Akkermansia muciniphila in neuropsychiatric disorders: friend or foe?

An accumulating body of evidence suggests that the bacterium Akkermansia muciniphila exhibits positive systemic effects on host health, mainly by improving immunological and metabolic functions, and it is therefore regarded as a promising potential probiotic. Recent clinical and preclinical studies have shown that A. muciniphila plays a vital role in a variety of neuropsychiatric disorders by influencing the host brain through the microbiota-gut-brain axis (MGBA). Numerous studies observed that A. muciniphila and its metabolic substances can effectively improve the symptoms of neuropsychiatric disorders by restoring the gut microbiota, reestablishing the integrity of the gut mucosal barrier, regulating host immunity, and modulating gut and neuroinflammation. However, A. muciniphila was also reported to participate in the development of neuropsychiatric disorders by aggravating inflammation and influencing mucus production. Therefore, the exact mechanism of action of A. muciniphila remains much controversial. This review summarizes the proposed roles and mechanisms of A. muciniphila in various neurological and psychiatric disorders such as depression, anxiety, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, strokes, and autism spectrum disorders, and provides insights into the potential therapeutic application of A. muciniphila for the treatment of these conditions.


Introduction
The gut microbiota plays a crucial role in maintaining host health and was once regarded as a "forgotten organ" (Cheng et al., 2020;Ling ZX. et al., 2022). A large number of commensal bacteria, viruses, fungi, parasites, and archaea thrive both within and on the human body and participate in human physiology, growth, development, immunity, nutrition, and metabolism. Recent advances in microbiology, particularly through the application of multi-omics approaches, have revealed that the gut microbiota transcends its previous characterization as a passive bystander and actively impacts host health and disease. Despite being previously overlooked, the role of the gut microbiota as a key contributor to the pathology of various host diseases is now gaining recognition. Mounting evidence from clinical and preclinical studies suggests that gut eubiosis is critical for host health, while gut dysbiosis disturbs gut homeostasis and contributes to the onset of host diseases. The intimate interplay between the gut microbiota and the host has revitalized our current understanding of disease pathogenesis, proposing novel targets for disease diagnosis and therapeutic interventions. Within the field of microbiota research, a considerable number of crucial functional microorganisms have been identified. Ongoing efforts to decipher the underlying roles and mechanisms of these microorganisms will contribute to our understanding of their functional impact on host health and disease.
Recently, A. muciniphila has received significant attention in scientific research. A. muciniphila is the sole representative of the phylum Verrucomicrobia in the human gut and is a normal component of its microbiota that is widely distributed in the mucus layer (Derrien et al., 2004). This strictly anaerobic gramnegative bacterium possesses oval non-motile cells and cannot produce endospores. A. muciniphila can use mucins as its sole nitrogen, carbon, and energy source and forms white colonies on soft agar mucin medium (Derrien et al., 2004). In healthy individuals, A. muciniphila accounts for approximately 3-5% of the gut microbiota (Belzer and De Vos, 2012). Qin et al. observed that A. muciniphila was among the top 20 most abundant species in the human gut (Qin et al., 2010). However, the colonization and abundance of A. muciniphila may be influenced by various confounding factors such as age, location, genotype, dietary habits, and physiological status of the host (Zhai et al., 2019). A. muciniphila is present in different parts of the human mucosa and feces, but is most abundant in the mucin-producing cecum (Derrien et al., 2011). Recent studies conducted on participants of different nationalities have shown that the abundance of A. muciniphila changes with host age (Collado et al., 2007;Cheng et al., 2016). A. muciniphila demonstrates stable colonization within the human gastrointestinal tract (GIT) during the first year of life, reaching similar levels as those found in healthy adults. However, a noticeable decline in its abundance is observed in older adults (Collado et al., 2007). These changes may be associated with the alterations in mucus quality and quantity that occur during aging. A. muciniphila exclusively degrades mucin and is equipped with an active acid-resistance system, allowing it to degrade human milk oligosaccharides within the stomachs of newborn infants, contributing to improved mucosal and metabolic health later in life (Bosscher et al., 2001;Kostopoulos et al., 2020).
Over the past decade, A. muciniphila has been increasingly investigated and recognized as a true gut symbiont that promotes beneficial interactions in the human GIT. A. muciniphila plays an important role in modulating glucose tolerance, energy metabolism, and the maturation and functioning of the immune system. A. muciniphila is currently a popular research subject due to its potential beneficial impact on various health conditions such as overweight, diabetes, obesity, hypertension, colitis, and age-related complications (Dao et al., 2016;Liu R. et al., 2017;Plovier et al., 2017;Grander et al., 2018;Bian et al., 2019;Depommier et al., 2019;Payahoo et al., 2019;Grajeda-Iglesias et al., 2021;Liu et al., 2021). The etiology of these conditions may stem from dysregulation in the gut microbiota, intestinal mucosal damage, and high permeability of the intestinal mucosa during the early stages of development. A. muciniphila contributes to the restoration of the gut microbiota and maintenance of a healthy gut mucosal barrier, thereby regulating gut immunity and limiting the onset of inflammation (Cani et al., 2022). Van der Lugt et al. showed that supplementation with A. muciniphila can increase the thickness of the colonic mucus layer by nearly threefold (Van Der Lugt et al., 2019). Zhao et al. also demonstrated that A. muciniphila can improve chronic low-grade inflammation by increasing antiinflammatory factors, such as a-tocopherol, and reducing levels of lipopolysaccharide (LPS)-binding protein . Another study found that A. muciniphila can increase the amount of 2-oleoylglycerol in the gut and stimulate the production of glucagon-like peptide-1 (GLP-1) in L-cells. GLP-1 is known for its beneficial effects, including appetite suppression, anti-diabetic properties, and weight loss (Everard et al., 2013). A. muciniphila secretes a GLP-1-inducing protein that can improve glucose homeostasis and ameliorate metabolic diseases in high-fat diet (HFD)-fed C57BL/6J mice (Yoon et al., 2021). Furthermore, Plovier et al. showed that supplementation with A. muciniphila or its protein extract significantly reduced plasma high-density lipoprotein (HDL) cholesterol concentrations and reversed HFDinduced hypercholesterolemia (Plovier et al., 2017). Everard et al. demonstrated that treatment with viable A. muciniphila could reverse HFD-induced metabolic disorders, including metabolic endotoxemia, fat mass gain, insulin resistance, and adipose tissue inflammation (Everard et al., 2013). Greer et al. revealed that A. muciniphila mediates the negative effects of interferon-gamma (IFN-g) on glucose metabolism, highlighting its significant role in promoting metabolic health (Greer et al., 2016). Moreover, A. muciniphila induces adaptive immune responses in the GIT, contributing to the maintenance of GIT homeostasis (Ansaldo et al., 2019). The increased endocannabinoids induced by A. muciniphila can play a role in controlling GIT inflammation, promote gut mucus production, and enhance the expression of antimicrobial peptides such as regenerating islet-derived 3-gamma (Reg3g), thereby supporting innate immunity (Everard et al., 2013). Derrien et al. observed that A. muciniphila modulates the pathways involved in establishing homeostasis for basal metabolism and immune tolerance of the gut commensal microbiota (Derrien et al., 2011). Through the activation of the non-canonical Toll-like receptor (TLR) heterodimer, TLR2-TLR1, by a phospholipid agonist, A. muciniphila selectively stimulates proinflammatory cytokines, thereby promoting homeostatic host immune responses (Bae et al., 2022). A recent study by Liu et al. found that A. muciniphila can also induce immune responses mediated by RORgt + regulatory T cells, leading to the amelioration of dextran sulfate sodium (DSS)-induced colitis . In addition, A. muciniphila has shown efficacy in improving obesity, hepatic steatosis, type 1 and 2 diabetes mellitus (T1DM and T2DM), and intestinal inflammation in mice (Cani et al., 2022). Currently, A. muciniphila is considered a promising probiotic candidate for the prevention and treatment of human metabolic diseases, inflammatory disorders, and other microbiota-related diseases; however, its potential adverse effects need to be further investigated as several studies have also observed the harmful effects of A. muciniphila on human host (Ganesh et al., 2013;Weir et al., 2013;Cekanaviciute et al., 2017;Wang F. et al., 2022).
The positive effects of A. muciniphila are not limited to the improvement of metabolic functions and modulation of the immune system. Recent studies have shown that A. muciniphila actively participates in various neurological and psychiatric disorders such as depression and anxiety Sun et al., 2023), multiple sclerosis (MS) (Berer et al., 2017;Ling et al., 2020a), Alzheimer's disease (AD) (Ling et al., 2020b;Ou et al., 2020), Parkinson's disease (PD) , autism spectrum disorders (ASDs) (Goo et al., 2020), and strokes (Stanley et al., 2018). Accumulating evidence suggests that the effects of A. muciniphila on these conditions are most likely mediated by the gut-brain axis (GBA). The GBA refers to the bidirectional communication between the gut and brain, representing the connection between the GIT and the central nervous system (CNS) (Grenham et al., 2011;Sherwin et al., 2016). The GBA plays a crucial role in maintaining and coordinating GIT function while also influencing mood, motivated behavior, and higher cognitive functions through feedback from the gut (Foster et al., 2017). In addition to this, the gut microbiota can directly produce metabolites and immunomodulatory factors that directly communicate with the CNS to regulate brain function (Sherwin et al., 2016). This review focuses on the role of A. muciniphila in various neuropsychiatric disorders, explores the possible underlying mechanisms behind its involvement, and discusses its therapeutic potential through GBA modulation.

