The relationship between the gut microbiota and oxidative stress in the cognitive function of schizophrenia: A pilot study in China.

Cognitive impairment is a core symptom of schizophrenia. The gut microbiota (GM) and oxidative stress may play important roles in the pathophysiological mechanisms of cognitive impairment. This study aimed to explore the relationship between GM and oxidative stress in the cognitive function of schizophrenia. GM obtained by 16S RNA sequencing and serum superoxide dismutase (SOD) levels from schizophrenia patients (N = 68) and healthy controls (HCs, N = 72) were analyzed. All psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Correlation analysis was used to explore the relationship between GM, SOD, and cognitive function. Machine learning models were used to identify potential biomarkers. Compared to HCs, the relative abundances of Collinsella, undefined Ruminococcus, Lactobacillus, Eubacterium, Mogibacterium, Desulfovibrio, Bulleidia, Succinivibrio, Corynebacterium, and Atopobium were higher in patients with schizophrenia, but Faecalibacterium, Anaerostipes, Turicibacter, and Ruminococcus were lower. In patients with schizophrenia, the positive factor, general factor, and total score of MCCB positively correlated with Lactobacillus, Collinsella, and Lactobacillus, respectively; SOD negatively correlated with Eubacterium, Collinsella, Lactobacillus, Corynebacterium, Bulleidia, Mogibacterium, and Succinivibrio, but positively correlated with Faecalibacterium, Ruminococcus, and MCCB verbal learning index scores; Faecalibacterium and Turicibacter were positively correlated with MCCB visual learning index scores and speed of processing index scores, respectively. Our findings revealed a correlation between SOD and GM and confirmed that cognitive dysfunction in patients with schizophrenia involves abnormal SOD levels and GM changes.

The Gut-Brain Axis in Schizophrenia: The Implications of the Gut Microbiome and SCFA Production.

Schizophrenia, a severe mental illness affecting about 1% of the population, manifests during young adulthood, leading to abnormal mental function and behavior. Its multifactorial etiology involves genetic factors, experiences of adversity, infection, and gene-environment interactions. Emerging research indicates that maternal infection or stress during pregnancy may also increase schizophrenia risk in offspring. Recent research on the gut-brain axis highlights the gut microbiome's potential influence on central nervous system (CNS) function and mental health, including schizophrenia. The gut microbiota, located in the digestive system, has a significant role to play in human physiology, affecting immune system development, vitamin synthesis, and protection against pathogenic bacteria. Disruptions to the gut microbiota, caused by diet, medication use, environmental pollutants, and stress, may lead to imbalances with far-reaching effects on CNS function and mental health. Of interest are short-chain fatty acids (SCFAs), metabolic byproducts produced by gut microbes during fermentation. SCFAs can cross the blood-brain barrier, influencing CNS activity, including microglia and cytokine modulation. The dysregulation of neurotransmitters produced by gut microbes may contribute to CNS disorders, including schizophrenia. This review explores the potential relationship between SCFAs, the gut microbiome, and schizophrenia. Our aim is to deepen the understanding of the gut-brain axis in schizophrenia and to elucidate its implications for future research and therapeutic approaches.

The association between greenery type and gut microbiome in schizophrenia: did all greenspaces play the equivalent role?

In recent years, attention has been focused on the benefit of greenspace on mental health, and it is suggested this link may vary with the type of greenspace. More and more studies have emphasized the influence of the gut microbiome on schizophrenia (SCZ). However, the effects of greenspaces on the gut microbiota in SCZ and the effect of different types of greenspaces on the gut microbiota remain unclear. We aim to examine if there were variations in the effects of various greenspace types on the gut microbiome in SCZ. Besides, we sink to explore important taxonomic compositions associated with different greenspace types. We recruited 243 objects with schizophrenia from Anhui Mental Health Center and collected fecal samples for 16Sr RNA gene sequencing. Three types of greenery coverage were calculated with different circular buffers (800, 1500, and 3000 m) corresponding to individual addresses. The association between greenspace and microbiome composition was analyzed with permutational analysis of variance (PERMANOVA). We conducted the linear regression to capture specific gut microbiome taxa associated with greenery coverage. Tree coverage was consistently associated with microbial composition in both 1500 m (R2 = 0.007, P = 0.030) and 3000 m (R2 = 0.007, P = 0.039). In contrast, there was no association with grass cover in any of the buffer zones. In the regression analysis, higher tree coverage was significantly correlated with the relative abundance of several taxa. Among them, tree coverage was positively associated with increased Bifidobacterium longum (ß = 1.069, P = 0.004), which was the dominant composition in the gut microbiota. The relationship between greenspace and gut microbiome in SCZ differed by the type of greenspace. Besides, "tree coverage" may present a dominant effect on the important taxonomic composition. Our findings might provide instructive evidence for the design of urban greenspace to optimize health and well-being in SCZ as well as the whole people.

