acts not only as a key sensor of innate immunity but may also regulate neuroimmune crosstalk and gut microenvironment homeostasis. Given that SZ patients also experience loss of gut microbiota homeostasis, targeting the TLR4 signaling pathway and focusing on bacterial translocation and microbiota may offer new avenues for immunomodulatory therapy in schizophrenia.

Specifically, in the “leaky gut” state, gut microbiota dysbiosis occurs, the expression of intestinal epithelial junction proteins (e.g., tight junction proteins) decreases, and intestinal permeability increases, forming a “leaky gut” (165). This breach facilitates bacterial translocation, as evidenced by the significant increase in markers such as soluble CD14 and LBP in the blood of individuals with schizophrenia (144, 166). Upon entering the systemic circulation, microbial products like LPS are recognized by and activate the TLR4 receptor on innate immune cells. This triggers downstream signaling pathways (e.g., NF-κB and MAPK), driving the massive release of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α (167–170). These peripheral inflammatory mediators can, in turn, compromise the blood-brain barrier and activate central immune cells, thereby linking gut-derived innate immune stimulation to the neuroinflammation characteristic of schizophrenia. This cascade establishes a self-perpetuating vicious cycle, wherein systemic inflammation exacerbates gut barrier dysfunction and dysbiosis, which then further fuels the inflammatory response.

6 Gut microbiota dysbiosis and cytokine abnormalities

6.1 Evidence for the association between cytokines and schizophrenia

Given the dysfunction of the BBB in patients with schizophrenia, changes in cytokine levels in the periphery (peripheral blood) and the center (cerebrospinal fluid, CSF) are valuable for assessing the CNS inflammatory state. Numerous studies have identified abnormal alterations in various cytokines in the CSF and peripheral blood of SZ patients (see Table 3), most of which are pro-inflammatory cytokines (IL-1β, IL-2, IL-8, TNF-α, and IFN-γ) (188–191), with a smaller proportion being anti-inflammatory cytokines (including TGF-β1, IL-4, and IL-10) (192). The prevailing research view is that a dynamic imbalance between pro-inflammatory and anti-inflammatory cytokines may contribute to the pathogenesis of schizophrenia and subsequent psychopathological symptoms (193–196).

According to Table 3, a characteristic pro-inflammatory state can be observed in SZ patients, manifested by persistently elevated levels of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α in both peripheral blood and CSF, accompanied by a relative deficiency of anti-inflammatory cytokines like IL-10 and TGF-β. This cytokine imbalance is closely related to symptom severity, cognitive deficits, and treatment response. This aligns with current mainstream research; for example, the TLR4/NF-κB/IL-1β signaling pathway is activated in chronic SZ patients (197), and clozapine reduces the expression of pro-inflammatory genes such as IL-1β and IL-6 by inhibiting the TLR4/NF-κB pathway (198). Additionally, IL-8 mediates the migration and survival of neural stem cells and oligodendrocyte progenitor cells early in life, and elevated CSF cytokines IL-1β and IL-6 suggest the possibility of microglial activation (199–201).

Aggregating data from Table 3 reveals consistent cross-barrier alterations in cytokine levels in both CSF and peripheral blood across different clinical stages (first-episode/FES, acute/ASZ, and chronic/CSZ), which hold clinical translational significance: 1). Significantly elevated levels of IL-1β, IL-6, and IL-8 in FES and ASZ SZ patients suggest they may be state markers for the onset or acute exacerbation of SZ; 2). The dose-dependent decrease in pro-inflammatory cytokine levels (e.g., IL-1β, IFN-γ, IL-6, TNF-α) following antipsychotic treatment (risperidone and clozapine) indicates value for monitoring treatment response; meanwhile, a significant increase in anti-inflammatory cytokine levels (e.g., sIL-2R) was observed in some patients (181, 184), a finding suggesting that antipsychotic drugs may exert anti-inflammatory-like effects.

6.2 Potential pathophysiological mechanisms of gut microbiota and metabolite SCFAs in cytokine abnormalities

SCFAs (such as acetate, propionate, and butyrate) activate receptors like FFAR2/3 and Gpr109a and inhibit histone deacetylase (HDAC), collectively suppressing the activation of the NF-κB signaling pathway, thereby downregulating the expression of pro-inflammatory cytokines (202–204). It is well-known that the NF-κB signaling pathway is typically activated in inflammatory and autoimmune diseases (205–207). Interestingly, all three cytokines elevated in SZ patients in Table 1 (IL-1β, IL-6, and IL-8) are regulated via the NF-κB pathway. Since cytokines can also regulate the activity of tryptophan catabolism in astrocytes and microglia, this finding corresponds to the alterations in the kynurenine pathway observed in the brains of individuals with schizophrenia (186).

SCFAs play an important regulatory role on various immune cells, particularly those central to maintaining immune homeostasis and anti-inflammatory responses, by inhibiting HDAC. For instance, SCFAs can inhibit NF-κB activation and the secretion of inflammatory cytokines like TNF-α in peripheral blood monocytes, neutrophils, and macrophages, thereby mitigating excessive immune responses. In dendritic cells, butyrate and propionate can impede their normal differentiation and induce an immune tolerant phenotype. Furthermore, SCFAs upregulate the expression of Foxp3, a key transcription factor for regulatory T cells, through HDAC inhibition (208, 209), promoting Treg differentiation and suppressing the production of pro-inflammatory cytokines (210). In SZ patients, the abundance of SCFA-producing bacteria is often altered, leading to reduced SCFA levels, which weakens the capacity to suppress inflammation; the abundance of SCFA-producing bacteria also changes post-treatment (211, 212).

6.3 The kynurenine pathway: an interactive mechanism linking gut microbiota, immunity, and neurotransmitters

Specific neurotransmitters, such as GABA, dopamine, glutamate, and serotonin (5-HT), are derived from precursors tyrosine and tryptophan, which are transported across the BBB into the CNS and subsequently converted into neurotransmitters (213). Tryptophan is primarily absorbed in the gut and metabolized by the gut microbiota through three downstream pathways: the 5-HT pathway, the kynurenine pathway, and the indole pathway (214). The kynurenine pathway of tryptophan metabolism represents a critical link through which the MGB axis participates in the immunopathology of schizophrenia. In schizophrenia, immune activation upregulates pro-inflammatory cytokines (e.g., IFN-γ, IL-1, TNF-α), which activate indoleamine 2,3-dioxygenase (IDO) via both IFN-γ receptor (IFN-γR)-dependent and independent pathways (e.g., synergistic action of TLR4, IL-1R, TNF-αR) (215). Enhanced activity of IDO enzymes (IDO-1 and IDO-2) shifts tryptophan metabolism towards the kynurenine pathway, leading to increased concentrations of kynurenic acid (KYNA) within the CNS (216–220). Kynurenine (KYN) is transported across the BBB and metabolized by glial cells into KYNA and quinolinic acid (221, 222) ultimately resulting in excessive KYNA production. Acting as an endogenous antagonist, KYNA inhibits NMDA receptor and α7 nicotinic receptor function (223), suppresses glutamate and acetylcholine neurotransmission (223, 224), and leads to an imbalance in the glutamate, dopamine, and acetylcholine systems, thereby affecting neurotransmission, synaptic organization, and brain connectivity (225, 226).

On the other hand, activation of the KP results in substantial tryptophan consumption, reducing the substrate available for 5-HT synthesis (see Figure 2). Over 90% of the body’s 5-HT is synthesized in the gut by enterochromaffin cells, which absorb tryptophan from dietary proteins as a substrate for 5-HT synthesis; this process is regulated by SCFAs and the kynurenine synthesis pathway (227, 228). Studies in animal models with gut microbiota depletion have shown increased plasma tryptophan, elevated brain serotonin concentrations, and reduced kynurenine pathway activity, all of which normalize following microbiota restoration (229–231). Gut microbiota dysbiosis and immune activation can further enhance IDO activity, exacerbating the conversion of tryptophan to KYNA. This leads to decreased peripheral and central 5-HT levels, impaired receptor function, reduced concentrations of tryptophan and 5-HT (232), worsened symptoms of affective disorders, elevated levels of tryptophan catabolites (233, 234), and increased concentrations of toxic metabolites in the CNS (235).

Figure 2

Animal experiments have demonstrated that acute tryptophan depletion reduces brain tryptophan concentration by 70%, leading to decreased serotonin levels, diminished 5-HT receptor binding (236, 237), and effects on compulsive behavior (238). Similar results have been observed in human cerebrospinal fluid (CSF) studies (239). This suggests that immune dysregulation-induced gut microbiota dysbiosis and activation of the kynurenine pathway cause acute tryptophan depletion in the gut. This, in turn, leads to reduced brain tryptophan concentration, decreased 5-HT levels, and diminished 5-HT receptor binding, which may underlie the 5-HT system dysfunction, impaired neurotransmission, and negative cognitive effects observed in SZ.

6.4 Limitations

This study has several limitations. First, despite conducting an extensive literature search, we cannot entirely exclude the possibility that some published studies may have been overlooked. Second, the multiple meta-analyses and systematic reviews cited in this article may carry a risk of accumulated type I errors (240). Furthermore, although we endeavored to include studies that performed stratified analyses of patients with schizophrenia, the interpretability and generalizability of the results may still be constrained by limited sample sizes and considerable population heterogeneity—such as confounding factors including age, gender, ethnicity, smoking history, and BMI (125).

7 Conclusions and discussion

7.1 Integrated mechanisms of the microbiota-gut-brain-immune axis in schizophrenia

By integrating the evidence discussed throughout this review, we propose a comprehensive model illustrating the MGB-immune interactions in schizophrenia (See Figure 3). At the peripheral level, gut microbiota dysbiosis and a reduction in microbial metabolites—particularly SCFAs—promote increased antigen exposure and activation of innate immune responses. This leads to the activation of immune cells (e.g., T cells, B cells, NK cells, monocytes/macrophages) and dysfunction of glial cells, culminating in the release of pro-inflammatory cytokines and complement components such as C4. Accompanied by impaired BBB integrity, these peripheral immune factors gain access to the CNS, where they mediate neuroinflammatory responses, resulting in synaptic damage and neuronal dysfunction.

Figure 3

In the CNS, dysbiosis directly or indirectly modulates the function of microglia and astrocytes via metabolites including SCFAs. Aberrantly activated glial cells exacerbate neuroinflammation and influence synaptic pruning processes, with complement C4-mediated synaptic phagocytosis playing a critical role. Concurrently, pro-inflammatory cytokines regulate the activity of key enzymes in tryptophan metabolism—indoleamine IDO and TDO—promoting the production of kynurenine pathway metabolites such as KYNA. This disrupts multiple neurotransmitter systems, including dopamine, GABA, glutamate, and serotonin, further exacerbating neurotransmission dysfunction. Moreover, compromised intestinal barrier integrity and gut-derived microbial components such as LPS activate TLR/NF-κB/NLRP3 pathways, which not only drive systemic inflammation but also modulate gut-derived tryptophan metabolism and serotonin synthesis, thereby coupling immune regulation with neuromodulatory functions.

