The mycobiome is now recognized as a critical part of the human microbial ecosystem, playing a significant role in both health and disease. Mycobiome research is currently in its infancy and relies on fungal-specific primers with challenges in bioinformatics to accurately determine the structure of the mycobiota community. In addition, the majority of computational and experimental methods currently in use have been optimized for bacteria rather than for fungi. Here, we provide a comparative analysis of extraction methodologies for metagenome sequencing and subsequent bioinformatic analysis that will enhance fungal species identification. We utilized cultured mock fungal communities, including both yeast and mold species, to evaluate the efficiency of extraction protocols. We further enhanced computational analysis of the mycobiome, using mock and human metagenome data together with our curated catalogue consisting of 984 fungal genomes specific to the human mycobiome. Application of this optimised workflow for oral and gut samples of healthy individuals detected of novel species from Puccinia and Lentinus genera among the established presence of Malassezia, Rhizophagus, Candida and Saccharomyces genera. In addition, Enterocytozoon, was identified specifically in the gut mycobiome. Our pipeline enabled the comprehensive sampling of all fungal genes in a microbial community within a human sample minimising bias, reducing errors and artefacts from amplification, and providing accurate diversity and abundance data for the human mycobiome. ### Competing Interest Statement VCP has delivered paid lectures for Norgine Pharmaceuticals Ltd and Menarini Diagnostics Ltd.

Background:Heterozygous variants in GBA1 are the commonest genetic risk factor for Parkinson's disease (PD), but penetrance is incomplete. GBA1 dysfunction can cause gastrointestinal disturbances and microbiome changes in preclinical models. Mounting evidence suggests that the microbiota-gut-brain axis is potentially implicated in PD pathogenesis. Whether the gut microbiome composition is influenced by host GBA1 genetics in heterozygosis has never been explored. Objectives:This study aimed to evaluate whether heterozygosity for the GBA1 pathogenic L444P variant can cause perturbations in gut microbiome composition. Methods:Faecal samples collected from GBA1 L444P/WT and GBA1 WT/WT mice at 3 and 6 months of age were analysed through shotgun metagenomic sequencing. Results:No differences in α- and β-diversities were detected between genotyped groups, at either time point. Overall, we found a little variation in the gut microbiome composition and functional potential between GBA1 L444P/WT and GBA1 WT/WT mice over time. Conclusion:Host GBA1 genotype does not impact gut microbiome structure and composition in the presented GBA1 L444P/WT mouse model. Studies investigating the effect of a second hit on gut physiology and microbiome composition could explain the partial penetrance of GBA1 variants in PD.

Individual lifestyle factors moderately impact the gut microbiome and host biology. This study explores whether their combined influence significantly alters the gut microbiome and determines the mediating role of the gut microbiome in the links between lifestyle and phenomes. Analyzing 1,643 individuals from the Metacardis European study, we created a non-exhaustive composite lifestyle score (QASD score) incorporating diet quality and diversity, physical activity and smoking. This score shows higher explanatory power for microbiome composition variation compared to individual lifestyle variables. It positively associates with microbiome gene richness, butyrate-producing bacteria, and serum metabolites like Hippurate linked metabolic health. It inversely associates with Clostridium bolteae and Ruminococcus gnavus, serum branched-chain amino acids and dipeptides observed in chronic diseases. Causal inference analyses found 135 cases where the microbiome mediates >20% of QASD score effects on host metabolome. Microbiome gene richness also emerged as a strong mediator in the QASD score’s impact on markers of host glucose metabolism (27.3% of the effect on HOMA- IR), despite bidirectional associations between the microbiome and clinical phenotypes. This study emphasizes the importance of combining lifestyle factors to understand their collective contribution to the gut microbiota and the mediating effects of the gut microbiome on the impact of lifestyle on host metabolic phenotypes and metabolomic profiles. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This work was supported by European Union s Seventh Framework Programme for research technological development and demonstration under grant agreement HEALTH-F4-2012-305312 (METACARDIS). Funding supports were also obtained from Leducq Foundation(17CVD01), JPI-Microdiet study (2017-01996_3). Part of the work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG): SFB 1052 (project B1) the Fondation pour la Recherche Medicale (FDT201904008276 FDT202106012793) and the French Agency of Research (ANR-CAPTOR, ANR-DeepIntegromics) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the Ethics Committee at the Medical Faculty at the University of Leipzig Germany (application number: 047-13-28012013) the ethical committees of the Capital Region of Denmark (H-3-2013-145) and the ethics committee Comite de Protection des Personnes (CPP) Ile-de-France III no.IDRCB2013-A00189-36 in France and was registered at https://clinicaltrials.gov/ ([NCT02059538][1]). The observational cohort design complied with all relevant ethical regulations, aligning with the Helsinki Declaration and in accordance with European privacy legislation. All participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Raw shotgun sequencing data that support the findings of this study have been deposited in the European Nucleotide Archive with accession codes PRJEB37249, PRJEB38742, PRJEB41311, PRJEB46098 and PRJEB71898, with public access. Metabolome data have been uploaded to Metabolights and MassIVE with respective accession numbers—that is, serum NMR and urine NMR with accession number MTBLS3429. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02059538&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F17%2F2024.01.12.24301195.atom