Profiling gut microbiota signatures associated with the deficit subtype of schizophrenia: Findings from a case-control study.

BACKGROUND: Previous studies have reported a variety of gut microbiota alterations in patients with schizophrenia. However, none of these studies has investigated gut microbiota in patients with the deficit subtype of schizophrenia (D-SCZ) that can be characterized by primary and enduring negative symptoms. Therefore, in this study we aimed to profile gut microbiota of individuals with D-SCZ, compared to those with non-deficit schizophrenia (ND-SCZ) and healthy controls (HCs). METHODS: A total of 115 outpatients (44 individuals with D-SCZ and 71 individuals with ND-SCZ) during remission of positive and disorganization symptoms as well as 120 HCs were enrolled. Gut microbiota was analyzed using the 16 rRNA amplicon sequencing. Additionally, the levels of C-reactive protein (CRP), glucose and lipid metabolism markers were determined in the peripheral blood samples. RESULTS: Altogether 14 genera showed differential abundance in patients with D-SCZ compared to ND-SCZ and HCs, including Candidatus Soleaferrea, Eubacterium, Fusobacterium, Lachnospiraceae UCG-002, Lachnospiraceae UCG-004, Lachnospiraceae UCG-010, Libanicoccus, Limosilactobacillus, Mogibacterium, Peptococcus, Prevotella, Prevotellaceae NK3B31 group, Rikenellaceae RC9 gut group, and Slackia after adjustment for potential confounding factors. Observed alterations were significantly associated with cognitive performance in both groups of patients. Moreover, several significant correlations of differentially abundant genera with the levels of CRP, lipid profile parameters, glucose and insulin were found across all subgroups of participants. CONCLUSION: Findings from the present study indicate that individuals with D-SCZ show a distinct profile of gut microbiota alterations that is associated with cognitive performance, metabolic parameters and subclinical inflammation.

Gut and oral microbiome modulate molecular and clinical markers of schizophrenia-related symptoms: A transdiagnostic, multilevel pilot study.

Although increasing evidence links microbial dysbiosis with the risk for psychiatric symptoms through the microbiome-gut-brain axis (MGBA), the specific mechanisms remain poorly characterized. In a diagnostically heterogeneous group of treated psychiatric cases and nonpsychiatric controls, we characterized the gut and oral microbiome, plasma cytokines, and hippocampal inflammatory processes via proton magnetic resonance spectroscopic imaging (1H-MRSI). Using a transdiagnostic approach, these data were examined in association with schizophrenia-related symptoms measured by the Positive and Negative Syndrome Scale (PANSS). Psychiatric cases had significantly greater heterogeneity of gut alpha diversity and an enrichment of pathogenic taxa, like Veillonella and Prevotella, in the oral microbiome, which was an accurate classifier of phenotype. Cases exhibited significantly greater positive, negative, and general PANSS scores that uniquely correlated with bacterial taxa. Strong, positive correlations of bacterial taxa were also found with cytokines and hippocampal gliosis, dysmyelination, and excitatory neurotransmission. This pilot study supports the hypothesis that the MGBA influences psychiatric symptomatology in a transdiagnostic manner. The relative importance of the oral microbiome in peripheral and hippocampal inflammatory pathways was highlighted, suggesting opportunities for probiotics and oral health to diagnose and treat psychiatric conditions.

Comparison of gut microbiome profile in patients with schizophrenia and healthy controls - A plausible non-invasive biomarker?