Underlying mechanisms of A. muciniphila in neuropsychiatric disorders
A. muciniphila is a potential next-generation probiotic that plays an important role in systemic metabolism, intestinal health, and immune regulation . However, limited information is available on the direct effects of A. muciniphila on neuropsychiatric disorders, as the majority of current clinical studies have primarily focused on exploring the association between the bacterium and the disorders without establishing causation. Nevertheless, several hypotheses explaining the mechanisms underlying the impact of A. muciniphila on brain function have been proposed. These hypotheses involve the production of neuroactive metabolites and derivatives, protection of the GIT mucosal barrier, regulation of host immunity, and modulation of metabolism.

Neuroactive metabolites and derivatives
A. muciniphila exhibits the ability to generate various neuroactive metabolites, including short-chain fatty acids (SCFAs), B-vitamins, kynurenic acid, and g-aminobutyric acid (GABA), through the breakdown of mucins or interactions with other beneficial microbes that play vital roles in the occurrence of neuropsychiatric disorders. Amuc_1100, the outer membrane protein of A. muciniphila, likely plays a crucial role in the interaction of the bacterium with its host and can restore the function of the GIT mucosal barrier and promote intestinal 5hydroxytryptamine (5-HT) biosynthesis through TLR2 signaling. A recent study identified P9, an 84 kDa protein, that stimulates the secretion of GLP-1 (Yoon et al., 2021). In addition, A. muciniphiladerived extracellular vesicles (AmEVs) serve as potent vehicles for intercellular communication, facilitating the normalization of the gut microbiota, improvement of GIT permeability, and modulation of inflammatory responses. Collectively, these findings establish A. muciniphila as a neuroactive microbe.

SCFAs
SCFAs are exclusively produced by microbial fermentation in the host and are regarded as indispensable signals in the communication between the gut and extraintestinal organs. A. muciniphila utilizes mucins to generate a diverse range of SCFAs, such as butyrate, acetate, and propionate. These SCFAs play a vital role in preserving gut health and have been associated with various health benefits, including immunoregulation and the protection of intestinal barrier integrity. Recent studies have suggested a possible connection between A. muciniphila-produced SCFAs and neuropsychiatric disorders, as A. muciniphila can directly alter bacterial composition and SCFAs production in the gut (Xia et al., 2022). Research has shown that individuals with depression and anxiety tend to have lower levels of certain types of SCFAs in their gut and that probiotics containing A. muciniphila can help increase the production of these SCFAs . Furthermore, preliminary findings suggest a link between A. muciniphila and neuropsychiatric disorders like ASD, schizophrenia, and PD, although more research is required to fully understand this connection. Studies have found that high concentrations of butyrate rapidly increase histone acetylation, leading to improved learning and memory, reduced depression and persistent behavior, and improved social skills in mouse models with ASD (De Theije et al., 2014;Kratsman et al., 2016). A recent clinical trial revealed that oral supplementation with butyrate can enhance cognitive performance and reduce negative symptoms in drug-naïve patients with first-episode schizophrenia . In mice, SCFAs improved schizophrenia-like symptoms, including social withdrawal, altered sensorimotor gating, and working memory deficits (Joseph et al., 2017;Dalile et al., 2019). In a PD mouse model, butyrate was found to improve motor impairment, alleviate dopaminergic neuronal degeneration, and inhibit neuroinflammation (Hou et al., 2021). Recent studies have shown that GLP-1 has the ability to influence brain function by improving movement disorders, alleviating inflammatory responses and oxidative stress, and inhibiting apoptosis (Chen et al., 2018;Batista et al., 2019). A. muciniphila-produced SCFAs specifically activate the expression of G-protein-coupled receptors in enteroendocrine L-cells in the distal small intestine and colon, regulating the production of GLP-1 and other hormones (Psichas et al., 2015). The available evidence suggests that A. muciniphilaproduced SCFAs also possess direct neuropsychiatric effects by modulating the activity of the enteric nervous system (ENS) and the vagus nerve, crossing the blood-brain barrier (BBB) and directly affecting the neurotransmitter and neuropeptide systems in the brain (Borre et al., 2014;Vicentini et al., 2021).
The mechanisms underlying the impact of A. muciniphilaproduced SCFAs on neuropsychiatric disorders are complex. Based on the results of preclinical and clinical studies, several hypotheses have emerged. First, SCFAs may modulate the GBA, which has a significant role in the regulation of mood, cognition, and behavior. Animal studies have demonstrated that supplementation with certain SCFAs can improve anxiety-and depression-like behaviors, reduce stress-induced neuroinflammation, and even increase the production of neurotransmitters such as serotonin and GABA, which are implicated in neuropsychiatric disorders. Second, SCFAs contribute to the reduction of systemic inflammation, which is strongly associated with the development of neuropsychiatric disorders (Yao et al., 2022). For example, patients with depression often exhibit elevated levels of inflammatory markers like C-reactive protein and IL-6, and anti-inflammatory drugs can improve depressive symptoms (Jiang et al., 2015). SCFAs have potent anti-inflammatory effects and may reduce inflammation in the CNS and gut. Finally, the beneficial effects of A. muciniphila-produced SCFAs on neuropsychiatric disorders may be mediated by other mechanisms, such as changes in gene expression, epigenetic modifications, or gut microbiota modulation. Considering the complexity of the GBA and the gut microbiota, it is likely that multiple mechanisms are involved. Overall, the exact mechanisms underlying the neuropsychiatric effects of A. muciniphila-produced SCFAs are still under investigation. However, the impact of these SCFAs on brain function presents a promising therapeutic target for the treatment of neuropsychiatric disorders.