The gut microbiota, as a critical “microbial organ,” has garnered extensive attention for its role in neuropsychiatric disorders such as SZ. However, the causal relationships among microbial dysbiosis, immune dysregulation, and disease onset remain elusive. It is still unclear whether dysbiosis acts as a driver, a consequence, or both. Elucidating this issue is complicated by multiple confounding factors, including population heterogeneity, medication use, dietary and lifestyle variations, disease staging, and inconsistencies in research methodologies. Although small-scale studies and disparities in technical procedures—such as sample processing, sequencing, and bioinformatic analyses—limit the reliability and generalizability of the findings. Therefore, further large-scale and better-standardized clinical studies with stratified populations are urgently needed to provide more robust data on the association between altered gut microbial features and schizophrenia.

7.2 Comparative analysis of gut microbiota in neuropsychiatric disorders

It is well established that the gut microbiota regulates brain function and behavior. The immune-mediated dysregulation of the MGB axis detailed in this review is observed not only in schizophrenia but also across various neurological disorders (241), including neurodevelopmental disorders (242), epilepsy (243), and depression (244), among others. Major depressive disorder is characterized by an elevated Bacteroidetes/Firmicutes ratio (5), accompanied by enrichment of Bacteroides and depletion of Blautia, Faecalibacterium, and Coprococcus, alongside increased abundance of Eggerthella and elevated levels of pro-inflammatory genera such as Escherichia (245). In contrast, anxiety disorders demonstrate an increased Firmicutes/Bacteroidetes ratio (246), reduced abundance of SCFA-producing genera including Bifidobacterium and Lactobacillus, while Akkermansia abundance shows a negative correlation with anxiety severity (247, 248). Bipolar disorder similarly exhibits disruption of the Firmicutes/Bacteroidetes ratio and reduced α-diversity, featuring increased Streptococcaceae and Bacteroidaceae abundance contrasting with depletion of anti-inflammatory commensals such as Faecalibacterium (249).Among neurodegenerative disorders, Parkinson’s disease shows increased abundance of Lactobacillus and Bifidobacterium with concurrent reduction in Faecalibacterium, Coprococcus, and Blautia (250, 251), where decreased Blautia abundance correlates with clinical severity and reduced fecal butyrate levels (252). Alzheimer’s disease manifests through reduced beneficial bacteria including Bifidobacterium and elevated opportunistic pathogens such as Escherichia and Clostridium (253, 254). Autism spectrum disorder(ASD) presents with reduced microbial diversity yet increased biomass in pediatric populations (255, 256), featuring a shift from beneficial microorganisms toward spore-forming, antibiotic-resistant, and/or neurotoxin-producing species (257). Specific alterations include reductions in Prevotella, Coprococcus, and Veillonellaceae, alongside overgrowth of Desulfovibrio (positively correlated with Autism spectrum disorder severity) (258), Sutterella, Ruminococcus, Clostridium, Megamonas, and Candida (259, 260), accompanied by an elevated Firmicutes/Bacteroidetes ratio (255). Notably, Candida overgrowth and associated toxin production may exacerbate neurobehavioral symptoms (37). Epilepsy research similarly reveals substantial gut microbiota dysbiosis, with most studies demonstrating reduced α-diversity in treatment-resistant epilepsy (261–264). Phylum-level analyses indicate predominant Firmicutes with relative Bacteroidetes reduction in some studies (264, 265), while others report increased Actinobacteria, Verrucomicrobia, or pro-inflammatory Proteobacteria, alongside potential reduction of beneficial Bacteroidetes and Actinobacteria (262, 266).

In summary, these disorders share fundamental microbial alterations: 1) Structural dysbiosis manifested through disrupted Bacteroidetes/Firmicutes ratios and reduced α-diversity; 2) Functional impairment characterized by universal depletion of anti-inflammatory, SCFA-producing genera including Faecalibacterium, Blautia, and Bifidobacterium; 3) Common pathophysiological mechanisms involving impaired SCFA production, immune-inflammatory activation, and dysregulated neuroactive metabolite metabolism. These alterations promote systemic low-grade inflammation through an imbalance between elevated pro-inflammatory cytokines (e.g., IL-6, TNF-α) and anti-inflammatory mediators (e.g., IL-10) (267–269). This systemic inflammation, akin to the processes described in schizophrenia, can traverse the blood-brain barrier or transmit via vagal afferents, subsequently activating microglia and exacerbating neuroinflammatory processes while impairing prefrontal cortex-mediated executive functions including decision-making and emotional regulation (270). Pro-inflammatory cytokines disrupt neurotransmitter metabolism through mechanisms such as inhibited tryptophan conversion to serotonin while driving microglial activation, thereby amplifying neuroinflammation (271). Activated microglia release chemokines, cytokines, and reactive oxygen species, crucially contributing to neuroinflammatory cascades while disrupting neurotransmitter balance and synaptic plasticity through pro-inflammatory phenotypic transformation. Notwithstanding these commonalities, disorder specific patterns emerge. Major depressive disorder demonstrates Bacteroidetes/Firmicutes ratio elevation contrasting with anxiety disorders, while ASD presents the distinct profile of reduced diversity with increased biomass and concurrent expansion of multiple opportunistic pathogens. These shared and distinct features collectively illustrate the multifaceted involvement of gut microbiota dysbiosis in neuropsychiatric disorders. Beyond inflammation, psychological stress represents another prevalent pathophysiological feature in microbiota-associated diseases. Stress contributes to depression (272), schizophrenia (273), autism spectrum disorder (274), epilepsy (275), and migraine (276). Significant comorbidity exists among these conditions, exemplified by the frequent co-occurrence of depression and ASD with epilepsy (277), the common comorbidity of depression with migraine (277), and the elevated prevalence of inflammatory bowel disease or irritable bowel syndrome among migraine patients (278).

8 Future perspectives

The gut microbiota can influence drug bioavailability and efficacy through metabolism, while most psychotropic medications possess anti-inflammatory properties and may directly alter microbial composition. A recent study revealed that gut microbiome abnormalities in schizophrenia patients were primarily associated with resistance to antipsychotic treatment, whereas this correlation was significantly weaker in patients who responded well to atypical antipsychotics (279). This suggests that structural changes in the gut microbiota may serve more as a potential biomarker for clozapine resistance rather than an intrinsic feature of schizophrenia itself. Underlying mechanisms may involve microbial-mediated drug metabolism, transformation, and modulation of intestinal barrier function.

Furthermore, current immunomodulatory therapies, including immunosuppressants and biologics, remain predominantly palliative. Long-term administration often leads to drug tolerance and opportunistic infections (280). The substantial comorbidity burden—approximately 30% of inflammatory bowel disease patients develop anxiety or depression—highlights the urgent need for dual-effect therapies that simultaneously address intestinal inflammation and gut-brain axis modulation. Combinatorial treatment strategies targeting the gut-brain interplay represent a paradigm shift in managing psychiatric comorbidities in systemic disorders.

By assessing baseline microbiome profiles, it becomes possible to identify individuals at high risk for poor response to relevant medications prior to treatment initiation. This enables the development of personalized dosing regimens or adjunctive microecological interventions (e.g., probiotic/prebiotic supplementation) to enhance therapeutic efficacy while reducing the incidence of drug resistance and adverse effects. These advances underscore the translational value of microbiome research in the precision medicine of mental disorders.

Although microbial-based interventions, such as probiotics, demonstrate therapeutic potential—for instance, certain strains of Lactobacillus and Bifidobacterium have shown preliminary efficacy in alleviating depressive symptoms (281)—their benefits in schizophrenia remain inconsistent and lack high-quality clinical support (282). Therapeutic strategies targeting the MGB axis, including prebiotics, synbiotics, and fecal microbiota transplantation, are not universally applicable. Instead, they should be tailored based on disease subtype, patient stratification, and bacterial functionality. Their clinical utility urgently requires validation through well-designed, large-scale randomized controlled trials.

References

• 1

  Solmi M Croatto G Fornaro M Schneider LK Rohani-Montez SC Fairley L et al . Regional differences in mortality risk and in attenuating or aggravating factors in schizophrenia: A systematic review and meta-analysis. Eur Neuropsychopharmacol. (2024) 80:55–69. doi: 10.1016/j.euroneuro.2023.12.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  Owen MJ Sawa A Mortensen PB . Schizophrenia. Lancet. (2016) 388:86–97. doi: 10.1016/s0140-6736(15)01121-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  McCutcheon RA Reis Marques T Howes OD . Schizophrenia-an overview. JAMA Psychiatry. (2020) 77:201–10. doi: 10.1001/jamapsychiatry.2019.3360

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  Tsuang M . Schizophrenia: genes and environment. Biol Psychiatry. (2000) 47:210–20. doi: 10.1016/s0006-3223(99)00289-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  Demjaha A MacCabe JH Murray RM . How genes and environmental factors determine the different neurodevelopmental trajectories of schizophrenia and bipolar disorder. Schizophr Bull. (2012) 38:209–14. doi: 10.1093/schbul/sbr100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  Modinos G Iyegbe C Prata D Rivera M Kempton MJ Valmaggia LR et al . Molecular genetic gene-environment studies using candidate genes in schizophrenia: A systematic review. Schizophr Res. (2013) 150:356–65. doi: 10.1016/j.schres.2013.09.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  Ripke S Neale BM Corvin A Walters JTR Farh K-H Holmans PA et al . Biological insights from 108 schizophrenia-associated genetic loci. Nature. (2014) 511:421–7. doi: 10.1038/nature13595

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  Sellgren CM Gracias J Watmuff B Biag JD Thanos JM Whittredge PB et al . Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. (2019) 22:374–85. doi: 10.1038/s41593-018-0334-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  Müller N Myint AM Krause D Weidinger E Schwarz MJ . Anti-inflammatory treatment in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. (2013) 42:146–53. doi: 10.1016/j.pnpbp.2012.11.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  Shi J Levinson DF Duan J Sanders AR Zheng Y Pe’er I et al . Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. (2009) 460:753–7. doi: 10.1038/nature08192

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  Stefansson H Ophoff RA Steinberg S Andreassen OA Cichon S Rujescu D et al . Common variants conferring risk of schizophrenia. Nature. (2009) 460:744–7. doi: 10.1038/nature08186

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  Purcell SM Wray NR Stone JL Visscher PM O’Donovan MC Sullivan PF et al . Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. (2009) 460:748–52. doi: 10.1038/nature08185

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  Kridin K Zelber-Sagi S Comaneshter D Cohen AD . Association between schizophrenia and an autoimmune bullous skin disease-pemphigus: A population-based large-scale study. Epidemiol Psychiatr Sci. (2019) 28:191–8. doi: 10.1017/s204579601700052x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  Maślińska M Trędzbor B Krzystanek M . Dysbiosis, gut-blood barrier rupture and autoimmune response in rheumatoid arthritis and schizophrenia. Reumatologia. (2021) 59:180–7. doi: 10.5114/reum.2021.107588