Species composition of the healthy adult gut microbiota tends to be stable over time. Destabilization of the gut microbiome under the influence of different factors is the main driver of the microbial dysbiosis and subsequent impacts on host physiology. Here, we used metagenomics data from a Swedish longitudinal cohort, to determine the stability of the gut microbiome and uncovered two distinct microbial species groups; persistent colonizing species (PCS) and transient colonizing species (TCS). We validated the continuation of this grouping, generating gut metagenomics data for additional time points from the same Swedish cohort. We evaluated the existence of PCS/TCS across different geographical regions and observed they are globally conserved features. To characterize PCS/TCS phenotypes, we performed bioreactor fermentation with faecal samples and metabolic modeling. Finally, using chronic disease gut metagenome and other multi-omics data, we identified roles of TCS in microbial dysbiosis and link with abnormal changes to host physiology.

The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identifiedFusobacterium nucleatumandAnaerostipes hadruswith the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts.

Over the past two decades, the gut microbiota has emerged as a key player in human health, being involved in many different clinical contexts. Yet, many aspects of the relationship with its host are poorly documented. One obstacle is the substantial variability in wet-lab procedures and data processing implemented during gut microbiota studies, which poses a challenge of comparability and potential meta-analysis. In order to better understand the relationship between health, dietary habits, and the observed heterogeneity of gut microbiota composition in the general population, « Le French Gut – Le microbiote français » aims to collect, sequence, and analyze 100,000 fecal samples from French residents using a high-quality shotgun metagenomic pipeline, complemented with comprehensive health, lifestyle, and dietary metadata. “Le French Gut – Le microbiote français” is a prospective, non-interventional French national study involving individuals , the creation of a biological collection (feces) and the exploitation of data from questionnaires and the National Health Data System (SNDS, Système National des Données de Santé). This national study is open to all metropolitan French adult residents, excluding those who have undergone a colectomy or digestive stoma, or who have had a colonoscopy or taken antibiotics in the last 3 months. This is a home-based trial in which volunteers complete a questionnaire with insights about their health, lifestyle, and dietary habits, and in which stool samples are self-collected. Recruitment has started in September 2022 and is still on going. As of July 2024, we enrolled 14160 participants. “Le French Gut” will provide a reference database and new ecosystem tools for understanding the relationship between the gut microbiota, its host and diet. It aims to find new signatures or targets and promote the design of innovative preventive strategies, personalized nutrition, and precision medicine. ClinicalTrials.gov NCT05758961. Registered on 8 March 2023. The trial was prospectively registered.

Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous β-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon.