Amuc_1100 and P9
Amuc_1100, a thermostable outer membrane protein specific to A. muciniphila, is speculated to play an important role in the intricate interaction between microbes and hosts, reproducing the beneficial effects of A. muciniphila (Anhe and Marette, 2017). The absence of mucin induces the expression of the gene encoding Amuc_1100 (Shin et al., 2019). Amuc_1100 can activate TLR2mediated signaling pathways which contribute to the enhancement of gut barrier integrity and the restoration of tight junction expression (Plovier et al., 2017). Recent studies have implicated Amuc_1100 in the modulation of brain function and behavior. As previously mentioned, Wang et al. discovered that Amuc_1100, through the TLR2 signaling pathway, upregulates the rate-limiting enzyme tryptophan hydroxylase 1 (Tph1), resulting in increased expression of 5-HT in the GIT and downregulation of the expression of the serotonin transporter (SERT) . 5-HT may improve GIT function and nutrition, and disturbances in the physiological function of the GIT have been associated with various mental health disorders, including ASD (Ferguson et al., 2017). 5-HT is a key regulator of the development and function of the ENS and CNS, and is likely able to connect the microbiota-gut-brain nexus. An insufficient amount of 5-HT may lead to the development of depression and other neuropsychiatric disorders. Recent findings have demonstrated the antidepressant effects of Amuc_1100, which improves dysregulated gut microbiota, increases the levels of brain-derived neurotrophic factor (BDNF), and inhibits inflammation in the hippocampus induced by chronic unpredictable mild stress (CUMS) . In addition, Amuc_1100 alleviates antibiotic-induced anxiety and depression by modulating the BDNF/tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway, thereby restoring the levels of BDNF and TrkB in the hippocampus and cortex (Sun et al., 2023). Amuc_1100 D80 , a truncated form of Amuc_1100 lacking the first 80 N-terminal amino acids, exhibits a higher affinity for TLR2 compared to the wild-type protein. Amuc_1100 D80 can affect the level of 5-HT and the downstream 5-HTR1A-CREB-BDNF signaling pathway through its interaction with TLR2 and the modulation of the gut microbial composition, leading to a superior antidepressant effect compared to Amuc_1100 in ameliorating CUMS-induced depression in mice . These studies suggest that Amuc_1100 or Amuc_1100 D80 can modulate brain function and behavior, providing a foundation for the development of new therapeutic strategies. However, further investigations are necessary to fully understand the mechanisms responsible for these effects.
Yoon et al. recently discovered P9, an 84 kDa protein secreted by A. muciniphila. Their study revealed that oral administration of P9 substantially improved glucose homeostasis in mice (Yoon et al., 2021). Notably, P9 can bind to intercellular adhesion molecule-2 (ICAM-2) and activate phospholipase C (PLC), leading to intracellular Ca 2+ signaling and cAMP response element-binding protein (CREB) activation (Si et al., 2022). Furthermore, purified P9 on its own is sufficient to trigger the production of GLP-1 by L-cells. P9-stimulated IL-6 expression in macrophages is involved in GLP-1 secretion, whereas IL-6 deficiency replicates the effects of P9 on glucose homeostasis while downregulating the expression of ICAM-2. This demonstrates that the anti-obesogenic effects are dependent on IL-6 (Yoon et al., 2021). Intestinal GLP-1 affects numerous neuronal processes. It can modulate activity in hippocampal circuits, stimulate neurite outgrowth, promote cell survival, and upregulate the production of enzymes and neurotransmitters (Holst et al., 2011). Evidence suggests that A. muciniphila P9 is involved in the regulation of brain function and behavior. Similar to Amuc_1100, P9 has been found to possess immunometabolic and immunomodulatory functions. Initial investigations have indicated that P9 may play a crucial role in balancing proinflammatory and anti-inflammatory responses in the GIT, leading to a decrease in the production of proinflammatory cytokines and an increase in the production of anti-inflammatory cytokines . Nevertheless, the precise roles and underlying mechanisms of P9 in brain function and behavior remain unknown. Further studies are required to fully understand the mechanisms involved and to explore the potential clinical applications of A. muciniphila P9 in neuropsychiatric disorders.

AmEVs
Extracellular vesicles (EVs) are submicron-sized lipid bilayer structures secreted by the gut microbiota (Ellis and Kuehn, 2010). Recent evidence suggests that bacteria-derived EVs are able to transfer genetic material and proteins from the bacteria to the host, demonstrating their diverse roles in the microbial community (Kuehn and Kesty, 2005). EVs can be considered as functional units of the gut microbiota that mediate the interaction between the host and microbiota by directly interacting with epithelial and immune cells to initiate various signaling pathways. AmEVs are small membrane-bound particles released by A. muciniphila and contain a variety of biomolecules, including lipids, proteins, and nucleic acids (Kim YS. et al., 2013). Chelakkot et al. observed a higher amount of AmEVs in the feces of healthy individuals compared to those with T2DM (Chelakkot et al., 2018). Furthermore, administration of AmEVs resulted in enhanced tight junction function, as evidenced by increased occluding expression. This treatment also improved glucose tolerance and reduced weight gain in HFD-induced diabetic mice, whereas EVs derived from Escherichia coli did not exhibit similar effects (Chelakkot et al., 2018). These findings suggest that AmEVs may serve as functional units involved in the regulation of gut permeability. By promoting the integrity of the intestinal mucosal barrier, metabolic functions in HFD-fed mice can be improved. In addition, AmEVs restored the gut microbiota composition, improved the integrity of the intestinal mucosal barrier, regulated inflammatory responses, and subsequently prevented liver injury in mice administered with HFD/CCl4 (Keshavarz Azizi Raftar et al., 2021). AmEVs decrease the expression of proinflammatory cytokines (IL-6 and TNF-a) and the LPS recognition marker TLR-4 (Alhawi et al., 2009), and they also activate TLR-2 to induce the expression of anti-inflammatory factors, suggesting that they play an important role in host anti-inflammatory responses (Ashrafian et al., 2019). In addition, AmEVs increase levels of 5-HT in the colon and hippocampus (Yaghoubfar et al., 2020). Considering their impact on the gut microbiota, gut mucosal barrier, and immunoregulation, AmEVs may also hold considerable potential in the treatment of neuropsychiatric disorders. This is a promising area of research in the field of gut microbiota-based therapeutics for neuropsychiatric disorders. However, to fully grasp the therapeutic potential of AmEVs and ensure their safe and effective utilization in treating neuropsychiatric disorders, further studies are necessary.