The human gut microbiome regulates brain function through the microbiome-gut-brain axis and is implicated in several neuropsychiatric disorders. However, the relationship between the gut microbiome and the pathogenesis of schizophrenia (SCZ) is poorly defined, and very few studies have examined the effect of antipsychotic treatment response. We aim to study the differences in the gut microbiota among drug-naïve (DN SCZ) and risperidone-treated SCZ patients (RISP SCZ), compared to healthy controls (HCs). We recruited a total of 60 participants, from the clinical services of a large neuropsychiatric hospital, which included DN SCZ, RISP SCZ and HCs (n = 20 each). Fecal samples were analyzed using 16s rRNA sequencing in this cross-sectional study. No significant differences were found in taxa richness (alpha diversity) but microbial composition differed between SCZ patients (both DN and RISP) and HCs (PERMANOVA, p = 0.02). Linear Discriminant Analysis Effect Size (LEfSe) and Random Forest model identified the top six genera, which significantly differed in abundance between the study groups. A specific genus-level microbial panel of Ruminococcus, UCG005, Clostridium_sensu_stricto_1 and Bifidobacterium could discriminate SCZ patients from HCs with an area under the curve (AUC) of 0.79, HCs vs DN SCZ (AUC: 0.68), HCs vs RISP SCZ (AUC: 0.93) and DN SCZ vs RISP SCZ (AUC: 0.87). Our study identified distinct microbial signatures that could aid in the differentiation of DN SCZ, RISP SCZ, and HCs. Our findings contribute to a better understanding of the role of the gut microbiome in SCZ pathophysiology and suggest potential targeted interventions.

Altered fecal microbiota composition in individuals who abuse methamphetamine.

As a severe public health problem, methamphetamine (METH) abuse places a heavy burden on families and society. A growing amount of evidence has indicated communication between gut microbiota and the CNS in drug addiction, with associations to neural, endocrine and immune pathways. Thus, we searched for alterations in the gut microbiota and their potential effects in METH users through 16S rRNA gene sequencing. A decreased Shannon index indicated lower bacterial diversity in the METH users than in the age-matched control group. The gut microbial community composition in the METH users was also altered, including reductions in Deltaproteobacteria and Bacteroidaceae abundances and increases in Sphingomonadales, Xanthomonadales, Romboutsia and Lachnospiraceae abundances. Moreover, the Fusobacteria abundance was correlated with the duration of METH use. Enterobacteriaceae, Ruminococcaceae, Bacteroides, and Faecalibacterium had statistically significant correlations with items related to the positive and negative symptoms of schizophrenia and to general psychopathology in the METH users, and all have previously been reported to be altered in individuals with psychotic syndromes, especially depression. Abstraction, one of the items of the cognitive assessment, was positively related to Blautia. These findings revealed alterations in the gut microbiota of METH users, and these alterations may play a role in psychotic syndrome and cognitive impairment. Although the mechanisms behind the links between these disorders and METH abuse are unknown, the relationships may indicate similarities in the pathogenesis of psychosis induced by METH abuse and other causes, providing a new paradigm for addiction and METH use disorder treatment.

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders.

Emerging evidence indicates that gut microbiota is important in the regulation of brain activity and cognitive functions. Microbes mediate communication among the metabolic, peripheral immune, and central nervous systems via the microbiota-gut-brain axis. However, it is not well understood how the gut microbiome and neurons in the brain mutually interact or how these interactions affect normal brain functioning and cognition. We summarize the mechanisms whereby the gut microbiota regulate the production, transportation, and functioning of neurotransmitters. We also discuss how microbiome dysbiosis affects cognitive function, especially in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

Hidden Role of Gut Microbiome Dysbiosis in Schizophrenia: Antipsychotics or Psychobiotics as Therapeutics?

Schizophrenia is a chronic, heterogeneous neurodevelopmental disorder that has complex symptoms and uncertain etiology. Mounting evidence indicates the involvement of genetics and epigenetic disturbances, alteration in gut microbiome, immune system abnormalities, and environmental influence in the disease, but a single root cause and mechanism involved has yet to be conclusively determined. Consequently, the identification of diagnostic markers and the development of psychotic drugs for the treatment of schizophrenia faces a high failure rate. This article surveys the etiology of schizophrenia with a particular focus on gut microbiota regulation and the microbial signaling system that correlates with the brain through the vagus nerve, enteric nervous system, immune system, and production of postbiotics. Gut microbially produced molecules may lay the groundwork for further investigations into the role of gut microbiota dysbiosis and the pathophysiology of schizophrenia. Current treatment of schizophrenia is limited to psychotherapy and antipsychotic drugs that have significant side effects. Therefore, alternative therapeutic options merit exploration. The use of psychobiotics alone or in combination with antipsychotics may promote the development of novel therapeutic strategies. In view of the individual gut microbiome structure and personalized response to antipsychotic drugs, a tailored and targeted manipulation of gut microbial diversity naturally by novel prebiotics (non-digestible fiber) may be a successful alternative therapeutic for the treatment of schizophrenia patients.

The gut microbiome is associated with brain structure and function in schizophrenia.