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  Wang LY Chen SF Chiang JH Hsu CY Shen YC . Autoimmune diseases are associated with an increased risk of schizophrenia: A nationwide population-based cohort study. Schizophr Res. (2018) 202:297–302. doi: 10.1016/j.schres.2018.06.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  Tandon R Nasrallah H Akbarian S Carpenter WT Jr. DeLisi LE Gaebel W et al . The schizophrenia syndrome, circa 2024: what we know and how that informs its nature. Schizophr Res. (2024) 264:1–28. doi: 10.1016/j.schres.2023.11.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  Massrali A Adhya D Srivastava DP Baron-Cohen S Kotter MR . Virus-induced maternal immune activation as an environmental factor in the etiology of autism and schizophrenia. Front Neurosci. (2022) 16:834058. doi: 10.3389/fnins.2022.834058

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  Liu T Gao P Bu D Liu D . Association between toxoplasma gondii infection and psychiatric disorders: A cross-sectional study in China. Sci Rep. (2022) 12:15092. doi: 10.1038/s41598-022-16420-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  Oncu-Oner T Can S . Meta-analysis of the relationship between toxoplasma gondii and schizophrenia. Ann Parasitol. (2022) 68:103–10. doi: 10.17420/ap6801.414

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  Zhu YT Yang XH Chen MR Hu Y Chang YF Wu X . Research progress on the association between schizophrenia and toxoplasma gondii infection. Biomed Environ sciences: BES. (2024) 37:647–60. doi: 10.3967/bes2024.071

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  Montazeri M Moradi E Moosazadeh M Hosseini SH Fakhar M . Relationship between toxoplasma gondii infection and psychiatric disorders in Iran: A systematic review with meta-analysis. PLoS One. (2023) 18:e0284954. doi: 10.1371/journal.pone.0284954

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  Fellerhoff B Laumbacher B Wank R . High risk of schizophrenia and other mental disorders associated with chlamydial infections: hypothesis to combine drug treatment and adoptive immunotherapy. Med Hypotheses. (2005) 65:243–52. doi: 10.1016/j.mehy.2005.03.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  Park MH Kwon YJ Jeong HY Lee HY Hwangbo Y Yoon HJ et al . Association between intracellular infectious agents and schizophrenia. Clin Psychopharmacol Neurosci. (2012) 10:117–23. doi: 10.9758/cpn.2012.10.2.117

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  Krause D Matz J Weidinger E Wagner J Wildenauer A Obermeier M et al . The association of infectious agents and schizophrenia. World J Biol Psychiatry. (2010) 11:739–43. doi: 10.3109/15622971003653246

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  Fellerhoff B Laumbacher B Mueller N Gu S Wank R . Associations between chlamydophila infections, schizophrenia and risk of hla-A10. Mol Psychiatry. (2007) 12:264–72. doi: 10.1038/sj.mp.4001925

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  Soleimani MF Ayubi E Khosronezhad S Hasler G Amiri MR Beikpour F et al . Human endogenous retroviruses type W (Herv-) activation and schizophrenia: A meta-analysis. Schizophr Res. (2024) 271:220–7. doi: 10.1016/j.schres.2024.07.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  Rangel SC da Silva MD Natrielli Filho DG Santos SN do Amaral JB Victor JR et al . Herv-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status. Retrovirology. (2024) 21:7. doi: 10.1186/s12977-024-00640-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  Mohagheghi M Eftekharian MM Taheri M Alikhani MY . Determining the igm and igg antibodies titer against hsv1, hsv2 and cmv in the serum of schizophrenia patients. Hum antibodies. (2018) 26:87–93. doi: 10.3233/hab-170325

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  Azami M Jalilian FA Khorshidi A Mohammadi Y Tardeh Z . The association between borna disease virus and schizophrenia: A systematic review and meta-analysis. Asian J Psychiatry. (2018) 34:67–73. doi: 10.1016/j.ajp.2017.11.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  Arias I Sorlozano A Villegas E de Dios Luna J McKenney K Cervilla J et al . Infectious agents associated with schizophrenia: A meta-analysis. Schizophr Res. (2012) 136:128–36. doi: 10.1016/j.schres.2011.10.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  Spencer SJ Meyer U . Perinatal programming by inflammation. Brain Behav Immun. (2017) 63:1–7. doi: 10.1016/j.bbi.2017.02.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  Prandovszky E Gaskell E Martin H Dubey JP Webster JP McConkey GA . The neurotropic parasite toxoplasma gondii increases dopamine metabolism. PLoS One. (2011) 6:e23866. doi: 10.1371/journal.pone.0023866

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  Torrey EF Yolken RH . Toxoplasma gondii and schizophrenia. Emerg Infect Dis. (2003) 9:1375–80. doi: 10.3201/eid0911.030143

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  Carruthers VB Suzuki Y . Effects of toxoplasma gondii infection on the brain. Schizophr Bull. (2007) 33:745–51. doi: 10.1093/schbul/sbm008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  Bhadra R Cobb DA Weiss LM Khan IA . Psychiatric disorders in toxoplasma seropositive patients–the cd8 connection. Schizophr Bull. (2013) 39:485–9. doi: 10.1093/schbul/sbt006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  Molloy MJ Grainger JR Bouladoux N Hand TW Koo LY Naik S et al . Intraluminal containment of commensal outgrowth in the gut during infection-induced dysbiosis. Cell Host Microbe. (2013) 14:318–28. doi: 10.1016/j.chom.2013.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  Tsuang MT Stone WS Faraone SV . Genes, environment and schizophrenia. Br J Psychiatry Suppl. (2001) 40:s18–24. doi: 10.1192/bjp.178.40.s18

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  Guarner F Hooper LV Núñez G . Understanding the microbiota in the midst of renaissance architecture and olive groves. Nat Immunol. (2013) 14:101–5. doi: 10.1038/ni.2512

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  Dinan TG Borre YE Cryan JF . Genomics of schizophrenia: time to consider the gut microbiome? Mol Psychiatry. (2014) 19:1252–7. doi: 10.1038/mp.2014.93

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  Ermakov EA Melamud MM Buneva VN Ivanova SA . Immune system abnormalities in schizophrenia: an integrative view and translational perspectives. Front Psychiatry. (2022) 13:880568. doi: 10.3389/fpsyt.2022.880568

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  DiGiulio DB . Diversity of microbes in amniotic fluid. Semin Fetal Neonatal Med. (2012) 17:2–11. doi: 10.1016/j.siny.2011.10.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  Jiménez E Fernández L Marín ML Martín R Odriozola JM Nueno-Palop C et al . Isolation of commensal bacteria from umbilical cord blood of healthy neonates born by cesarean section. Curr Microbiol. (2005) 51:270–4. doi: 10.1007/s00284-005-0020-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  Aagaard K Ma J Antony KM Ganu R Petrosino J Versalovic J . The placenta harbors a unique microbiome. Sci Transl Med. (2014) 6:237ra65. doi: 10.1126/scitranslmed.3008599

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  Clemente JC Ursell LK Parfrey LW Knight R . The impact of the gut microbiota on human health: an integrative view. Cell. (2012) 148:1258–70. doi: 10.1016/j.cell.2012.01.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  Maynard CL Elson CO Hatton RD Weaver CT . Reciprocal interactions of the intestinal microbiota and immune system. Nature. (2012) 489:231–41. doi: 10.1038/nature11551

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  Lozupone CA Stombaugh JI Gordon JI Jansson JK Knight R . Diversity, stability and resilience of the human gut microbiota. Nature. (2012) 489:220–30. doi: 10.1038/nature11550

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  Parfrey LW Knight R . Spatial and temporal variability of the human microbiota. Clin Microbiol Infect. (2012) 18 Suppl 4:8–11. doi: 10.1111/j.1469-0691.2012.03861.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  Golubeva AV Crampton S Desbonnet L Edge D O’Sullivan O Lomasney KW et al . Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood. Psychoneuroendocrinology. (2015) 60:58–74. doi: 10.1016/j.psyneuen.2015.06.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  Gur TL Shay L Palkar AV Fisher S Varaljay VA Dowd S et al . Prenatal stress affects placental cytokines and neurotrophins, commensal microbes, and anxiety-like behavior in adult female offspring. Brain Behav Immun. (2017) 64:50–8. doi: 10.1016/j.bbi.2016.12.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  Jašarević E Howard CD Misic AM Beiting DP Bale TL . Stress during pregnancy alters temporal and spatial dynamics of the maternal and offspring microbiome in a sex-specific manner. Sci Rep. (2017) 7:44182. doi: 10.1038/srep44182

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  Jin Y Wu S Zeng Z Fu Z . Effects of environmental pollutants on gut microbiota. Environ pollut. (2017) 222:1–9. doi: 10.1016/j.envpol.2016.11.045

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  Nuncio-Mora L Lanzagorta N Nicolini H Sarmiento E Ortiz G Sosa F et al . The role of the microbiome in first episode of psychosis. Biomedicines. (2023) 11:1770. doi: 10.3390/biomedicines11061770

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  Xu R Wu B Liang J He F Gu W Li K et al . Altered gut microbiota and mucosal immunity in patients with schizophrenia. Brain Behav Immun. (2020) 85:120–7. doi: 10.1016/j.bbi.2019.06.039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  Wang Y Bi S Li X Zhong Y Qi D . Perturbations in gut microbiota composition in schizophrenia. PLoS One. (2024) 19:e0306582. doi: 10.1371/journal.pone.0306582

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  Zhuang Z Yang R Wang W Qi L Huang T . Associations between gut microbiota and alzheimer’s disease, major depressive disorder, and schizophrenia. J Neuroinflamm. (2020) 17:288. doi: 10.1186/s12974-020-01961-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  Ling Z Lan Z Cheng Y Liu X Li Z Yu Y et al . Altered gut microbiota and systemic immunity in chinese patients with schizophrenia comorbid with metabolic syndrome. J Transl Med. (2024) 22:729. doi: 10.1186/s12967-024-05533-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  Murray N Al Khalaf S Bastiaanssen TFS Kaulmann D Lonergan E Cryan JF et al . Compositional and functional alterations in intestinal microbiota in patients with psychosis or schizophrenia: A systematic review and meta-analysis. Schizophr Bull. (2023) 49:1239–55. doi: 10.1093/schbul/sbad049

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  Wu H Jiawei X Wen Z Han Y Liu Y Chen S et al . Microbiome-gut-brain profiles in schizophrenia and their potential link to cognitive performance: findings from a case-control study. Schizophr Bull. (2025). doi: 10.1093/schbul/sbaf028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  Yuan X Wang Y Li X Jiang J Kang Y Pang L et al . Gut microbial biomarkers for the treatment response in first-episode, drug-naïve schizophrenia: A 24-week follow-up study. Transl Psychiatry. (2021) 11:422. doi: 10.1038/s41398-021-01531-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  Coughlin JM Ishizuka K Kano SI Edwards JA Seifuddin FT Shimano MA et al . Marked reduction of soluble superoxide dismutase-1 (Sod1) in cerebrospinal fluid of patients with recent-onset schizophrenia. Mol Psychiatry. (2013) 18:10–1. doi: 10.1038/mp.2012.6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  Dickerson F Severance E Yolken R . The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun. (2017) 62:46–52. doi: 10.1016/j.bbi.2016.12.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  Severance EG Alaedini A Yang S Halling M Gressitt KL Stallings CR et al . Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res. (2012) 138:48–53. doi: 10.1016/j.schres.2012.02.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  Severance EG Gressitt KL Yang S Stallings CR Origoni AE Vaughan C et al . Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder. Bipolar Disord. (2014) 16:230–40. doi: 10.1111/bdi.12159