Gut mucosal barrier protection
Dysfunction of the gut mucosal barrier contributes to the development of several neuropsychiatric disorders, such as depression, anxiety, and ASD. The gut mucosal barrier is the interface between the GIT microbes and host tissue, and it plays a key role in maintaining a balanced response between the host and its microbiota (Konig et al., 2016). Preserving the integrity of the gut epithelial barrier is of utmost importance for maintaining overall host health, as it is serves as a key defense mechanism against pathogens. Previous research has demonstrated the significant role of A. muciniphila in the mutualistic relationship between the gut microbiota and the host, particularly in manipulating the function of the gut mucosal barrier as well as other physiological and homeostatic processes associated with obesity and T2DM (Everard et al., 2013). A. muciniphila primarily resides in the mucus layer of the large intestine where it regulates the proliferation of intestinal epithelial cells through the Wnt/bcatenin signaling pathway, thereby facilitating the repair of the gut mucosal barrier in vivo (Ring et al., 2014). Reunanen et al. found that A. muciniphila can improve the integrity of intestinal cells by forming strong associations with the cultured colony epithelial cell lines, Caco-2 and HT-29 (Reunanen et al., 2015). Furthermore, A. muciniphila has been shown to mitigate damage to the gut mucosal barrier in recipient mice by upregulating the expression of mucin 2 and increasing the number of goblet cells and mucin 2-positive cells in each villus . The mucus layer, primarily composed of mucin 2 secreted by goblet cells, serves as the initial physical barrier, effectively shielding the colon from toxins and pathogenic microbes (Johansson et al., 2011;Ambort et al., 2012). Mucin 2 plays a key role in maintaining a suitable distance between the GIT microbes and the epithelial surface. Aberrant expression of mucins is observed in various gastrointestinal pathologies, including infections and inflammation (Breugelmans et al., 2022). In children with ASD and their siblings, a lower number of A. muciniphila was found to be positively correlated with a thinner GIT mucus barrier (De Magistris et al., 2010). Despite being recognized as a mucin degrader, the ability of A. muciniphila to increase the thickness of the mucus layer has been previously reported (Everard et al., 2013;Li et al., 2016). The observed increase in mucus layer thickness following supplementation with A. muciniphila suggests that this bacterium can actively stimulate host colonic mucus production (Derrien et al., 2017). Chen et al. demonstrated that the administration of A. muciniphila, by restoring colonic mucus and modifying the gut microbiota, could protect against the aggravation of colitis and gut microbiotamediated colonic mucosal barrier damage induced by psychological disorders . Yu et al. observed that A. muciniphila ameliorated the disruption of the GIT mucosal barrier caused by high levels of fructose and restraint stress through maintaining normal secretion of antimicrobial peptides in Paneth cells, promotion of tight junction protein expression, and inhibition of proinflammatory cytokines expression . The expression of tight junction proteins affects the permeability of the GIT mucosal barrier (Feldman et al., 2005). Chelakkot et al. demonstrated that AmEVs increased the levels of tight junction proteins and activated AMPK (Chelakkot et al., 2018). AMPK is involved in tight junction regulation by assembling tight junction proteins at cell-cell junctions (Zheng et al., 2007). Additionally, Amuc_1100 was recently found to promote gut barrier integrity by upregulating the expression of tight junction proteins (Anhe and Marette, 2017). Previous studies have demonstrated the ability of A. muciniphila to degrade the mucus layer, raising concerns about its potential pathogenicity in the gut mucosal barrier. However, unlike gut pathogens, A. muciniphila primarily resides in the outer mucosal layer and does not invade the inner one, which is a crucial requirement for pathogenicity (Tuomola et al., 2001;Derrien et al., 2010;Goḿez-Gallego et al., 2016;Zhang et al., 2019). Overall, these findings suggest that A. muciniphila plays an important role in maintaining and protecting the mucosal barrier in the GIT.

Immune regulation
In addition to maintaining and protecting the gut mucosal barrier, A. muciniphila also plays an important role in regulating the GIT immune system. Inflammation causes damage to the CNS in both neonates and adults (Hagberg and Mallard, 2005;Degos et al., 2010;Dickson et al., 2017). A. muciniphila has been found to exert anti-inflammatory effects in both animal and human studies. Guo et al. demonstrated that supplementation with A. muciniphila reduced the levels of proinflammatory factors such as IL-1b, IL-6, and TNF-a . Another study showed that treatment with A. muciniphila can induce the synthesis of systemic and gut anti-inflammatory cytokines, while reducing the amounts of serum proinflammatory cytokines (TNF-a, IL-1a, and IL-6) and chemokines (G-CSF, MIP-1a and KC) in mice with DSS-induced colitis, thereby alleviating inflammation (Bian et al., 2019). Studies have also shown that A. muciniphila or its protein component, Amuc_1100, can induce the synthesis of the anti-inflammatory cytokine, IL-10, thereby improving immunological homeostasis in the GIT mucosa and enhancing gut mucosal barrier function (Ottman et al., 2017;Bian et al., 2019). Hu et al. found that the oral administration of A. muciniphila to H7N9-infected mice resulted in a significant reduction in pulmonary viral titers and levels of IL-6 and IL-1b. On the other hand, levels of IL-10, IFN-b and IFN-g were enhanced, suggesting that the anti-influenza activity of A. muciniphila can most likely be attributed to its antiinflammatory and immunoregulatory properties (Hu et al., 2020). Nishimura et al. demonstrated the ability of cytotoxic Tlymphocytes (CTLs) to promote the recruitment and activation of macrophages during inflammation (Nishimura et al., 2009). By reducing the number of CTLs, A. muciniphila and Amuc_1100 both inhibit the recruitment and activation of macrophages, most notably CD16/32 + macrophages (M1) . Since M1 macrophages can cause a rapid proinflammatory response to infection and tissue injury (Liu PS. et al., 2017;Na et al., 2019). Thus, the reduction of M1 macrophages can alleviate the inflammatory symptoms of the body, a reduction in their population can alleviate inflammatory symptoms in the body. A. muciniphila also affects the structure and composition of the gut microbiota, potentially reducing host proinflammatory factors and cytotoxins . While a higher relative abundance of A. muciniphila is associated with the development of several neuropsychiatric disorders such as AD, increased levels of A. muciniphila in Ab precursor protein (APP)/presenilin (PS1) transgenic mice improved the function of the intestinal barrier and prevented the inflammatory response caused by LPS translocation (Xin et al., 2018). Furthermore, microgliosis has been implicated in the development of several neuropsychiatric disorders, and treatment with A. muciniphila can reduce hippocampal microglial proliferation and restore neuronal development and synaptic plasticity . The results from these studies suggest that A. muciniphila plays an important role in immune regulation and may participate in the modulation of the microbiota-gut-brain axis (MGBA).