AbstractBackgroundHeterozygous variants inGBA1are the commonest genetic risk factor for Parkinson disease (PD) but penetrance is incomplete.GBA1dysfunction can cause gastrointestinal disturbances and microbiome changes in preclinical models. Mounting evidence suggests that the microbiota-gut-brain axis is potentially implicated in PD pathogenesis. Whether the gut microbiome composition is influenced by hostGBA1genetics in heterozygosis has never been explored.ObjectivesTo evaluate whether heterozygosity for theGBA1pathogenic L444P variant can cause perturbations in gut microbiome composition.MethodsFaecal samples collected fromGBA1L444P/WTandGBA1WT/WTmice at 3 and 6 months of age were analysed through shotgun metagenomic sequencing.ResultsNo differences in α- and β-diversity were detected between genotyped groups, at either time points. Overall, we found a little variation of the gut microbiome composition and functional potential betweenGBA1L444P/WTandGBA1WT/WTmice over time.ConclusionHostGBA1genotype does not impact gut microbiome structure and composition in the presentedGBA1L444P/WTmouse model. Studies investigating the effect of a second hit on gut physiology and microbiome composition could explain the partial penetrance ofGBA1variants in PD.

Human microbiomes are essential to health throughout the lifespan and are increasingly recognized and studied for their roles in metabolic, immunological and neurological processes. Although the full complexity of these microbial communities is not fully understood, their clinical and industrial exploitation is well advanced and expanding, needing greater oversight guided by a consensus from the research community. One of the most controversial issues in microbiome research is the definition of a 'healthy' human microbiome. This concept is complicated by the microbial variability over different spatial and temporal scales along with the challenge of applying a unified definition to the spectrum of healthy microbiome configurations. In this Perspective, we examine the progress made and the key gaps that remain to be addressed to fully harness the benefits of the human microbiome. We propose a road map to expand our knowledge of the microbiome-health relationship, incorporating epidemiological approaches informed by the unique ecological characteristics of these communities.

There is increasing evidence that interactions between microbes and their hosts not only play a role in determining health and disease but also in emotions, thought, and behavior. Built environments greatly influence microbiome exposures because of their built-in highly specific microbiomes coproduced with myriad metaorganisms including humans, pets, plants, rodents, and insects. Seemingly static built structures host complex ecologies of microorganisms that are only starting to be mapped. These microbial ecologies of built environments are directly and interdependently affected by social, spatial, and technological norms. Advances in technology have made these organisms visible and forced the scientific community and architects to rethink gene-environment and microbe interactions respectively. Thus, built environment design must consider the microbiome, and research involving host-microbiome interaction must consider the built-environment. This paradigm shift becomes increasingly important as evidence grows that contemporary built environments are steadily reducing the microbial diversity essential for human health, well-being, and resilience while accelerating the symptoms of human chronic diseases including environmental allergies, and other more life-altering diseases. New models of design are required to balance maximizing exposure to microbial diversity while minimizing exposure to human-associated diseases. Sustained trans-disciplinary research across time (evolutionary, historical, and generational) and space (cultural and geographical) is needed to develop experimental design protocols that address multigenerational multispecies health and health equity in built environments.

Environmental toxicants (ETs) are associated with adverse health outcomes. Here we hypothesized that exposures to ETs are linked with obesity and insulin resistance partly through a dysbiotic gut microbiota and changes in the serum levels of secondary bile acids (BAs). Serum BAs, per- and polyfluoroalkyl substances (PFAS) and additional twenty-seven ETs were measured by mass spectrometry in 264 Danes (121 men and 143 women, aged 56.6 ± 7.3 years, BMI 29.7 ± 6.0 kg/m2) using a combination of targeted and suspect screening approaches. Bacterial species were identified based on whole-genome shotgun sequencing (WGS) of DNA extracted from stool samples. Personalized genome-scale metabolic models (GEMs) of gut microbial communities were developed to elucidate regulation of BA pathways. Subsequently, we compared findings from the human study with metabolic implications of exposure to perfluorooctanoic acid (PFOA) in PPARα-humanized mice. Serum levels of twelve ETs were associated with obesity and insulin resistance. High chemical exposure was associated with increased abundance of several bacterial species (spp.) of genus (Anaerotruncus, Alistipes, Bacteroides, Bifidobacterium, Clostridium, Dorea, Eubacterium, Escherichia, Prevotella, Ruminococcus, Roseburia, Subdoligranulum, and Veillonella), particularly in men. Conversely, females in the higher exposure group, showed a decrease abundance of Prevotella copri. High concentrations of ETs were correlated with increased levels of secondary BAs including lithocholic acid (LCA), and decreased levels of ursodeoxycholic acid (UDCA). In silico causal inference analyses suggested that microbiome-derived secondary BAs may act as mediators between ETs and obesity or insulin resistance. Furthermore, these findings were substantiated by the outcome of the murine exposure study. Our combined epidemiological and mechanistic studies suggest that multiple ETs may play a role in the etiology of obesity and insulin resistance. These effects may arise from disruptions in the microbial biosynthesis of secondary BAs.