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  Severance EG Prandovszky E Castiglione J Yolken RH . Gastroenterology issues in schizophrenia: why the gut matters. Curr Psychiatry Rep. (2015) 17:27. doi: 10.1007/s11920-015-0574-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  Severance EG Yolken RH Eaton WW . Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res. (2016) 176:23–35. doi: 10.1016/j.schres.2014.06.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  Nguyen TT Kosciolek T Eyler LT Knight R Jeste DV . Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. J Psychiatr Res. (2018) 99:50–61. doi: 10.1016/j.jpsychires.2018.01.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  Li S Zhuo M Huang X Huang Y Zhou J Xiong D et al . Altered gut microbiota associated with symptom severity in schizophrenia. PeerJ. (2020) 8:e9574. doi: 10.7717/peerj.9574

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  Schwarz E Maukonen J Hyytiäinen T Kieseppä T Orešič M Sabunciyan S et al . Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res. (2018) 192:398–403. doi: 10.1016/j.schres.2017.04.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  Xing M Gao H Yao L Wang L Zhang C Zhu L et al . Profiles and diagnostic value of intestinal microbiota in schizophrenia patients with metabolic syndrome. Front Endocrinol (Lausanne). (2023) 14:1190954. doi: 10.3389/fendo.2023.1190954

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  Nemani K Hosseini Ghomi R McCormick B Fan X . Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry. (2015) 56:155–60. doi: 10.1016/j.pnpbp.2014.08.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  Fan Y Gao Y Ma Q Yang Z Zhao B He X et al . Multi-omics analysis reveals aberrant gut-metabolome-immune network in schizophrenia. Front Immunol. (2022) 13:812293. doi: 10.3389/fimmu.2022.812293

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  Li C Wang A Wang C Ramamurthy J Zhang E Guadagno E et al . Metabolomics in patients with psychosis: A systematic review. Am J Med Genet B Neuropsychiatr Genet. (2018) 177:580–8. doi: 10.1002/ajmg.b.32662

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  Krzyściak W Bystrowska B Karcz P Chrzan R Bryll A Turek A et al . Association of blood metabolomics biomarkers with brain metabolites and patient-reported outcomes as a new approach in individualized diagnosis of schizophrenia. Int J Mol Sci. (2024) 25:2294. doi: 10.3390/ijms25042294

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  Shi L Ju P Meng X Wang Z Yao L Zheng M et al . Intricate role of intestinal microbe and metabolite in schizophrenia. BMC Psychiatry. (2023) 23:856. doi: 10.1186/s12888-023-05329-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  Li S Song J Ke P Kong L Lei B Zhou J et al . The gut microbiome is associated with brain structure and function in schizophrenia. Sci Rep. (2021) 11:9743. doi: 10.1038/s41598-021-89166-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  Fogelson KA Dorrestein PC Zarrinpar A Knight R . The gut microbial bile acid modulation and its relevance to digestive health and diseases. Gastroenterology. (2023) 164:1069–85. doi: 10.1053/j.gastro.2023.02.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  Liang Y Shi X Shen Y Huang Z Wang J Shao C et al . Enhanced intestinal protein fermentation in schizophrenia. BMC Med. (2022) 20:67. doi: 10.1186/s12916-022-02261-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  Zhu F Ju Y Wang W Wang Q Guo R Ma Q et al . Metagenome-wide association of gut microbiome features for schizophrenia. Nat Commun. (2020) 11:1612. doi: 10.1038/s41467-020-15457-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  Nguyen TT Kosciolek T Daly RE Vázquez-Baeza Y Swafford A Knight R et al . Gut microbiome in schizophrenia: altered functional pathways related to immune modulation and atherosclerotic risk. Brain Behav Immun. (2021) 91:245–56. doi: 10.1016/j.bbi.2020.10.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  Qing Y Wang P Cui G Zhang J Liang K Xia Z et al . Targeted metabolomics reveals aberrant profiles of serum bile acids in patients with schizophrenia. Schizophr (Heidelb). (2022) 8:65. doi: 10.1038/s41537-022-00273-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  Khosravi M . Ursodeoxycholic acid augmentation in treatment-refractory schizophrenia: A case report. J Med Case Rep. (2020) 14:137. doi: 10.1186/s13256-020-02484-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  Quinn M McMillin M Galindo C Frampton G Pae HY DeMorrow S . Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via rac1-dependent mechanisms. Dig Liver Dis. (2014) 46:527–34. doi: 10.1016/j.dld.2014.01.159

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  Tofalo R Cocchi S Suzzi G . Polyamines and gut microbiota. Front Nutr. (2019) 6:16. doi: 10.3389/fnut.2019.00016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  Richardson-Andrews RC . A central role for the polyamines in the aetiology of schizophrenia. Med Hypotheses. (1983) 11:157–66. doi: 10.1016/0306-9877(83)90059-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  Spathopoulou A Sauerwein GA Marteau V Podlesnic M Lindlbauer T Kipura T et al . Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia. Mol Psychiatry. (2024) 29:3128–40. doi: 10.1038/s41380-024-02568-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  Leppik L Kriisa K Koido K Koch K Kajalaid K Haring L et al . Profiling of Amino Acids and Their Derivatives Biogenic Amines before and after Antipsychotic Treatment in First-Episode Psychosis. Front Psychiatry. (2018) 9:155. doi: 10.3389/fpsyt.2018.00155

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  Svinarev VI . Serum spermidine levels of schizophrenic patients. Zh Nevropatol Psikhiatr Im S S Korsakova. (1987) 87:732–4.

  • Pubmed Abstract
  • Google Scholar

• 88

  Ramchand CN Das I Gliddon A Hirsch SR . Role of polyamines in the membrane pathology of schizophrenia. A study using fibroblasts from schizophrenic patients and normal controls. Schizophr Res. (1994) 13:249–53. doi: 10.1016/0920-9964(94)90049-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  Gilad GM Gilad VH Casanova MF Casero RA Jr . Polyamines and their metabolizing enzymes in human frontal cortex and hippocampus: preliminary measurements in affective disorders. Biol Psychiatry. (1995) 38:227–34. doi: 10.1016/0006-3223(94)00256-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  Garip B Kayir H Uzun O . L-Arginine Metabolism before and after 10 Weeks of Antipsychotic Treatment in First-Episode Psychotic Patients. Schizophr Res. (2019) 206:58–66. doi: 10.1016/j.schres.2018.12.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  Uzbay T Goktalay G Kayir H Eker SS Sarandol A Oral S et al . Increased plasma agmatine levels in patients with schizophrenia. J Psychiatr Res. (2013) 47:1054–60. doi: 10.1016/j.jpsychires.2013.04.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  Liu P Jing Y Collie ND Dean B Bilkey DK Zhang H . Altered brain arginine metabolism in schizophrenia. Transl Psychiatry. (2016) 6:e871. doi: 10.1038/tp.2016.144

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  Knox LT Jing Y Bawazier-Edgecombe J Collie ND Zhang H Liu P . Effects of withdrawal from repeated phencyclidine administration on behavioural function and brain arginine metabolism in rats. Pharmacol Biochem Behav. (2017) 153:45–59. doi: 10.1016/j.pbb.2016.12.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  Syatkin S Smirnova IP Kuznetsova O Lobaeva TA Blagonravov M Ryskina EA et al . The Levels of Polyamines in Autopsy Materials of Some Structures of Brain Lymbic System and Reticular Formation of Patients with Schizophrenia. Research Journal of Pharmaceutical, Biological and Chemical Sciences. (2014) 5:1486–90.

  • Google Scholar

• 95

  Bernstein HG Müller M . The cellular localization of the L-ornithine decarboxylase/polyamine system in normal and diseased central nervous systems. Prog Neurobiol. (1999) 57:485–505. doi: 10.1016/s0301-0082(98)00065-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  Flayeh KA . Spermidine oxidase activity in serum of normal and schizophrenic subjects. Clin Chem. (1988) 34:401–3. doi: 10.1093/clinchem/34.2.401

  • CrossRef
  • Google Scholar

• 97

  Dahel KA Al-Saffar NM Flayeh KA . Polyamine oxidase activity in sera of depressed and schizophrenic patients after ect treatment. Neurochem Res. (2001) 26:415–8. doi: 10.1023/a:1010959300545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  Middleton FA Mirnics K Pierri JN Lewis DA Levitt P . Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci. (2002) 22:2718–29. doi: 10.1523/jneurosci.22-07-02718.2002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  Ayalew M Le-Niculescu H Levey DF Jain N Changala B Patel SD et al . Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry. (2012) 17:887–905. doi: 10.1038/mp.2012.37

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  Williams K . Modulation and block of ion channels: A new biology of polyamines. Cell Signal. (1997) 9:1–13. doi: 10.1016/s0898-6568(96)00089-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  Schmitz MP Combs DJ Dempsey RJ . Difluoromethylornithine decreases postischemic brain edema and blood-brain barrier breakdown. Neurosurgery. (1993) 33:882–7. doi: 10.1227/00006123-199311000-00016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  Temiz C Dogan A Baskaya MK Dempsey RJ . Effect of difluoromethylornithine on reperfusion injury after temporary middle cerebral artery occlusion. J Clin Neurosci. (2005) 12:449–52. doi: 10.1016/j.jocn.2004.05.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  Wu D Chen Q Chen X Han F Chen Z Wang Y . The blood-brain barrier: structure, regulation, and drug delivery. Signal Transduct Target Ther. (2023) 8:217. doi: 10.1038/s41392-023-01481-w

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  Wishart DS Feunang YD Marcu A Guo AC Liang K Vázquez-Fresno R et al . Hmdb 4.0: the human metabolome database for 2018. Nucleic Acids Res. (2018) 46:D608–d17. doi: 10.1093/nar/gkx1089

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  Braniste V Al-Asmakh M Kowal C Anuar F Abbaspour A Tóth M et al . The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. (2014) 6:263ra158. doi: 10.1126/scitranslmed.3009759

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  Sun N Hu H Wang F Li L Zhu W Shen Y et al . Antibiotic-induced microbiome depletion in adult mice disrupts blood-brain barrier and facilitates brain infiltration of monocytes after bone-marrow transplantation. Brain Behav Immun. (2021) 92:102–14. doi: 10.1016/j.bbi.2020.11.032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  Chenghan M Wanxin L Bangcheng Z Yao H Qinxi L Ting Z et al . Short-chain fatty acids mediate gut microbiota-brain communication and protect the blood-brain barrier integrity. Ann N Y Acad Sci. (2025) 1545:116–31. doi: 10.1111/nyas.15299