Metabolic regulation
Metabolic syndromes, such as obesity and diabetes, have been associated with an increased risk of neuropsychiatric disorders, such as AD, PD, and Huntington's disease. Both human and animal studies have been utilized to explore the concurrence of neuropsychiatric disorders and metabolic diseases, revealing shared pathophysiological mechanisms, such as dyslipidemia (Yu et al., 2020), insulin resistance (Ma et al., 2022), neurovascular dysfunction , neuronal cell loss (Bharadwaj et al., 2017), and tubulin-associated unit (tau) phosphorylation (Freude et al., 2005). Song et al. found that the number of patients with cognitive decline due to metabolic imbalances has increased considerably (Song, 2023). Mounting evidence suggests that metabolic regulation is necessary to prevent and treat neuropsychiatric disorders. A. muciniphila plays an important role in metabolic regulation, particularly in energy metabolism and glucose homeostasis. A large portion of the A. muciniphila genome consists of genes encoding proteins involved in metabolic processes. These include proteases, sialate esterases, and glycohydrolases (Van Passel et al., 2011). A. muciniphila can influence triglyceride synthesis by modulating the expression of sterol regulatory element-binding protein (SREBP) genes (Linden et al., 2018). In addition, A. muciniphila was found to decrease the production of serum 3bchenodeoxycholic acid, an inhibitor of insulin secretion in T2DM patients , suggesting that A. muciniphila may improve insulin secretion in these patients. Fujisaka et al. demonstrated that A. muciniphila was also able to improve gut motility, further contributing to metabolic regulation (Fujisaka et al., 2020). Therefore, A. muciniphila is believed to play a vital role in regulating metabolism and potentially reducing the risk of developing neuropsychiatric disorders.

A. muciniphila in neuropsychiatric disorders
Accumulating evidence suggests an association between A. muciniphila and the development of neuropsychiatric disorders. However, the observed patterns of A. muciniphila have been inconsistent across different studies. The relative abundance of A. muciniphila varied significantly among different neuropsychiatric disorders. We have described the changes in the abundance and role of A. muciniphila in several neuropsychiatric disorders, including depression, AD, PD, MS, ASD, and stroke (Table 1).

Depression
Depression is one of the most common mental health disorders worldwide. Individuals affected by depression experience symptoms such as persistent low mood, loss of interest, difficulty concentrating, psychomotor retardation or agitation, insomnia and other sleep disturbances, or suicidal thoughts. The World Health Organization estimates that approximately 350 million people suffer from depression, and the condition may result in disabilities or mortality (Smith, 2014). Owing to the peculiarities of depression and the subjective nature of its diagnosis, the number of    (Continued) Lei et al. 10.3389/fcimb.2023.1224155 undiagnosed patients with subclinical depressive symptoms is estimated to be even higher. At present, the etiology of depression is not clear, although biochemical alterations in monoamines and their receptors are suspected to contribute to the development of depression (Ruiz et al., 2018). Experimental and genetic research has revealed several mechanisms for the development of depression, including dysregulation of the hypothalamus-pituitary-adrenal disorder (HPA) axis in response to stress, inflammation, impaired neural plasticity, disrupted neural circuits, and dysfunction of nerve regulation systems such as the monoamine and endocannabinoid (eCB) systems (Chevalier et al., 2020;Mlynarska et al., 2022). Recent studies have revealed that the gut microbiota plays an important role in the pathogenesis of depression (Jiang et al., 2015;Liang et al., 2018;. Over the course of evolution, the gut microbiome, a virtual endocrine organ that communicates with the CNS via the MGBA, has developed a bidirectional communication relationship with its host (Clarke et al., 2014;O'mahony et al., 2015). A. muciniphila is believed to participate in this pathway by producing metabolites that influence neuroendocrine signaling in the brain. Furthermore, studies have observed decreased levels of A. muciniphila in mice exhibiting depression-like behavior following social defeat (Mcgaughey et al., 2019) and rats displaying depression-like behavior after chronic paradoxical sleep deprivation . Studies have shown that individuals with depression exhibit reduced levels of BDNF in the brain (Takebayashi et al., 2012;Jiang et al., 2015). The neurotrophic hypothesis proposes that a decrease in BDNF is implicated in the pathophysiology of depression, while an increase in BDNF is essential for the therapeutic effect of antidepressants (Yohn et al., 2017). BDNF is a neurotrophic factor, which is widely distributed in the hippocampus and closely related to neuronal regeneration and repair (Rakhit et al., 2005). A decrease in BDNF mRNA levels is observed in the hippocampus of chronically stressed rats and patients with depression (Duman and Monteggia, 2006). However, A. muciniphila increases the expression of BDNF mRNA in the hippocampus, indicating its potential to enhance synaptic signaling pathways, promote neuronal connectivity, and improve the condition of patients with depression . Clinically, patients with depression exhibit reduced levels of 5-HT, which is a protective factor (Tundo et al., 2015). According to the monoamine deficiency hypothesis, depression is caused by a deficiency in monoamine transmitters, such as 5-HT, within the brain (Gordon and Goelman, 2016). A. muciniphila directly influences the host 5-HT system and can increases 5-HT levels in the host intestine . As previously mentioned, Amuc_1100 upregulates the expression of 5-HT in the intestine . Ding et al. found that oral supplementation with A. muciniphila improves depression by modulating cholinergic synapses, fat digestion and absorption, aromatic compound degradation, vitamin digestion and absorption, fatty acid degradation, butanoate metabolism, carbon metabolism, biosynthesis of pantothenic acid and CoA, metabolic pathways, and digestion and absorption . A. muciniphila also increased the expression of two metabolites, edaravone and b-alanyl-3methyl-L-histidine, both of which showed a tendency to restore BDNF expression in the hippocampus. Furthermore, both metabolites significantly reduced corticosterone concentrations. In addition, edaravone significantly increased serotonin concentration, while b-alanyl-3-methyl-l-histidine increased dopamine concentration. The experimental results also showed that A. muciniphila alleviated as the symptoms of depression by influencing the levels of monoamine neurotransmitters and BDNF. A. muciniphila increases the expression of BDNF mRNA in the hippocampus, indicating that A. muciniphila can enhance synaptic signaling pathways and neuronal connections . Recently, Sun et al. found that A. muciniphila and   5-HT, 5-hydroxytryptamine; AD, Alzheimer's disease; AI, non-lacunar acute ischemic infarction; ASD, autism spectrum disorder; BDNF, brain-derived neurotrophic factor; CBD, cannabidiol; CFU, colony forming unit; CI, cerebral ischemic stroke; CRS, Chronic restraint stress; EAE, Experimental autoimmune encephalomyelitis; EDSS, expanded disability status score; FMT, fecal microbiota transplantation; HAMD-17, 17-Hamilton Depression Rating Scale; HC, healthy controls; IFN, interferon; IL, interleukin; IS, ischemia; KO, knock out; KRG, Korean red ginseng; LI, lacunar infarction; LPS, lipopolysaccharide; MMSE, Mini-mental State Examination; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MRI, magnetic resonance imaging; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder; PD, Parkinson's disease; PI, post-ischemic stroke; PSD, post-stroke depression; RRMS, Relapsing remitting multiple sclerosis; SIB, siblings; SN, Substantia Nigra; SPMS, secondary progressive multiple sclerosis; TGF, transforming growth factor; THC, delta-9-tetrahydrocannabinol; TNF, tumor necrosis factor; VPA, valproic acid; VTA, ventral tegmental area; WAIS, Wechsler Adult Intelligent Scale.
Amuc_1100 could alleviate anxiety-and depression-like behaviors in mice (Sun et al., 2023). Following treatment with A. muciniphila and Amuc_1100, levels of BDNF and its receptor, TrkB, were restored in the hippocampus and cortex. TrkB undergoes autophosphorylation after interacting with BDNF, which participates in signaling cascades that regulate neuronal migration and differentiation (Andreska et al., 2020). Previous studies have also demonstrated the association of both BDNF and TrkB with mood disorders and antidepressant effects (Castreń and Kojima, 2017;Hing et al., 2018). Therefore, A. muciniphila and Amuc_1100 may alleviate antibiosis-induced anxiety and depression by regulating the BDNF/TrkB signaling pathway, or by increasing 5-HT levels in the serum and hippocampus (Sun et al., 2023). Additionally, A. muciniphila may assist in alleviating the symptoms of depression by regulating gut inflammation. Studies have shown that individuals with depression have higher levels of inflammation, and that A. muciniphila may help mitigate this inflammation by producing anti-inflammatory molecules. In conclusion, A. muciniphila may play a critical role in mood regulation and depression prevention by affecting the MGBA, regulating inflammation, producing SCFAs, and modulating BDNF levels.