The past decade has witnessed a transformative evolution in hu-man microbiome research,shifting from a focus on structural ge-nomics to a profound exploration of functional dynamics.Initially,the field was predominantly characterized by identifying and cataloging microbial communities through structural genomics,using genetic markers for microbial profiling,and assembling ge-nomes to understand the composition of these complex ecosys-tems.These foundational studies laid the groundwork for a deeper understanding of the human microbiome,revealing its astonishing diversity and potential roles in human health and disease.However,the narrative of microbiome research has since evolved,moving beyond mere description to embrace a functional understanding of these microbial communities.

Abstract Background and Aims Many uremic toxins (UTs) originate from gut microbiome, and contribute to chronic kidney disease (CKD) progression and cardiovascular morbidity. In order to reduce uremic symptoms and CKD progression, patients have several dietary restrictions, which may influence gut microbiome composition, and impact UTs production. An altered microbiome may contribute to UTs increase in those patients. However, the role of key bacterial taxa in producing UTs and the impact of diet on UTs variance in non-dialyzed patients are not well known. The objectives of this study were, first, to compare microbial features between CKD patients and healthy controls, and, second, to investigate the relation of gut microbiome with uremic toxicity, as well as the potential impact of diet on such relationship. Method Characterization of gut metagenomes, 10 UTs and 3 precursors’ serum concentrations by LC-MS/MS, host characteristics and diet were obtained from 240 non-dialysis CKD patients from the CKD-REIN cohort (mean ± SD): age: 68 ± 11 years, 71% male, estimated glomerular filtration rate (eGFR): 33.2 ± 12.7 ml/min/1.73m². First, to identify microbial biomarkers characterizing the gut microbiome-related toxicity in CKD, we compared microbiome features between 78 CKD patients and 78 age-, sex-, and BMI-matched healthy controls from the Milieu Interieur (MI) cohort: age: 58 ± 10 years, 60% male, eGFR: 89 ± 13. Second, we performed a multiomics’ data integration analysis via a supervised modelling to investigate cross-sectionally the association between host characteristics, gut microbiome, UTs, and diet-related features according to CKD severity (eGFR<30, n = 110 vs eGFR ≥30 mL/min/1.73m², n = 130). Results Compared to healthy controls, CKD patients had a significant reduced gut microbiome health index. Several Metagenomic Species Pan-genomes (MSPs) were significantly contrasted between MI and CKD cohorts: 43 species were enriched in CKD patients vs 24 in controls. Species most enriched in CKD patients included several UTs producers such as Lachnospiraceae spp, Dysosmobacter – Oscillibacter spp, Butyricimonas faecihominis, Victivallis vadensis and Hungatella spp, some of which were positively correlated with the following UTs: 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), trimethylamine-N-oxide (TMAO), and indole-3-acetic acid (3-IAA). Moreover, species belonging to Enterocloster and Hungatella genera (both members of Lachnospiraceae family) were found to be negatively correlated with eGFR. Among species associated with CKD severity, species carrying genes for UTs production were observed such as Desuflovibiro fairfieldensis, Bacteroides clarus and Blautia obeum along with increasing alcohol and hot drinks consumption, CRP and several UTs (kynurenic acid, indoxyl sulfate and Phenylacetylglutamine) levels. In contrast, some taxa like Faecalibacterium prausnitzii and Dysosmobacter welbionis were associated with legume intake but not with UTs. Conclusion Our study highlights an alteration of gut microbiome in CKD patients compared to healthy controls, with increased abundance of UTs producer species. The results of the multidimensional data integration modelling suggest a strong interplay between food intake, gut microbiome modifications, UTs accumulation and clinical features. These findings might open to promising therapeutic strategies to reduce microbiome-related toxicity.