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  Wu Q Zhang Y Zhang Y Xia C Lai Q Dong Z et al . Potential effects of antibiotic-induced gut microbiome alteration on blood-brain barrier permeability compromise in rhesus monkeys. Ann N Y Acad Sci. (2020) 1470:14–24. doi: 10.1111/nyas.14312

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  Uhlén M Fagerberg L Hallström BM Lindskog C Oksvold P Mardinoglu A et al . Proteomics. Tissue-based map of the human proteome. Science. (2015) 347:1260419. doi: 10.1126/science.1260419

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  Hoyles L Snelling T Umlai UK Nicholson JK Carding SR Glen RC et al . Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier. Microbiome. (2018) 6:55. doi: 10.1186/s40168-018-0439-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  Ji J Shu D Zheng M Wang J Luo C Wang Y et al . Microbial metabolite butyrate facilitates M2 macrophage polarization and function. Sci Rep. (2016) 6:24838. doi: 10.1038/srep24838

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  Nastasi C Candela M Bonefeld CM Geisler C Hansen M Krejsgaard T et al . The effect of short-chain fatty acids on human monocyte-derived dendritic cells. Sci Rep. (2015) 5:16148. doi: 10.1038/srep16148

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  Tan J McKenzie C Potamitis M Thorburn AN Mackay CR Macia L . The role of short-chain fatty acids in health and disease. Adv Immunol. (2014) 121:91–119. doi: 10.1016/b978-0-12-800100-4.00003-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  Purves-Tyson TD Robinson K Brown AM Boerrigter D Cai HQ Weissleder C et al . Increased macrophages and C1qa, C3, C4 transcripts in the midbrain of people with schizophrenia. Front Immunol. (2020) 11:2002. doi: 10.3389/fimmu.2020.02002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  Severance EG Gressitt KL Buka SL Cannon TD Yolken RH . Maternal complement C1q and increased odds for psychosis in adult offspring. Schizophr Res. (2014) 159:14–9. doi: 10.1016/j.schres.2014.07.053

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  Kopczynska M Zelek W Touchard S Gaughran F Di Forti M Mondelli V et al . Complement system biomarkers in first episode psychosis. Schizophr Res. (2019) 204:16–22. doi: 10.1016/j.schres.2017.12.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  Jenkins AK Lewis DA Volk DW . Altered expression of microglial markers of phagocytosis in schizophrenia. Schizophr Res. (2023) 251:22–9. doi: 10.1016/j.schres.2022.12.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  Yu H Ni P Tian Y Zhao L Li M Li X et al . Association of elevated levels of peripheral complement components with cortical thinning and impaired logical memory in drug-naïve patients with first-episode schizophrenia. Schizophr (Heidelb). (2023) 9:79. doi: 10.1038/s41537-023-00409-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  Cao Y Xu Y Xia Q Shan F Liang J . Peripheral complement factor-based biomarkers for patients with first-episode schizophrenia. Neuropsychiatr Dis Treat. (2023) 19:1455–62. doi: 10.2147/ndt.S420475

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  Koskuvi M Malwade S Gracias Lekander J Hörbeck E Bruno S Holmen Larsson J et al . Lower complement C1q levels in first-episode psychosis and in schizophrenia. Brain Behav Immun. (2024) 117:313–9. doi: 10.1016/j.bbi.2024.01.219

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  Laskaris L Zalesky A Weickert CS Di Biase MA Chana G Baune BT et al . Investigation of peripheral complement factors across stages of psychosis. Schizophr Res. (2019) 204:30–7. doi: 10.1016/j.schres.2018.11.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  Li H Zhang Q Li N Wang F Xiang H Zhang Z et al . Plasma levels of th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia. Psychiatry Res. (2016) 246:700–6. doi: 10.1016/j.psychres.2016.10.061

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  Kamitaki N Sekar A Handsaker RE de Rivera H Tooley K Morris DL et al . Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. (2020) 582:577–81. doi: 10.1038/s41586-020-2277-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  Xia XW Li LJ Chen ZC Qiu Y Zhao JS Wu JY et al . Correlation of the peripheral serum complement protein levels and cognitive function in first-episode drug-naive patients with schizophrenia. Zhonghua Yi Xue Za Zhi. (2020) 100:3081–5. doi: 10.3760/cma.j.cn112137-20200425-01316

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  Mohd Asyraf AJ Nour El Huda AR Hanisah MN Norsidah KZ Norlelawati AT . Relationship of selective complement markers with schizophrenia. J Neuroimmunol. (2022) 363:577793. doi: 10.1016/j.jneuroim.2021.577793

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  Borbye-Lorenzen N Zhu Z Agerbo E Albiñana C Benros ME Bian B et al . The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders. Cell Genom. (2023) 3:100457. doi: 10.1016/j.xgen.2023.100457

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  Ji E Boerrigter D Cai HQ Lloyd D Bruggemann J O’Donnell M et al . Peripheral complement is increased in schizophrenia and inversely related to cortical thickness. Brain Behav Immun. (2022) 101:423–34. doi: 10.1016/j.bbi.2021.11.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  Chen Y Zhao Z Lin F Wang L Lin Z Yue W . Associations between genotype and peripheral complement proteins in first-episode psychosis: evidences from C3 and C4. Front Genet. (2021) 12:647246. doi: 10.3389/fgene.2021.647246

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  Kalinowski A Liliental J Anker LA Linkovski O Culbertson C Hall JN et al . Increased activation product of complement 4 protein in plasma of individuals with schizophrenia. Transl Psychiatry. (2021) 11:486. doi: 10.1038/s41398-021-01583-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  Zhang S Zhou N Liu R Rao W Yang M Cao B et al . Association between polymorphisms of the complement 3 gene and schizophrenia in a han chinese population. Cell Physiol Biochem. (2018) 46:2480–6. doi: 10.1159/000489654

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  Nsaiba MJ Lapointe M Mabrouk H Douki W Gaha L Pérusse L et al . C3 polymorphism influences circulating levels of C3, asp and lipids in schizophrenic patients. Neurochem Res. (2015) 40:906–14. doi: 10.1007/s11064-015-1543-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  Sekar A Bialas AR de Rivera H Davis A Hammond TR Kamitaki N et al . Schizophrenia risk from complex variation of complement component 4. Nature. (2016) 530:177–83. doi: 10.1038/nature16549

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  Yilmaz M Yalcin E Presumey J Aw E Ma M Whelan CW et al . Overexpression of schizophrenia susceptibility factor human complement C4a promotes excessive synaptic loss and behavioral changes in mice. Nat Neurosci. (2021) 24:214–24. doi: 10.1038/s41593-020-00763-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  Comer AL Jinadasa T Sriram B Phadke RA Kretsge LN Nguyen TPH et al . Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction. PLoS Biol. (2020) 18:e3000604. doi: 10.1371/journal.pbio.3000604

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  Zhang T Tang Y Yang X Wang X Ding S Huang K et al . Expression of gsk3β, pick1, nefl, C4, nkcc1 and synaptophysin in peripheral blood mononuclear cells of the first-episode schizophrenia patients. Asian J Psychiatr. (2021) 55:102520. doi: 10.1016/j.ajp.2020.102520

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  Rey R Suaud-Chagny MF Bohec AL Dorey JM d’Amato T Tamouza R et al . Overexpression of complement component C4 in the dorsolateral prefrontal cortex, parietal cortex, superior temporal gyrus and associative striatum of patients with schizophrenia. Brain Behav Immun. (2020) 90:216–25. doi: 10.1016/j.bbi.2020.08.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  Prasad KM Chowdari KV D’Aiuto LA Iyengar S Stanley JA Nimgaonkar VL . Neuropil contraction in relation to complement C4 gene copy numbers in independent cohorts of adolescent-onset and young adult-onset schizophrenia patients-a pilot study. Transl Psychiatry. (2018) 8:134. doi: 10.1038/s41398-018-0181-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  Chen CC Howie J Ebrahimi M Teymouri K Woo JJ Tiwari AK et al . Analysis of the complement component C4 gene with schizophrenia subphenotypes. Schizophr Res. (2024) 271:309–18. doi: 10.1016/j.schres.2024.07.039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  Ji RN Zhang LL Zhao MF He HF Bai W Duan RX et al . Decreased serum complement component 4 levels in patients with schizophrenia. Psychiatr Genet. (2019) 29:127–9. doi: 10.1097/ypg.0000000000000226

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  Gracias J Orhan F Hörbeck E Holmén-Larsson J Khanlarkani N Malwade S et al . Cerebrospinal fluid concentration of complement component 4a is increased in first episode schizophrenia. Nat Commun. (2022) 13:6427. doi: 10.1038/s41467-022-33797-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  Ishii T Hattori K Miyakawa T Watanabe K Hidese S Sasayama D et al . Increased cerebrospinal fluid complement C5 levels in major depressive disorder and schizophrenia. Biochem Biophys Res Commun. (2018) 497:683–8. doi: 10.1016/j.bbrc.2018.02.131

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  Severance EG Yolken RH . From infection to the microbiome: an evolving role of microbes in schizophrenia. Curr Top Behav Neurosci. (2020) 44:67–84. doi: 10.1007/7854_2018_84

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  Severance EG Leister F Lea A Yang S Dickerson F Yolken RH . Complement C4 associations with altered microbial biomarkers exemplify gene-by-environment interactions in schizophrenia. Schizophr Res. (2021) 234:87–93. doi: 10.1016/j.schres.2021.02.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  Severance EG Gressitt KL Stallings CR Origoni AE Khushalani S Leweke FM et al . Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res. (2013) 148:130–7. doi: 10.1016/j.schres.2013.05.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  Presumey J Bialas AR Carroll MC . Complement system in neural synapse elimination in development and disease. Adv Immunol. (2017) 135:53–79. doi: 10.1016/bs.ai.2017.06.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  Nissilä E Korpela K Lokki AI Paakkanen R Jokiranta S de Vos WM et al . C4b gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease. Clin Exp Immunol. (2017) 190:394–405. doi: 10.1111/cei.13040

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  Ifuku M Hinkelmann L Kuhrt LD Efe IE Kumbol V Buonfiglioli A et al . Activation of toll-like receptor 5 in microglia modulates their function and triggers neuronal injury. Acta Neuropathol Commun. (2020) 8:159. doi: 10.1186/s40478-020-01031-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  Schilling S Chausse B Dikmen HO Almouhanna F Hollnagel JO Lewen A et al . Tlr2- and tlr3-activated microglia induce different levels of neuronal network dysfunction in a context-dependent manner. Brain Behav Immun. (2021) 96:80–91. doi: 10.1016/j.bbi.2021.05.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  Weickert TW Ji E Galletly C Boerrigter D Morishima Y Bruggemann J et al . Toll-like receptor mrna levels in schizophrenia: association with complement factors and cingulate gyrus cortical thinning. Schizophr Bull. (2024) 50:403–17. doi: 10.1093/schbul/sbad171