Alzheimer's disease
AD is characterized by memory impairment, loss of visual skills, performance decline, and behavioral changes (Kuhlmann et al., 2017). Currently, AD is regarded as the main cause of dementia and is quickly becoming one of the most expensive, lethal, and burdensome diseases of this century (Scheltens et al., 2021). The neuropathology of AD is characterized by the accumulation and aggregation of amyloid-b (Ab) and tau proteins in the brain, causing excessive phosphorylation of tau proteins, leading to neurofibrillary tangles, neuroinflammation, and neuronal and synaptic loss (Griciuc and Tanzi, 2021;Knopman et al., 2021). Ab is a peptide produced by the proteolytic hydrolysis of APP by b-and g-secretase. Ab40 and Ab42 are highly toxic and are highly likely to aggregate and exert neurotoxic effects. Hence, they are widely recognized as a key biomarker for AD (Kuhlmann et al., 2017). Accumulated Ab also increases intestinal permeability, promoting the expression of proinflammatory cytokines such as IL-17A and IL-22, which can cross the gut mucosal barrier and BBB and trigger neuroinflammation. Studies have shown a bidirectional relationship between metabolic syndromes such as obesity or insulin resistance and AD. On one hand, individuals with metabolic syndromes have a higher risk of cognitive impairment and AD (Craft, 2005;De Felice, 2013). On the other hand, the presence of AD pathology, such as Ab deposits, can interfere with insulin signaling and contribute to insulin resistance (Carvalho et al., 2013;Barbagallo and Dominguez, 2014). These findings suggest that insulin resistance is a key link between metabolic dysfunction and AD.
In AD mouse models, a significant decrease in the number of A. muciniphila is observed (Harach et al., 2017). A reduced amount of A. muciniphila is associated with impairment of the intestinal barrier (Grander et al., 2018), which is linked to cognitive function deficits and learning and memory impairment in AD mouse models (Ou et al., 2020). Increased intestinal permeability can lead to the translocation of bacteria-derived LPS and amyloid proteins from the gut into the bloodstream and eventually the brain, which further aggravates intestinal permeability (Pistollato et al., 2016). The damaged intestinal barrier can be repaired by treatment with A. muciniphila, which reduces blood endotoxin levels and improves insulin resistance (Everard et al., 2013;Shin et al., 2014). Ou et al. discovered that A. muciniphila may increase the number of goblet cells and promote mucus secretion to repair the damaged gut mucosal barrier, thereby reducing LPS and other proinflammatory substances. This repair mechanism improves metabolic levels, alleviates insulin resistance, reduces Ab protein deposition, and protects nerves from damage (Ou et al., 2020). In addition, daily administration of the Chinese strain A. muciniphila GP01 to APP/ PS1 mice for 6 months not only impacted the integrity of the gut mucosal barrier (Ou et al., 2020), but also resulted in decreased Ab deposition and led to improved performance in the Y-maze test. A. muciniphila intervention can reduce Ab40-42 in the cerebral cortex of AD animal models and alleviate cognitive disorders, such as spatial learning and memory deficits (Ou et al., 2020). These findings highlight the potential of A. muciniphila treatment in improving gut mucosal barrier dysfunction, as well as glucose and lipid metabolism disorders associated with cognitive impairment. However, it should be noted that the patterns observed in humans regarding the effects of A. muciniphila have been inconsistent. Increases in the abundance of the gut microbiota in patients with AD have been widely reported (Zhuang et al., 2018;Ling et al., 2020b;Khedr et al., 2022;Wang Y. et al., 2022). This challenged the positive role of A. muciniphila in AD animal models. However, a modified Mediterranean-ketogenic diet, along with increased A. muciniphila, has been shown to ameliorate markers of AD in patients with mild cognitive impairment (Nagpal et al., 2019). These conflicting results between human and animal studies stresses the need for further research to fully comprehend the roles and mechanisms of A. muciniphila in the development and progression of AD prior to considering it as a therapeutic target.