BACKGROUND:The gut microbiota plays a crucial role in regulating host metabolism and producing uremic toxins in patients with end-stage renal disease (ESRD). Our objective is to advance toward a holistic understanding of the gut ecosystem and its functional capacity in such patients, which is still lacking.RESULTS:Herein, we explore the gut microbiome of 378 hemodialytic ESRD patients and 290 healthy volunteers from two independent cohorts via deep metagenomic sequencing and metagenome-assembled-genome-based characterization of their feces. Our findings reveal fundamental alterations in the ESRD microbiome, characterized by a panel of 348 differentially abundant species, including ESRD-elevated representatives of Blautia spp., Dorea spp., and Eggerthellaceae, and ESRD-depleted Prevotella and Roseburia species. Through functional annotation of the ESRD-associated species, we uncover various taxon-specific functions linked to the disease, such as antimicrobial resistance, aromatic compound degradation, and biosynthesis of small bioactive molecules. Additionally, we show that the gut microbial composition can be utilized to predict serum uremic toxin concentrations, and based on this, we identify the key toxin-contributing species. Furthermore, our investigation extended to 47 additional non-dialyzed chronic kidney disease (CKD) patients, revealing a significant correlation between the abundance of ESRD-associated microbial signatures and CKD progression.CONCLUSION:This study delineates the taxonomic and functional landscapes and biomarkers of the ESRD microbiome. Understanding the role of gut microbiota in ESRD could open new avenues for therapeutic interventions and personalized treatment approaches in patients with this condition.

Background Multiple sclerosis is a chronic immune-mediated disease of the brain and spinal cord resulting in physical and cognitive impairment in young adults. It is hypothesized that a disrupted bacterial and viral gut microbiota is a part of the pathogenesis mediating disease impact through an altered gut microbiota-brain axis. The aim of this study is to explore the characteristics of gut microbiota in multiple sclerosis and to associate it with disease variables, as the etiology of the disease remains only partially known. Methods Here, in a case-control setting involving 148 Danish cases with multiple sclerosis and 148 matched healthy control subjects, we performed shotgun sequencing of fecal microbial DNA and associated bacterial and viral microbiota findings with plasma cytokines, blood cell gene expression profiles, and disease activity. Results We found 61 bacterial species that were differentially abundant when comparing all multiple sclerosis cases with healthy controls, among which 31 species were enriched in cases. A cluster of inflammation markers composed of blood leukocytes, CRP, and blood cell gene expression of IL17A and IL6 was positively associated with a cluster of multiple sclerosis-related species. Bacterial species that were more abundant in cases with disease-active treatment-naïve multiple sclerosis were positively linked to a group of plasma cytokines including IL-22, IL-17A, IFN-β, IL-33, and TNF-α. The bacterial species richness of treatment-naïve multiple sclerosis cases was associated with number of relapses over a follow-up period of 2 years. However, in non-disease-active cases, we identified two bacterial species, Faecalibacterium prausnitzii and Gordonibacter urolithinfaciens , whose absolute abundance was enriched. These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. In addition, cases with multiple sclerosis had a higher viral species diversity and a higher abundance of Caudovirales bacteriophages . Conclusions Considerable aberrations are present in the gut microbiota of patients with multiple sclerosis that are directly associated with blood biomarkers of inflammation, and in treatment-naïve cases bacterial richness is positively associated with disease activity. Yet, the finding of two symbiotic bacterial species in non-disease-active cases that produce favorable immune-modulating compounds provides a rationale for testing these bacteria as adjunct therapeutics in future clinical trials.