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  McKernan DP Dennison U Gaszner G Cryan JF Dinan TG . Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. Transl Psychiatry. (2011) 1:e36. doi: 10.1038/tp.2011.37

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  Akira S Takeda K . Toll-like receptor signalling. Nat Rev Immunol. (2004) 4:499–511. doi: 10.1038/nri1391

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  García Bueno B Caso JR Madrigal JL Leza JC . Innate immune receptor toll-like receptor 4 signalling in neuropsychiatric diseases. Neurosci Biobehav Rev. (2016) 64:134–47. doi: 10.1016/j.neubiorev.2016.02.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  Balaji R Subbanna M Shivakumar V Abdul F Venkatasubramanian G Debnath M . Pattern of expression of toll like receptor (Tlr)-3 and -4 genes in drug-naïve and antipsychotic treated patients diagnosed with schizophrenia. Psychiatry Res. (2020) 285:112727. doi: 10.1016/j.psychres.2019.112727

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  Kéri S Szabó C Kelemen O . Antipsychotics influence toll-like receptor (Tlr) expression and its relationship with cognitive functions in schizophrenia. Brain Behav Immun. (2017) 62:256–64. doi: 10.1016/j.bbi.2016.12.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  Müller N Wagner JK Krause D Weidinger E Wildenauer A Obermeier M et al . Impaired monocyte activation in schizophrenia. Psychiatry Res. (2012) 198:341–6. doi: 10.1016/j.psychres.2011.12.049

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  García-Bueno B Gassó P MacDowell KS Callado LF Mas S Bernardo M et al . Evidence of activation of the toll-like receptor-4 proinflammatory pathway in patients with schizophrenia. J Psychiatry Neurosci. (2016) 41:E46–55. doi: 10.1503/jpn.150195

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  Wang Y Sadike D Huang B Li P Wu Q Jiang N et al . Regulatory T cells alleviate myelin loss and cognitive dysfunction by regulating neuroinflammation and microglial pyroptosis via tlr4/myd88/nf-Κb pathway in lpc-induced demyelination. J Neuroinflamm. (2023) 20:41. doi: 10.1186/s12974-023-02721-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  Zhong Q Zou Y Liu H Chen T Zheng F Huang Y et al . Toll-like receptor 4 deficiency ameliorates Β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice. Mol Brain. (2020) 13:20. doi: 10.1186/s13041-020-0559-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  Dai QD Wu KS Xu LP Zhang Y Lin N Jiang Y et al . Toll-like receptor 4 deficiency ameliorates propofol-induced impairments of cognitive function and synaptic plasticity in young mice. Mol Neurobiol. (2024) 61:519–32. doi: 10.1007/s12035-023-03606-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  Xiao X Zhang H Ning W Yang Z Wang Y Zhang T . Knockdown of fstl1 inhibits microglia activation and alleviates depressive-like symptoms through modulating tlr4/myd88/nf-Κb pathway in cums mice. Exp Neurol. (2022) 353:114060. doi: 10.1016/j.expneurol.2022.114060

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  Kim YK Shin C . The microbiota-gut-brain axis in neuropsychiatric disorders: pathophysiological mechanisms and novel treatments. Curr Neuropharmacol. (2018) 16:559–73. doi: 10.2174/1570159x15666170915141036

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  MacDowell KS Caso JR Martín-Hernández D Madrigal JL Leza JC García-Bueno B . Paliperidone prevents brain toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress. Int J Neuropsychopharmacol. (2014) 18. doi: 10.1093/ijnp/pyu070

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  Gárate I García-Bueno B Madrigal JL Caso JR Alou L Gómez-Lus ML et al . Toll-like 4 receptor inhibitor tak-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflamm. (2014) 11:8. doi: 10.1186/1742-2094-11-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  Chen Y Li D Sun L Qi K Shi L . Pharmacological inhibition of toll-like receptor 4 with tlr4-in-C34 modulates the intestinal flora homeostasis and the myd88/nf-Κb axis in ulcerative colitis. Eur J Pharmacol. (2022) 934:175294. doi: 10.1016/j.ejphar.2022.175294

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  Cryan JF O’Riordan KJ Cowan CSM Sandhu KV Bastiaanssen TFS Boehme M et al . The microbiota-gut-brain axis. Physiol Rev. (2019) 99:1877–2013. doi: 10.1152/physrev.00018.2018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  González-Blanco L Dal Santo F García-Portilla MP Alfonso M Hernández C Sánchez-Autet M et al . Intestinal permeability biomarkers in patients with schizophrenia: additional support for the impact of lifestyle habits. Eur Psychiatry. (2024) 67:e84. doi: 10.1192/j.eurpsy.2024.1765

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  Schirmer M Smeekens SP Vlamakis H Jaeger M Oosting M Franzosa EA et al . Linking the human gut microbiome to inflammatory cytokine production capacity. Cell. (2016) 167:1125–36.e8. doi: 10.1016/j.cell.2016.10.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  Yarandi SS Peterson DA Treisman GJ Moran TH Pasricha PJ . Modulatory effects of gut microbiota on the central nervous system: how gut could play a role in neuropsychiatric health and diseases. J Neurogastroenterol Motil. (2016) 22:201–12. doi: 10.5056/jnm15146

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  Mhanna A Martini N Hmaydoosh G Hamwi G Jarjanazi M Zaifah G et al . The correlation between gut microbiota and both neurotransmitters and mental disorders: A narrative review. Med (Baltimore). (2024) 103:e37114. doi: 10.1097/md.0000000000037114

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  Zheng P Zeng B Liu M Chen J Pan J Han Y et al . The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-gaba cycle and schizophrenia-relevant behaviors in mice. Sci Adv. (2019) 5:eaau8317. doi: 10.1126/sciadv.aau8317

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  González-Castro TB Tovilla-Zárate CA Juárez-Rojop IE Hernández-Díaz Y López-Narváez ML Ortiz-Ojeda RF . Effects of il-6/il-6r axis alterations in serum, plasma and cerebrospinal fluid with the schizophrenia: an updated review and meta-analysis of 58 studies. Mol Cell Biochem. (2024) 479:525–37. doi: 10.1007/s11010-023-04747-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  Yan J Xia Q Sun X Yang P Gao H Pan Z et al . Dysregulation of interleukin-8 is involved in the onset and relapse of schizophrenia: an independent validation and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. (2024) 133:111018. doi: 10.1016/j.pnpbp.2024.111018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  Patlola SR Donohoe G McKernan DP . Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis. J Psychiatr Res. (2023) 160:126–36. doi: 10.1016/j.jpsychires.2023.01.042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  Zhang Y Wang J Ye Y Zou Y Chen W Wang Z et al . Peripheral cytokine levels across psychiatric disorders: A systematic review and network meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. (2023) 125:110740. doi: 10.1016/j.pnpbp.2023.110740

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  Halstead S Siskind D Amft M Wagner E Yakimov V Shih-Jung Liu Z et al . Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: A systematic review and network meta-analysis. Lancet Psychiatry. (2023) 10:260–71. doi: 10.1016/s2215-0366(23)00025-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  Dunleavy C Elsworthy RJ Upthegrove R Wood SJ Aldred S . Inflammation in first-episode psychosis: the contribution of inflammatory biomarkers to the emergence of negative symptoms, a systematic review and meta-analysis. Acta Psychiatr Scand. (2022) 146:6–20. doi: 10.1111/acps.13416

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  Çakici N Sutterland AL Penninx B de Haan L van Beveren NJM . Changes in peripheral blood compounds following psychopharmacological treatment in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: A meta-analysis. Psychol Med. (2021) 51:538–49. doi: 10.1017/s0033291721000155

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  Çakici N Sutterland AL Penninx B Dalm VA de Haan L van Beveren NJM . Altered peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: A meta-analysis. Brain Behav Immun. (2020) 88:547–58. doi: 10.1016/j.bbi.2020.04.039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  Park S Miller BJ . Meta-analysis of cytokine and C-reactive protein levels in high-risk psychosis. Schizophr Res. (2020) 226:5–12. doi: 10.1016/j.schres.2019.03.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  Fraguas D Díaz-Caneja CM Ayora M Hernández-Álvarez F Rodríguez-Quiroga A Recio S et al . Oxidative stress and inflammation in first-episode psychosis: A systematic review and meta-analysis. Schizophr Bull. (2019) 45:742–51. doi: 10.1093/schbul/sby125

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  Romeo B Brunet-Lecomte M Martelli C Benyamina A . Kinetics of cytokine levels during antipsychotic treatment in schizophrenia: A meta-analysis. Int J Neuropsychopharmacol. (2018) 21:828–36. doi: 10.1093/ijnp/pyy062

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  Zhang J Luo W Huang P Peng L Huang Q . Maternal C-reactive protein and cytokine levels during pregnancy and the risk of selected neuropsychiatric disorders in offspring: A systematic review and meta-analysis. J Psychiatr Res. (2018) 105:86–94. doi: 10.1016/j.jpsychires.2018.09.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  Capuzzi E Bartoli F Crocamo C Clerici M Carrà G . Acute variations of cytokine levels after antipsychotic treatment in drug-naïve subjects with a first-episode psychosis: A meta-analysis. Neurosci Biobehav Rev. (2017) 77:122–8. doi: 10.1016/j.neubiorev.2017.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  Goldsmith DR Rapaport MH Miller BJ . A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. (2016) 21:1696–709. doi: 10.1038/mp.2016.3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  Upthegrove R Manzanares-Teson N Barnes NM . Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis. Schizophr Res. (2014) 155:101–8. doi: 10.1016/j.schres.2014.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  Wang AK Miller BJ . Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder, and depression. Schizophr Bull. (2018) 44:75–83. doi: 10.1093/schbul/sbx035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  Gallego JA Blanco EA Husain-Krautter S Madeline Fagen E Moreno-Merino P Del Ojo-Jiménez JA et al . Cytokines in cerebrospinal fluid of patients with schizophrenia spectrum disorders: new data and an updated meta-analysis. Schizophr Res. (2018) 202:64–71. doi: 10.1016/j.schres.2018.07.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  Pape K Tamouza R Leboyer M Zipp F . Immunoneuropsychiatry - novel perspectives on brain disorders. Nat Rev Neurol. (2019) 15:317–28. doi: 10.1038/s41582-019-0174-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  Pillinger T Osimo EF Brugger S Mondelli V McCutcheon RA Howes OD . A meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis. Schizophr Bull. (2019) 45:1120–33. doi: 10.1093/schbul/sby160

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  Lv Y Wen L Hu W-J Deng C Ren H-W Bao Y-N et al . Schizophrenia in the genetic era: A review from development history, clinical features and genomic research approaches to insights of susceptibility genes. Metab Brain Dis. (2023) 39:147–171. doi: 10.1007/s11011-023-01271-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  Lv H Guo M Guo C He K . The interrelationships between cytokines and schizophrenia: A systematic review. Int J Mol Sci. (2024) 25:8477. doi: 10.3390/ijms25158477