Parkinson's disease
PD is a neurodegenerative disease characterized by motor symptoms such as stiffness, resting tremors, bradykinesia, postural instability, and gait disturbances, in addition to nonmotor symptoms such as cognitive, neuropsychiatric, and autonomic impairment (Reich and Savitt, 2019). With the aging global population, global burden of disease studies project that the number of cases of PD will reach approximately 13 million by 2040 (Collaborators, G.B.D.P.S.D., 2018). The exact etiology of PD has not yet been clarified; however, studies have shown that the loss of dopaminergic activity, presence of Lewy bodies, intestinal exposure to neurotoxins, gut dysbiosis, cytokine-induced toxicity, oxidative damage from inflammation, and aging are all associated with the pathogenesis and progression of PD (Barichella et al., 2016). Dopaminergic neurons in the substantia nigra pars compacta (SNpc) appear to be particularly vulnerable to aggregates of aSyn, which can activate immune cells, including microglia in the brain (Kim C. et al., 2013). The abnormally soluble oligomeric conformation of aSyn, known as protofibrils, is widely recognized as a toxic agent that disrupts cellular homeostasis and contributes to neuronal death by influencing various intracellular processes (Stefanis, 2012). Elevated levels of glycoprotein non-metastatic melanoma protein B (GPNMB) have been observed in the blood of patients with PD and its expression is correlated with disease severity, suggesting that GPNMB may serve as a biomarker for PD progression (Smith and Schapira, 2022). GPNMB is a transmembrane glycoprotein (Mollenhauer and Caf., 2022), and genetic variations in the form of single nucleotide polymorphisms (SNPs) in this gene are associated with an increased risk of PD (Kia et al., 2021).
Similar to the findings in AD, gut dysbiosis has been observed even in the prodromal phase of PD, with enrichment of A. muciniphila occurring in patients with PD (Keshavarzian et al., 2015;Bedarf et al., 2017;Hill-Burns et al., 2017;Baldini et al., 2020;Cirstea et al., 2020;Zapała et al., 2021). Additionally, an increased number of A. muciniphila has been found in MPTP-induced (Jeon et al., 2021) and rotenone-treated PD mouse models (Dodiya et al., 2020). These findings suggest that A. muciniphila plays an important role in the pathogenesis of PD, and its increase may serve as a potential early biomarker for PD. The positive correlation between A. muciniphila and PD neural pathologies may be attributed to its role in mucin degradation, which can aggravate gut inflammation and permeability, leading to elevated endotoxemia and systemic inflammation. Notably, mucus degradation by A. muciniphila may result in a compensatory increase in mucus synthesis and exert anti-inflammatory effects in the host (Derrien et al., 2017). Using metagenomic analysis, Qian et al. found that A. muciniphila-related proteins might play an important role in the progression of PD (Qian et al., 2020). In addition, Ansaldo et al. found that the specific T cell responses induced by A. muciniphila can vary depending on other species present in the gut microbiota (Ansaldo et al., 2019). This variability may help explain why A. muciniphila, generally believed to mediate anti-inflammatory effects, is found in excessive amounts in individuals with PD. However, it remains unknown whether A. muciniphila can alleviate cognitive decline in patients with PD and dementia. Further investigation is warranted to fully understand the roles and mechanisms of A. muciniphila in PD, especially considering that it is a potential probiotic treatment for PD.

Multiple sclerosis
MS is a common, chronic, nontraumatic, and disabling autoimmune disease that primarily affects the CNS by targeting the myelin sheath. It is characterized by demyelination, loss of oligodendrocytes, reactive glial cell proliferation, and axonal degeneration (Ransohoff et al., 2015). The disease gradually erodes the CNS through the immune system, leading to a decline in the physical flexibility of patients (Pettigrew et al., 2016); hence, progressive MS is associated with increased physical disability and a significant impairment of the quality of life, including symptoms such as depression and fatigue (Cox et al., 2021). MS typically manifests in young individuals aged 20-40 years, and its occurrence and prevalence are increasing globally (Oh et al., 2018). Although the exact pathogenesis of MS is unknown, it is believed to involve a complex interplay between genetic and environmental factors. Among the environmental factors, the gut microbiota has been found to influence both the susceptibility to MS and the progression of the disease. The gut microbiota has the ability to modulate the differentiation and function of peripheral immune cells that regulate CNS inflammation (Cheng Y. et al., 2021); thus, studies have highlighted their significant role in autoimmune CNS disorders (Berer et al., 2011;Lee et al., 2011).
Gut dysbiosis has been observed in various stages of MS, suggesting an active involvement of the gut microbiota in the development of the disease (Takewaki et al., 2020). Among gut bacteria that are altered in individuals with MS, A. muciniphila has attracted considerable attention. Using 16S ribosomal RNA gene sequencing, Baranzini et al. observed that patients with MS had higher levels of A. muciniphila and lower levels of SCFA-producing bacteria in their guts compared to those in healthy individuals , which is consistent with the findings of other studies (Berer et al., 2017;Tankou et al., 2018;Al-Ghezi et al., 2019;Kozhieva et al., 2019;Takewaki et al., 2020). A. muciniphila can induce proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice, which may contribute to the development of autoimmune diseases like MS . Cekanaviciute et al. found a significant positive correlation between the relative abundance of Akkermansia and the differentiation of IFN-g + Th1 lymphocytes (Cekanaviciute et al., 2018), further suggesting the involvement of A. muciniphila in MS pathogenesis. In contrast to the notion that a higher relative abundance of A. muciniphila in MS is detrimental, Cox et al. identified a negative association between the abundance of A. muciniphila and disability, and a positive correlation between A. muciniphila and brain volume, demonstrating that A. muciniphila could also play a beneficial role. Consistent with this finding, their study revealed that Akkermansia isolated from MS patients was able to ameliorate experimental autoimmune encephalomyelitis (EAE) by reducing RORgt + and IL-17-producing gd T cells (Cox et al., 2021). This suggests an overall beneficial role of A. muciniphila, similar to that observed in obesity, diabetes, and age-related complications (Gurung et al., 2020). Convincing evidence identified IL-17-producing gd T cells as the initiators of the inflammatory process in EAE (Mcginley et al., 2018). Additionally, Colpitts et al. found that mice with higher levels of A. muciniphila exhibited slower disease progression in a non-obese diabetic progressive EAE model (Colpitts et al., 2017). Koutrolos et al. observed that A. muciniphila can up-regulate TGF-b and down-regulate IL-6 and IL-1b in mesenteric lymph node dendritic cells, which is beneficial to control the Treg expansion of effector T cells during EAE (Koutrolos et al., 2014). Liu et al. demonstrated that oral administration of miR-30d, found in the feces of MS patients, increased the number of Tregs and suppressed EAE symptoms in mice by increasing A. muciniphila in the gut (Liu et al., 2019). These findings suggest that elevated levels of A. muciniphila in MS patients may be a compensatory beneficial response of the MS microbiota. However, A. muciniphila also exerts strain-specific physiological functions, as inter-species or intergenetic differences of A. muciniphila have been observed , implying that not all strains of A. muciniphila are beneficial to the host. Different strains of the same species may exhibit contradictory effects on the same disease, suggesting the importance of analyzing bacterial functions at strain level (Wu G. et al., 2017). Thus, the beneficial effects of A. muciniphila may be strain-specific, warranting further studies on the effect of different strains of A. muciniphila on MS.