The effect of the gut microbiome on the central nervous system and its possible role in mental disorders have received increasing attention. However, knowledge about the relationship between the gut microbiome and brain structure and function is still very limited. Here, we used 16S rRNA sequencing with structural magnetic resonance imaging (sMRI) and resting-state functional (rs-fMRI) to investigate differences in fecal microbiota between 38 patients with schizophrenia (SZ) and 38 demographically matched normal controls (NCs) and explored whether such differences were associated with brain structure and function. At the genus level, we found that the relative abundance of Ruminococcus and Roseburia was significantly lower, whereas the abundance of Veillonella was significantly higher in SZ patients than in NCs. Additionally, the analysis of MRI data revealed that several brain regions showed significantly lower gray matter volume (GMV) and regional homogeneity (ReHo) but significantly higher amplitude of low-frequency fluctuation in SZ patients than in NCs. Moreover, the alpha diversity of the gut microbiota showed a strong linear relationship with the values of both GMV and ReHo. In SZ patients, the ReHo indexes in the right STC (r = - 0.35, p = 0.031, FDR corrected p = 0.039), the left cuneus (r = - 0.33, p = 0.044, FDR corrected p = 0.053) and the right MTC (r = - 0.34, p = 0.03, FDR corrected p = 0.052) were negatively correlated with the abundance of the genus Roseburia. Our results suggest that the potential role of the gut microbiome in SZ is related to alterations in brain structure and function. This study provides insights into the underlying neuropathology of SZ.

The Gut Microbiome in Schizophrenia and the Potential Benefits of Prebiotic and Probiotic Treatment.

The gut microbiome (GMB) plays an important role in developmental processes and has been implicated in the etiology of psychiatric disorders. However, the relationship between GMB and schizophrenia remains unclear. In this article, we review the existing evidence surrounding the gut microbiome in schizophrenia and the potential for antipsychotics to cause adverse metabolic events by altering the gut microbiome. We also evaluate the current evidence for the clinical use of probiotic and prebiotic treatment in schizophrenia. The current data on microbiome alteration in schizophrenia remain conflicting. Longitudinal and larger studies will help elucidate the confounding effect on the microbiome. Current studies help lay the groundwork for further investigations into the role of the GMB in the development, presentation, progression and potential treatment of schizophrenia.

Targeting the microbiome-gut-brain axis for improving cognition in schizophrenia and major mood disorders: A narrative review.

Cognitive impairment has been consistently found to be a core feature of serious mental illnesses such as schizophrenia and major mood disorders (major depression and bipolar disorder). In recent years, a great effort has been made in elucidating the biological causes of cognitive deficits and the search for new biomarkers of cognition. Microbiome and gut-brain axis (MGB) hormones have been postulated to be potential biomarkers of cognition in serious mental illnesses. The main aim of this review was to synthesize current evidence on the association of microbiome and gut-brain hormones on cognitive processes in schizophrenia and major mood disorders and the association of MGB hormones with stress and the immune system. Our review underscores the role of the MGB axis on cognitive aspects of serious mental illnesses with the potential use of agents targeting the gut microbiota as cognitive enhancers. However, the current evidence for clinical trials focused on the MGB axis as cognitive enhancers in these clinical populations is scarce. Future clinical trials using probiotics, prebiotics, antibiotics, or faecal microbiota transplantation need to consider potential mechanistic pathways such as the HPA axis, the immune system, or gut-brain axis hormones involved in appetite control and energy homeostasis.

The gut microbiome and antipsychotic treatment response.

Patients with psychosis usually respond to one antipsychotic drug and not to another; one third fail to respond to any. Some patients, who initially do well, stop responding. Some develop serious side effects even at low doses. While several of the reasons for this variability are known, many are not. The aim of this review is to explore the potential role of intestinal organisms in response/non-response to antipsychotics. Much of the literature in this field is relatively new and still, for the most part, theoretical. A growing number of animal experiments and clinical trials are starting to point, however, to substantial effects of antipsychotics on the composition of gut bacteria and, reciprocally, to the effects of microbiota on the pharmacokinetics of antipsychotic medication. Because so many factors influence the constituents of the human intestine, it is difficult, at present, to sort out how much one or more either enhance or dampen the benefits of antipsychotics or the character/severity of the adverse effects they induce. Dietary and other therapies are being devised to reverse dysbiosis. If successful, such therapies plus the modification of factors that, together, are known to determine the composition of microbiota could help to maximize the effectiveness of currently available antipsychotic therapy.