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  Liang PY Diao LH Huang CY Lian RC Chen X Li GG et al . The pro-inflammatory and anti-inflammatory cytokine profile in peripheral blood of women with recurrent implantation failure. Reprod BioMed Online. (2015) 31:823–6. doi: 10.1016/j.rbmo.2015.08.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  Momtazmanesh S Zare-Shahabadi A Rezaei N . Cytokine alterations in schizophrenia: an updated review. Front Psychiatry. (2019) 10:892. doi: 10.3389/fpsyt.2019.00892

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  Wang Y Wei Y Edmiston EK Womer FY Zhang X Duan J et al . Altered structural connectivity and cytokine levels in schizophrenia and genetic high-risk individuals: associations with disease states and vulnerability. Schizophr Res. (2020) 223:158–65. doi: 10.1016/j.schres.2020.05.044

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  Clark SM Notarangelo FM Li X Chen S Schwarcz R Tonelli LH . Maternal immune activation in rats blunts brain cytokine and kynurenine pathway responses to a second immune challenge in early adulthood. Prog Neuropsychopharmacol Biol Psychiatry. (2019) 89:286–94. doi: 10.1016/j.pnpbp.2018.09.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  Mondelli V Blackman G Kempton MJ Pollak TA Iyegbe C Valmaggia LR et al . Serum immune markers and transition to psychosis in individuals at clinical high risk. Brain Behav Immun. (2023) 110:290–6. doi: 10.1016/j.bbi.2023.03.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  Li H Chen W Gou M Li W Tong J Zhou Y et al . The relationship between tlr4/nf-Κb/il-1β Signaling, cognitive impairment, and white-matter integrity in patients with stable chronic schizophrenia. Front Psychiatry. (2022) 13:966657. doi: 10.3389/fpsyt.2022.966657

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  Jeon S Kim SH Shin SY Lee YH . Clozapine reduces toll-like receptor 4/nf-Κb-mediated inflammatory responses through inhibition of calcium/calmodulin-dependent akt activation in microglia. Prog Neuropsychopharmacol Biol Psychiatry. (2018) 81:477–87. doi: 10.1016/j.pnpbp.2017.04.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  Banati R Hickie IB . Therapeutic signposts: using biomarkers to guide better treatment of schizophrenia and other psychotic disorders. Med J Aust. (2009) 190:S26–32. doi: 10.5694/j.1326-5377.2009.tb02371.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  Doorduin J de Vries EF Willemsen AT de Groot JC Dierckx RA Klein HC . Neuroinflammation in schizophrenia-related psychosis: A pet study. J Nucl Med. (2009) 50:1801–7. doi: 10.2967/jnumed.109.066647

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  van Berckel BN Bossong MG Boellaard R Kloet R Schuitemaker A Caspers E et al . Microglia activation in recent-onset schizophrenia: A quantitative (R)-[11c]Pk11195 positron emission tomography study. Biol Psychiatry. (2008) 64:820–2. doi: 10.1016/j.biopsych.2008.04.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  Lee SU In HJ Kwon MS Park BO Jo M Kim MO et al . Β-arrestin 2 mediates G protein-coupled receptor 43 signals to nuclear factor-Κb. Biol Pharm Bull. (2013) 36:1754–9. doi: 10.1248/bpb.b13-00312

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  Place RF Noonan EJ Giardina C . Hdac inhibition prevents nf-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha. Biochem Pharmacol. (2005) 70:394–406. doi: 10.1016/j.bcp.2005.04.030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  Zandi-Nejad K Takakura A Jurewicz M Chandraker AK Offermanns S Mount D et al . The role of hca2 (Gpr109a) in regulating macrophage function. FASEB J. (2013) 27:4366–74. doi: 10.1096/fj.12-223933

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  Pace TW Miller AH . Cytokines and glucocorticoid receptor signaling. Relevance to major depression. Ann N Y Acad Sci. (2009) 1179:86–105. doi: 10.1111/j.1749-6632.2009.04984.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  Thomas R . The traf6-nf kappa B signaling pathway in autoimmunity: not just inflammation. Arthritis Res Ther. (2005) 7:170–3. doi: 10.1186/ar1784

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  Derry HM Fagundes CP Andridge R Glaser R Malarkey WB Kiecolt-Glaser JK . Lower subjective social status exaggerates interleukin-6 responses to a laboratory stressor. Psychoneuroendocrinology. (2013) 38:2676–85. doi: 10.1016/j.psyneuen.2013.06.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  Tao R de Zoeten EF Ozkaynak E Chen C Wang L Porrett PM et al . Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med. (2007) 13:1299–307. doi: 10.1038/nm1652

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  Rooks MG Garrett WS . Gut microbiota, metabolites and host immunity. Nat Rev Immunol. (2016) 16:341–52. doi: 10.1038/nri.2016.42

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  Wang L de Zoeten EF Greene MI Hancock WW . Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of foxp3+ Regulatory T cells. Nat Rev Drug Discov. (2009) 8:969–81. doi: 10.1038/nrd3031

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  Peng H Ouyang L Li D Li Z Yuan L Fan L et al . Short-chain fatty acids in patients with schizophrenia and ultra-high risk population. Front Psychiatry. (2022) 13:977538. doi: 10.3389/fpsyt.2022.977538

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  Li Z Qing Y Cui G Li M Liu T Zeng Y et al . Shotgun metagenomics reveals abnormal short-chain fatty acid-producing bacteria and glucose and lipid metabolism of the gut microbiota in patients with schizophrenia. Schizophr Res. (2023) 255:59–66. doi: 10.1016/j.schres.2023.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  Chen Y Xu J Chen Y . Regulation of neurotransmitters by the gut microbiota and effects on cognition in neurological disorders. Nutrients. (2021) 13:2099. doi: 10.3390/nu13062099

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  Agus A Planchais J Sokol H . Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. (2018) 23:716–24. doi: 10.1016/j.chom.2018.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  Savitz J . The kynurenine pathway: A finger in every pie. Mol Psychiatry. (2020) 25:131–47. doi: 10.1038/s41380-019-0414-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  Golimbet VE Korovaĭtseva GI Gabaeva MV Velikaia NV Snegireva AA Kasparov SV et al . a study of il-1β and ido gene polymorphisms in patients with schizophrenia. Zh Nevrol Psikhiatr Im S S Korsakova. (2014) 114:46–9.

  • Pubmed Abstract
  • Google Scholar

• 217

  O’Connor JC André C Wang Y Lawson MA Szegedi SS Lestage J et al . Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus calmette-guerin. J Neurosci. (2009) 29:4200–9. doi: 10.1523/jneurosci.5032-08.2009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  Babcock TA Carlin JM . Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells. Cytokine. (2000) 12:588–94. doi: 10.1006/cyto.1999.0661

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  Connor TJ Starr N O’Sullivan JB Harkin A . Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: A role for ifn-gamma? Neurosci Lett. (2008) 441:29–34. doi: 10.1016/j.neulet.2008.06.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  Zunszain PA Anacker C Cattaneo A Choudhury S Musaelyan K Myint AM et al . Interleukin-1β: A new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology. (2012) 37:939–49. doi: 10.1038/npp.2011.277

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  Martín-Hernández D Tendilla-Beltrán H Madrigal JLM García-Bueno B Leza JC Caso JR . Chronic mild stress alters kynurenine pathways changing the glutamate neurotransmission in frontal cortex of rats. Mol Neurobiol. (2019) 56:490–501. doi: 10.1007/s12035-018-1096-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  Kennedy PJ Cryan JF Dinan TG Clarke G . Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. (2017) 112:399–412. doi: 10.1016/j.neuropharm.2016.07.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  Albuquerque EX Schwarcz R . Kynurenic acid as an antagonist of Α7 nicotinic acetylcholine receptors in the brain: facts and challenges. Biochem Pharmacol. (2013) 85:1027–32. doi: 10.1016/j.bcp.2012.12.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  Moroni F Cozzi A Sili M Mannaioni G . Kynurenic acid: A metabolite with multiple actions and multiple targets in brain and periphery. J Neural Transm (Vienna). (2012) 119:133–9. doi: 10.1007/s00702-011-0763-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  Kanchanatawan B Sirivichayakul S Thika S Ruxrungtham K Carvalho AF Geffard M et al . Physio-somatic symptoms in schizophrenia: association with depression, anxiety, neurocognitive deficits and the tryptophan catabolite pathway. Metab Brain Dis. (2017) 32:1003–16. doi: 10.1007/s11011-017-9982-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  Müller N . Neuroprogression in schizophrenia and psychotic disorders: the possible role of inflammation. Mod Trends Pharmacopsychiatry. (2017) 31:1–9. doi: 10.1159/000470802

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  Bailey MT Cryan JF . The microbiome as a key regulator of brain, behavior and immunity: commentary on the 2017 named series. Brain Behav Immun. (2017) 66:18–22. doi: 10.1016/j.bbi.2017.08.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  Reigstad CS Salmonson CE Rainey JF 3rd Szurszewski JH Linden DR Sonnenburg JL et al . Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. (2015) 29:1395–403. doi: 10.1096/fj.14-259598

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  Roth W Zadeh K Vekariya R Ge Y Mohamadzadeh M . Tryptophan metabolism and gut-brain homeostasis. Int J Mol Sci. (2021) 22:2973. doi: 10.3390/ijms22062973

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  Desbonnet L Clarke G Traplin A O’Sullivan O Crispie F Moloney RD et al . Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav Immun. (2015) 48:165–73. doi: 10.1016/j.bbi.2015.04.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  Clarke G Stilling RM Kennedy PJ Stanton C Cryan JF Dinan TG . Minireview: gut microbiota: the neglected endocrine organ. Mol Endocrinol. (2014) 28:1221–38. doi: 10.1210/me.2014-1108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  Myint AM Kim YK . Network beyond ido in psychiatric disorders: revisiting neurodegeneration hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. (2014) 48:304–13. doi: 10.1016/j.pnpbp.2013.08.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  Zádor F Joca S Nagy-Grócz G Dvorácskó S Szűcs E Tömböly C et al . Pro-inflammatory cytokines: potential links between the endocannabinoid system and the kynurenine pathway in depression. Int J Mol Sci. (2021) 22:5903. doi: 10.3390/ijms22115903

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  Cryan JF Dinan TG . Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. (2012) 13:701–12. doi: 10.1038/nrn3346

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  Wichers MC Maes M . The role of indoleamine 2,3-dioxygenase (Ido) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci. (2004) 29:11–7. doi: 10.1139/jpn.0402