ABSTRACTRecent advances in the human microbiome characterization have revealed significant oral microbial detection in stools of dysbiotic patients. However, little is known about the potential interactions of these invasive oral microorganisms with commensal intestinal microbiota and host. In this proof of concept study, we propose a new model of oral to gut invasion by the combined use of anin vitromodel simulating both the physicochemical and microbial (lumen and mucus-associated microbes) parameters of the human colon (M-ARCOL), a salivary enrichment protocol and whole metagenome shotgun sequencing. Oral invasion of the intestinal microbiota was simulated by injection of enriched saliva in thein vitrocolon model inoculated with faecal sample from the same healthy adult donor. The mucosal compartment of M-ARCOL was able to retain the highest species richness levels over time, whilst it decreased in the luminal compartment. This study also showed that oral microorganisms preferably colonized the mucosal microenvironment, suggesting potential oral-to-intestinal mucosal competitions. This new model of oral-to-gut invasion can provide useful mechanistic insights into the role of oral microbiome in various disease processes.

Anorexia nervosa (AN) is an eating disorder with a high mortality. About 95% of cases are women and it has a population prevalence of about 1%, but evidence-based treatment is lacking. The pathogenesis of AN probably involves genetics and various environmental factors, and an altered gut microbiota has been observed in individuals with AN using amplicon sequencing and relatively small cohorts. Here we investigated whether a disrupted gut microbiota contributes to AN pathogenesis. Shotgun metagenomics and metabolomics were performed on faecal and serum samples, respectively, from a cohort of 77 females with AN and 70 healthy females. Multiple bacterial taxa (for example, Clostridium species) were altered in AN and correlated with estimates of eating behaviour and mental health. The gut virome was also altered in AN including a reduction in viral-bacterial interactions. Bacterial functional modules associated with the degradation of neurotransmitters were enriched in AN and various structural variants in bacteria were linked to metabolic features of AN. Serum metabolomics revealed an increase in metabolites associated with reduced food intake (for example, indole-3-propionic acid). Causal inference analyses implied that serum bacterial metabolites are potentially mediating the impact of an altered gut microbiota on AN behaviour. Further, we performed faecal microbiota transplantation from AN cases to germ-free mice under energy-restricted feeding to mirror AN eating behaviour. We found that the reduced weight gain and induced hypothalamic and adipose tissue gene expression were related to aberrant energy metabolism and eating behaviour. Our 'omics' and mechanistic studies imply that a disruptive gut microbiome may contribute to AN pathogenesis.

BACKGROUND: Schizophrenia (SCZ) is a heterogeneous neuropsychiatric disorder for which current treatment has insufficient efficacy and severe adverse effects. The modifiable gut microbiome might be a potential target for intervention to improve neurobiological functions through the gut-microbiome-brain axis. METHODS: In this case-control study, gut microbiota of 132 patients with SCZ and increased waist circumference were compared with gut microbiota of two age-and sex-matched control groups, composed of 132 healthy individuals and 132 individuals with metabolic syndrome. Shotgun sequencing was used to characterize fecal samples at the taxonomic and functional levels. Cognition of the patients with SCZ was evaluated using the Brief Assessment of Cognition instrument.RESULTS: SCZ gut microbiota differed significantly from those of healthy control subjects and individuals with metabolic syndrome in terms of richness and global composition. SCZ gut microbiota were notably enriched in Flavonifractor plautii, Collinsella aerofaciens, Bilophila wadsworthia, and Sellimonas intestinalis, while depleted in Faecalibacterium prausnitzii, Ruminococcus lactaris, Ruminococcus bicirculans, and Veillonella rogosae. Functional potential of the gut microbiota accounted for 11% of cognition variability. In particular, the bacterial functional module for synthesizing tyrosine, a precursor for dopamine, was in SCZ cases positively associated with cognitive score (r = 0.34, q # .1).CONCLUSIONS: Overall, this study shows that the gut microbiome of patients with SCZ differs greatly from that of healthy control subjects or individuals with metabolic syndrome. Cognitive function of patients with SCZ is associated with the potential for gut bacterial biosynthesis of tyrosine, a precursor for dopamine, suggesting that gut microbiota might be an intervention target for alleviation of cognitive dysfunction in SCZ.