The oropharyngeal microbiome is altered in individuals with schizophrenia and mania.

It is being increasingly recognized that human mucosal surfaces are not sterile but are colonized with microorganisms collectively known as the microbiome. The microbiome can alter brain functioning in humans and animals by way of a series of interactions operative in the brain-immune-gut interactome. We characterized the oropharyngeal microbiome in 316 individuals, including 121 with schizophrenia, 62 with mania, 48 with major depressive disorder, and 85 controls without a psychiatric disorder. We found that the oropharyngeal microflora of individuals with schizophrenia and individuals with mania differed from controls in composition and abundance as measured by the weighted UniFrac distance (both p < .003 adjusted for covariates and multiple comparisons). This measure in individuals with major depressive disorder did not differ from that of controls. We also identified five bacterial taxa which differed among the diagnostic groups. Three of the taxa, Neisseria subflava, Weeksellaceae, and Prevotella, were decreased in individuals with schizophrenia or mania as compared to controls, while Streptococci was increased in these groups. One taxa, Schlegelella, was only found in individuals with mania. Neisseria subflava was also positively associated with cognitive functioning as measured by the Repeatable Battery for the Assessment of Neuropsychological Status. There were no taxa significantly altered in individuals with major depression. Individuals with schizophrenia and mania have altered compositions of the oropharyngeal microbiome. An understanding of the biology of the microbiome and its effect on the brain might lead to new insights into the pathogenesis, and ultimately, the prevention and treatment of these disorders.

Analysis of the diversity of intestinal microbiome and its potential value as a biomarker in patients with schizophrenia: A cohort study.

Exploring the gut microbiota characteristics of patients with acute and remission schizophrenia (SCZ) and evaluating the potential of the gut microbiome as a non-invasive biomarker for SCZ. A total of 87 fecal samples were collected, including a total of 58 samples from 29 SCZ patients over two different periods (remission and onset period) and 29 samples from the control group for 16S rRNA Miseq.The changes of intestinal microbiota in SCZ patients from remission to onset were analyzed, and a random forest model was constructed to recognize biomarkers. The optimal three genus-level diagnosis biomarkers were identified through an AUC validation on a random forest model, furthermore, an AUC of 0.76 (95% CI (0.63, 0.89)) was achieved between 29 aSCZ and 29 HCs. Compared with the control group, the first 11 OUT-level' biomarkers were identified in rSCZ group. As a status marker of the disease, the AUC of 0.7 (95% CI (0.56, 0.84)) was achieved between 29 rSCZ and 29 HCs. There were differences between SCZ patients and HCs, acute and remission patients as well, suggesting that the potential of the gut microbiota as a non-invasive diagnostic tool. Moreover, the features of the gut microbiome of SCZ provide clues for disease prognosis assessment and targeted intervention.

Microbiota-Orientated Treatments for Major Depression and Schizophrenia.

BACKGROUND AND SIGNIFICANCE: There is a need to develop new hypothesis-driven treatment for both both major depression (MD) and schizophrenia in which the risk of depression is 5 times higher than the general population. Major depression has been also associated with poor illness outcomes including pain, metabolic disturbances, and less adherence. Conventional antidepressants are partly effective, and 44% of the subjects remain unremitted under treatment. Improving MD treatment efficacy is thus needed to improve the SZ prognosis. Microbiota-orientated treatments are currently one of the most promising tracks. METHOD: This work is a systematic review synthetizing data of arguments to develop microbiota-orientated treatments (including fecal microbiota transplantation (FMT)) in major depression and schizophrenia. RESULTS: The effectiveness of probiotic administration in MD constitutes a strong evidence for developing microbiota-orientated treatments. Probiotics have yielded medium-to-large significant effects on depressive symptoms, but it is still unclear if the effect is maintained following probiotic discontinuation. Several factors may limit MD improvement when using probiotics, including the small number of bacterial strains administered in probiotic complementary agents, as well as the presence of a disturbed gut microbiota that probably limits the probiotics' impact. FMT is a safe technique enabling to improve microbiota in several gut disorders. The benefit/risk ratio of FMT has been discussed and has been recently improved by capsule administration. CONCLUSION: Cleaning up the gut microbiota by transplanting a totally new human gut microbiota in one shot, which is referred to as FMT, is likely to strongly improve the efficacy of microbiota-orientated treatments in MD and schizophrenia and maintain the effect over time. This hypothesis should be tested in future clinical trials.

Metagenome-wide association of gut microbiome features for schizophrenia.