  • CrossRef
  • Google Scholar

• 236

  Lieben CK Blokland A Westerink B Deutz NE . Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat. Neurochem Int. (2004) 44:9–16. doi: 10.1016/s0197-0186(03)00102-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  Cahir M Ardis T Reynolds GP Cooper SJ . Acute and chronic tryptophan depletion differentially regulate central 5-ht1a and 5-ht 2a receptor binding in the rat. Psychopharmacol (Berl). (2007) 190:497–506. doi: 10.1007/s00213-006-0635-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  Merchán A Navarro SV Klein AB Aznar S Campa L Suñol C et al . Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms. Psychopharmacol (Berl). (2017) 234:1223–36. doi: 10.1007/s00213-017-4561-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  Moreno FA Parkinson D Palmer C Castro WL Misiaszek J El Khoury A et al . Csf neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls. Eur Neuropsychopharmacol. (2010) 20:18–24. doi: 10.1016/j.euroneuro.2009.10.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  Owens JK . Systematic reviews: brief overview of methods, limitations, and resources. Nurse Author Editor. (2021) 31:69–72. doi: 10.1111/nae2.28

  • CrossRef
  • Google Scholar

• 241

  Nakhal MM Yassin LK Alyaqoubi R Saeed S Alderei A Alhammadi A et al . The microbiota-gut-brain axis and neurological disorders: A comprehensive review. Life (Basel). (2024) 14:1234. doi: 10.3390/life14101234

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  Loh JS Mak WQ Tan LKS Ng CX Chan HH Yeow SH et al . Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduct Target Ther. (2024) 9:37. doi: 10.1038/s41392-024-01743-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  Ding M Lang Y Shu H Shao J Cui L . Microbiota-gut-brain axis and epilepsy: A review on mechanisms and potential therapeutics. Front Immunol. (2021) 12:742449. doi: 10.3389/fimmu.2021.742449

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  Zhu F Tu H Chen T . The microbiota-gut-brain axis in depression: the potential pathophysiological mechanisms and microbiota combined antidepression effect. Nutrients. (2022) 14:2081. doi: 10.3390/nu14102081

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  Liu P Liu Z Wang J Wang J Gao M Zhang Y et al . Immunoregulatory role of the gut microbiota in inflammatory depression. Nat Commun. (2024) 15:3003. doi: 10.1038/s41467-024-47273-w

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  Lai Y Xiong P . Analysis of gut microbiota and depression and anxiety: mendelian randomization from three datasets. Gen Hosp Psychiatry. (2025) 94:206–18. doi: 10.1016/j.genhosppsych.2025.03.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  Pan M Qian C Huo S Wu Y Zhao X Ying Y et al . Gut-derived lactic acid enhances tryptophan to 5-hydroxytryptamine in regulation of anxiety via akkermansia muciniphila. Gut Microbes. (2025) 17:2447834. doi: 10.1080/19490976.2024.2447834

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  Zhang X Hou Y Li Y Wei W Cai X Shao H et al . Taxonomic and metabolic signatures of gut microbiota for assessing the severity of depression and anxiety in major depressive disorder patients. Neuroscience. (2022) 496:179–89. doi: 10.1016/j.neuroscience.2022.06.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  Sublette ME Cheung S Lieberman E Hu S Mann JJ Uhlemann AC et al . Bipolar disorder and the gut microbiome: A systematic review. Bipolar Disord. (2021) 23:544–64. doi: 10.1111/bdi.13049

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  Hasegawa S Goto S Tsuji H Okuno T Asahara T Nomoto K et al . Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in parkinson’s disease. PLoS One. (2015) 10:e0142164. doi: 10.1371/journal.pone.0142164

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  Unger MM Spiegel J Dillmann KU Grundmann D Philippeit H Bürmann J et al . Short chain fatty acids and gut microbiota differ between patients with parkinson’s disease and age-matched controls. Parkinsonism Relat Disord. (2016) 32:66–72. doi: 10.1016/j.parkreldis.2016.08.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  Liu J Lv X Ye T Zhao M Chen Z Zhang Y et al . Microbiota-microglia crosstalk between blautia producta and neuroinflammation of parkinson’s disease: A bench-to-bedside translational approach. Brain Behav Immun. (2024) 117:270–82. doi: 10.1016/j.bbi.2024.01.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  Chen C Liao J Xia Y Liu X Jones R Haran J et al . Gut microbiota regulate alzheimer’s disease pathologies and cognitive disorders via pufa-associated neuroinflammation. Gut. (2022) 71:2233–52. doi: 10.1136/gutjnl-2021-326269

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 254

  Kesika P Suganthy N Sivamaruthi BS Chaiyasut C . Role of gut-brain axis, gut microbial composition, and probiotic intervention in alzheimer’s disease. Life Sci. (2021) 264:118627. doi: 10.1016/j.lfs.2020.118627

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  Kang DW Park JG Ilhan ZE Wallstrom G Labaer J Adams JB et al . Reduced incidence of prevotella and other fermenters in intestinal microflora of autistic children. PLoS One. (2013) 8:e68322. doi: 10.1371/journal.pone.0068322

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 256

  Srikantha P Mohajeri MH . The possible role of the microbiota-gut-brain-axis in autism spectrum disorder. Int J Mol Sci. (2019) 20:2115. doi: 10.3390/ijms20092115

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 257

  Socała K Doboszewska U Szopa A Serefko A Włodarczyk M Zielińska A et al . The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol Res. (2021) 172:105840. doi: 10.1016/j.phrs.2021.105840

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  Tomova A Husarova V Lakatosova S Bakos J Vlkova B Babinska K et al . Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav. (2015) 138:179–87. doi: 10.1016/j.physbeh.2014.10.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 259

  Wang L Christophersen CT Sorich MJ Gerber JP Angley MT Conlon MA . Increased abundance of sutterella spp. And ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism. (2013) 4:42. doi: 10.1186/2040-2392-4-42

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 260

  Parracho HM Bingham MO Gibson GR McCartney AL . Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. (2005) 54:987–91. doi: 10.1099/jmm.0.46101-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  Xie G Zhou Q Qiu CZ Dai WK Wang HP Li YH et al . Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World J Gastroenterol. (2017) 23:6164–71. doi: 10.3748/wjg.v23.i33.6164

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 262

  Gong X Liu X Chen C Lin J Li A Guo K et al . Alteration of gut microbiota in patients with epilepsy and the potential index as a biomarker. Front Microbiol. (2020) 11:517797. doi: 10.3389/fmicb.2020.517797

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 263

  Lee K Kim N Shim JO Kim GH . Gut bacterial dysbiosis in children with intractable epilepsy. J Clin Med. (2020) 10:5. doi: 10.3390/jcm10010005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 264

  Lee H Lee S Lee DH Kim DW . A comparison of the gut microbiota among adult patients with drug-responsive and drug-resistant epilepsy: an exploratory study. Epilepsy Res. (2021) 172:106601. doi: 10.1016/j.eplepsyres.2021.106601

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 265

  Peng A Qiu X Lai W Li W Zhang L Zhu X et al . Altered composition of the gut microbiome in patients with drug-resistant epilepsy. Epilepsy Res. (2018) 147:102–7. doi: 10.1016/j.eplepsyres.2018.09.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  Şafak B Altunan B Topçu B Eren Topkaya A . The gut microbiome in epilepsy. Microb Pathog. (2020) 139:103853. doi: 10.1016/j.micpath.2019.103853

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 267

  Rao J Qiu P Zhang Y Wang X . Gut microbiota trigger host liver immune responses that affect drug-metabolising enzymes. Front Immunol. (2024) 15:1511229. doi: 10.3389/fimmu.2024.1511229

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  Wang X Ye C Xun T Mo L Tong Y Ni W et al . Bacteroides fragilis polysaccharide a ameliorates abnormal voriconazole metabolism accompanied with the inhibition of tlr4/nf-Κb pathway. Front Pharmacol. (2021) 12:663325. doi: 10.3389/fphar.2021.663325

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  Deng X Li Y Jiang L Xie X Wang X . 1-methylnicotinamide modulates il-10 secretion and voriconazole metabolism. Front Immunol. (2025) 16:1529660. doi: 10.3389/fimmu.2025.1529660

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  Wang YL Chen L Zhong XL Liu QS Li WQ Cheng Y et al . Antidepressant effects of ershiwei roudoukou pills and its active ingredient macelignan: multiple mechanisms involving oxidative stress, neuroinflammation and synaptic plasticity. Transl Psychiatry. (2025) 15:163. doi: 10.1038/s41398-025-03378-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 271

  Park SY Kim YH Kim Y Lee SJ . Aromatic-turmerone’s anti-inflammatory effects in microglial cells are mediated by protein kinase a and heme oxygenase-1 signaling. Neurochem Int. (2012) 61:767–77. doi: 10.1016/j.neuint.2012.06.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  Willner P Scheel-Krüger J Belzung C . The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev. (2013) 37:2331–71. doi: 10.1016/j.neubiorev.2012.12.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  Golofast B Vales K . The connection between microbiome and schizophrenia. Neurosci Biobehav Rev. (2020) 108:712–31. doi: 10.1016/j.neubiorev.2019.12.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 274

  Theoharides TC Kavalioti M Tsilioni I . Mast cells, stress, fear and autism spectrum disorder. Int J Mol Sci. (2019) 20:3611. doi: 10.3390/ijms20153611

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  Kotwas I McGonigal A Bastien-Toniazzo M Bartolomei F Micoulaud-Franchi JA . Stress regulation in drug-resistant epilepsy. Epilepsy Behav. (2017) 71:39–50. doi: 10.1016/j.yebeh.2017.01.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 276

  Goadsby PJ Holland PR Martins-Oliveira M Hoffmann J Schankin C Akerman S . Pathophysiology of migraine: A disorder of sensory processing. Physiol Rev. (2017) 97:553–622. doi: 10.1152/physrev.00034.2015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  Paudel YN Shaikh MF Shah S Kumari Y Othman I . Role of inflammation in epilepsy and neurobehavioral comorbidities: implication for therapy. Eur J Pharmacol. (2018) 837:145–55. doi: 10.1016/j.ejphar.2018.08.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  Amoozegar F . Depression comorbidity in migraine. Int Rev Psychiatry. (2017) 29:504–15. doi: 10.1080/09540261.2017.1326882

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 279

  Vasileva SS Yang Y Baker A Siskind D Gratten J Eyles D . Associations of the gut microbiome with treatment resistance in schizophrenia. JAMA Psychiatry. (2024) 81:292–302. doi: 10.1001/jamapsychiatry.2023.5371

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 280

  Starr AE Deeke SA Ning Z de Nanassy J Singleton R Benchimol EI et al . Associations between cellular energy and pediatric inflammatory bowel disease patient response to treatment. J Proteome Res. (2021) 20:4393–404. doi: 10.1021/acs.jproteome.1c00341

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  Mörkl S Butler MI Holl A Cryan JF Dinan TG . Probiotics and the microbiota-gut-brain axis: focus on psychiatry. Curr Nutr Rep. (2020) 9:171–82. doi: 10.1007/s13668-020-00313-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  Ribera C Sánchez-Ortí JV Clarke G Marx W Mörkl S Balanzá-Martínez V . Probiotic, prebiotic, synbiotic and fermented food supplementation in psychiatric disorders: A systematic review of clinical trials. Neurosci Biobehav Rev. (2024) 158:105561. doi: 10.1016/j.neubiorev.2024.105561

  • Pubmed Abstract
  • CrossRef
  • Google Scholar