Strokes
A stroke can be classified as ischemic or hemorrhagic based on neuropathology. Ischemic strokes account for 85% of all stroke cases, while hemorrhagic strokes account for approximately 15% (Parr et al., 2017). A stroke is caused by the interruption of blood supply to regions of the brain, which can lead to permanent neurological deficits or death (Hossmann, 2006). It is a global health problem and is now the second leading cause of death and the third leading cause of disability (Parr et al., 2017). Brain damage caused by ischemic stroke is the result of a complex series of neuropathophysiological events, including oxidative stress, neuroinflammation, apoptosis, excitotoxicity, amyloid production, and tau dysfunction Radenovic et al., 2020;Ulamek-Koziol et al., 2020). Studies revealed that bacterial pneumonia is the main cause of death after a stroke (Chamorro and Urra, 2007). Selective bacterial translocation from the host gut microbiota to the lungs is the key factor causing bacterial pneumonia, suggesting that the gut epithelial mucosa and gut microbiota play a significant role in post-stroke mortality (Stanley et al., 2018).
Gut dysbiosis has been observed in both rodents and humans following the onset of an acute ischemic stroke. Singh et al. found that a stroke can induce gut dysbiosis and that changes in the gut microbiota can affect neuroinflammatory and functional outcomes after brain injury, while fecal microbiota transplantation (FMT) can improve stroke outcomes by normalizing post-stroke dysbiosis (Singh et al., 2016). Benakis et al. observed that antibiotic treatment-induced gut dysbiosis influences post-stroke neuroinflammation and outcome (Benakis et al., 2016). Clinical studies have reported a significant increase in A. muciniphila in the feces of patients who have experienced cerebral ischemic strokes Tan et al., 2021;Yao et al., 2023), proposing it as a gut microbiological marker following ischemic strokes (Xiang et al., 2020). In a rodent stroke model, an increase in A. municiphila was observed compared to that in control animals (Stanley et al., 2018;Ryuk et al., 2022). Patterns of changes in the abundance of A. muciniphila in stroke patients are not always consistent, similar to the observations in patients with AD and PD. Contrary to the results described above, a decrease in A. muciniphila was observed in patients with post-stroke (Ji et al., 2017). The role of A. muciniphila in stroke patients remains unclear. Stanley et al. demonstrated that A. muciniphila may prevent the migration of pathogens to epithelial cells through active inhibition, resulting in reduced translocation and dissemination of pathogens in the lungs after a stroke (Stanley et al., 2016). A. muciniphila can also promote wound healing and strengthen epithelial integrity to repair the intestinal mucosa. Some researchers propose that A. muciniphila can induce mucus production and Reg3g expression in the colon, remodeling the gut microbiota (Hänninen et al., 2018). In addition, A. muciniphila may inhibit the production of TNF-a and free radicals by interacting with TLRs in intestinal epithelial cells, which is associated with the reduction of serum TNF-a, IL-6, and IL-10 levels, positively impacting post-stroke recovery (Akhoundzadeh et al., 2018;Zhong et al., 2021). Further studies are required to determine the role of A. muciniphila in strokes.

Autism spectrum disorder
ASD is a complex neurodevelopmental disorder characterized by persistent deficits in social communication and interactions, with limited interests and repetitive behaviors (Persico et al., 2019). ASD typically emerges in early childhood and its prevalence is estimated at 1-2% based on numerous studies conducted in Asia, Europe, and North America (Valentino et al., 2021). Research and intervention in ASDs have become a pressing priority for public health due to the associated healthcare costs and complexity of the disorder. Multiple mechanisms such as decreased neurogenesis, an imbalance of excitatory/inhibitory neurotransmission, and dysregulation of the immune response, have been proposed as potential contributors to the onset of ASD (Adhya et al., 2021;Baranova et al., 2021;Cast et al., 2021). A recent study has provided direct and strong evidence suggesting that the gut microbiota plays a role in mediating the core symptom of ASD, the social behavioral phenotype (Buffington et al., 2021). While the exact etiology and pathology of ASD are still unclear, MGBA dysfunction is emerging as a prominent factor contributing to the development of autistic behaviors.
Increasing evidence supports the involvement of the gut microbiota in ASD (Foster, 2022). Altered gut microbiota composition and metabolic activities have also been detected in both many previous clinical (Finegold et al., 2010;Gondalia et al., 2012;De Angelis et al., 2013;Kang et al., 2013;Kushak et al., 2017;Strati et al., 2017;Coretti et al., 2018;Wang et al., 2019) and preclinical studies (Hsiao et al., 2013;De Theije et al., 2014;Buffington et al., 2016;Coretti et al., 2017;Kim et al., 2017;Liu et al., 2018;Sauer et al., 2019). Conflicting results have been reported for the involvement of A. muciniphila in ASD. Two sequencing studies have found increased levels of A. muciniphila in patients with ASD (De Angelis et al., 2013;Kang et al., 2013), while other studies have reported reduced levels of A. muciniphila in the gut microbiota of children with ASD (Finegold et al., 2010;Wang et al., 2011;Kang et al., 2013;Zou et al., 2020). Consistent with a previous study, the decreased number of A. muciniphila suggests abnormally elevated gut permeability in children (De Magistris et al., 2010). In a murine model of ASD, Newell et al. observed that a ketogenic diet could elevate the levels of A. muciniphila in cecal and fecal matter. This increase is associated with the alleviation of some of the neurological symptoms related to ASD (Newell et al., 2016). Using an Fmr1 knock out (KO) ASD mouse model, Goo et al. found a significant decrease in the number of A. muciniphila. However, FMT with feces from wild-type mice normalized the levels of A. muciniphila, reduced the expression level of TNF-a, and inhibited the activation of microglia cells (Goo et al., 2020). reestablishing the gut microbiota ameliorated autistic-like behaviors, especially cognitive dysfunction and deficits in social novelty preference behaviors. The beneficial effects of FMT on ASD involving the regulation of A. muciniphila, suggest that A. muciniphila might play a key role in ASD development. However, whether the decrease in A. muciniphila is an important causative factor of the autistic-like behavior observed in Fmr1 KO mice remains uncertain. Further research is required to validate this hypothesis. Recently, Liu et al. discovered that supplementation with A. muciniphila during early life could mitigate social deficits induced by exposure to valproic acid through activating dopaminergic neurons in the ventral tegmental area . These findings suggest that A. muciniphila may serve as a potential probiotic treatment for ASD, although the exact mechanism by which it influences ASD requires further investigation.

Conclusions
A. muciniphila has recently emerged as a promising potential probiotic with significant metabolic and immunological properties. It influences brain and behavioral functions through the MGBA. Mounting clinical and preclinical evidence suggest that differences in the number of A. muciniphila play an active role in the development of various neuropsychiatric disorders, such as depression, anxiety, AD, PD, MS, stroke, and ASD. Its effects are mediated through the production of neuroactive metabolites, adjustment of the gut microbiota, modulation of the gut mucosal barrier, and regulation of host immunity and metabolism. A. muciniphila is considered an important diagnostic and therapeutic target for these neuropsychiatric disorders, and could be regarded as a "friend" in terms of host microbiota. However, contradictory findings have been reported regarding the relationship between the relative abundance of A. muciniphila and several neuropsychiatric disorders, making it challenging to determine the precise role of A. muciniphila in some of these disorders. However, there is still insufficient evidence to classify A. muciniphila as a "foe" based on current studies. Nevertheless, there is still a long way to go to develop A. muciniphila as a probiotic for neuropsychiatric disorders. Most studies have focused on correlation analysis between the number of A. muciniphila and neuropsychiatric disorders, but little is known about the causal relationship. Further research utilizing germ-free neuropsychiatric disorder animal models, organoid models, specific strains of A. muciniphila, and comprehensive behavioral and immunological analyses is necessary to provide more mechanistic insights to support the use of A. muciniphila for the prevention and treatment of neuropsychiatric disorders, prior to evaluating its efficacy in human clinical trials.

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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