Evidence is mounting that the gut-brain axis plays an important role in mental diseases fueling mechanistic investigations to provide a basis for future targeted interventions. However, shotgun metagenomic data from treatment-naïve patients are scarce hampering comprehensive analyses of the complex interaction between the gut microbiota and the brain. Here we explore the fecal microbiome based on 90 medication-free schizophrenia patients and 81 controls and identify a microbial species classifier distinguishing patients from controls with an area under the receiver operating characteristic curve (AUC) of 0.896, and replicate the microbiome-based disease classifier in 45 patients and 45 controls (AUC = 0.765). Functional potentials associated with schizophrenia include differences in short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters. Transplantation of a schizophrenia-enriched bacterium, Streptococcus vestibularis, appear to induces deficits in social behaviors, and alters neurotransmitter levels in peripheral tissues in recipient mice. Our findings provide new leads for further investigations in cohort studies and animal models.

Host-parasite interaction associated with major mental illness.

Clinical studies frequently report that patients with major mental illness such as schizophrenia and bipolar disorder have co-morbid physical conditions, suggesting that systemic alterations affecting both brain and peripheral tissues might underlie the disorders. Numerous studies have reported elevated levels of anti-Toxoplasma gondii (T. gondii) antibodies in patients with major mental illnesses, but the underlying mechanism was unclear. Using multidisciplinary epidemiological, cell biological, and gene expression profiling approaches, we report here multiple lines of evidence suggesting that a major mental illness-related susceptibility factor, Disrupted in schizophrenia (DISC1), is involved in host immune responses against T. gondii infection. Specifically, our cell biology and gene expression studies have revealed that DISC1 Leu607Phe variation, which changes DISC1 interaction with activating transcription factor 4 (ATF4), modifies gene expression patterns upon T. gondii infection. Our epidemiological data have also shown that DISC1 607 Phe/Phe genotype was associated with higher T. gondii antibody levels in sera. Although further studies are required, our study provides mechanistic insight into one of the few well-replicated serological observations in major mental illness.

Investigation of the Gut Microbiome in Patients with Schizophrenia and Clozapine-Induced Weight Gain: Protocol and Clinical Characteristics of First Patient Cohorts.

BACKGROUND: Emerging evidence suggests an important role of the human gut microbiome in psychiatry and neurodevelopmental disorders. An increasing body of literature based on animal studies has reported that the gut microbiome influences brain development and behavior by interacting with the gut-brain axis. Furthermore, as the gut microbiome has an important role in metabolism and is known to interact with pharmaceuticals, recent evidence suggests a role for the microbiome in antipsychotic-induced metabolic side effects in animals and humans. PURPOSE: Here we present the protocol for a two-phase study investigating the gut microbiome in healthy controls and in patients with schizophrenia treated with antipsychotics. METHODS: Phase I of our study involves humans exclusively. We recruit 25 patients who are chronically treated with clozapine and compare them with 25 healthy controls matched for age, sex, BMI, and smoking status. A second cohort consists of 25 patients newly starting on clozapine, and a third cohort includes 25 antipsychotic-naive patients. The patients in the second cohort and third cohort are prospectively assessed for up to 6 and 12 weeks, respectively. Phase II of this study will incorporate microbiota humanized mouse models to examine the influence of human fecal transplant on metabolic parameters and the gut-brain axis. Progress and Future Directions: We are underway with the first participants enrolled in all phase I treatment cohorts. This study will contribute to elucidating the role of the gut microbiome in schizophrenia and metabolic side effects. In addition, its results may help to explore potential therapeutic targets for antipsychotic-induced metabolic side effects.

Epidemiological Studies of Prenatal and Childhood Infection and Schizophrenia.

Certain infectious agents can target the brain and interfere with its growth, development, and/or function. A number of studies indicate that exposure to common infectious agents during fetal and postnatal life may also contribute to the later development of schizophrenia and other non-affective psychoses. Epidemiological studies of maternal infections during pregnancy have provided somewhat contradictory results with regard to infections in general but have reported surprisingly consistent associations with specific maternal exposures such as Toxoplasma gondii. Childhood is also beginning to emerge as a sensitive period for the influence of infections including infectious agents not known to target the brain. Recent studies have associated childhood infections not only with a later diagnosis of schizophrenia but also with impaired cognitive function. Importantly, independent studies indicate that the associations between early life infection and the later development of schizophrenia are not explained by factors shared between related individuals or by genetic liability for schizophrenia.