Exposure to environmental toxicants is associated with gut microbiome dysbiosis, insulin resistance and obesity.

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.

Alteration of Gut Microbiome in Patients With Schizophrenia Indicates Links Between Bacterial Tyrosine Biosynthesis and Cognitive Dysfunction.

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 (ρ = 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.

The gut microbiota in multiple sclerosis varies with disease activity.

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-ß, 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.

Diet Supplementation with NUTRIOSE, a Resistant Dextrin, Increases the Abundance of Parabacteroides distasonis in the Human Gut.

SCOPE: An imbalance of the gut microbiota ("dysbiosis") is associated with numerous chronic diseases, and its modulation is a promising novel therapeutic approach. Dietary supplementation with soluble fiber is one of several proposed modulation strategies. This study aims at confirming the impact of the resistant dextrin NUTRIOSE (RD), a soluble fiber with demonstrated beneficial health effects, on the gut microbiota of healthy individuals. METHODS AND RESULTS: Fifty healthy women are enrolled and supplemented daily with either RD (n = 24) or a control product (n = 26) during 6 weeks. Characterization of the fecal metagenome with shotgun sequencing reveals that RD intake dramatically increases the abundance of the commensal bacterium Parabacteroides distasonis. Furthermore, presence in metagenomes of accessory genes from P. distasonis, coding for susCD (a starch-binding membrane protein complex) is associated with a greater increase of the species. This suggests that response to RD might be strain-dependent. CONCLUSION: Supplementation with RD can be used to specifically increase P. distasonis in gut microbiota of healthy women. The magnitude of the response may be associated with fiber-metabolizing capabilities of strains carried by subjects. Further research will seek to confirm that P. distasonis directly modulates the clinical effects observed in other studies.

Long-term diosmectite use does not alter the gut microbiota in adults with chronic diarrhea.

BACKGROUND: Diosmectite, a natural colloidal clay, has been used worldwide for a number of approved indications, including the treatment of chronic functional diarrhea. Here, we used high-resolution whole metagenome shotgun sequencing to assess the impact of a 5 weeks administration of diosmectite (3 g/sachet, 3 sachets/day) on the fecal microbiota of 35 adults with functional chronic diarrhea. RESULTS: Gut microbiota was not impacted by diosmectite administration. In particular, richness remained stable and no microbial species displayed a significant evolution. Segregating patients either by diosmectite response (non responder, early responder, late responder) or by nationality (Great-Britain or Netherlands) yielded the same results. CONCLUSION: We concluded that no microbiota-related physiological alterations are expected upon long-term treatment with diosmectite. TRIAL REGISTRATION: Clinicaltrials.gov NCT03045926.

A catalog of microbial genes from the bovine rumen unveils a specialized and diverse biomass-degrading environment.

BACKGROUND: The rumen microbiota provides essential services to its host and, through its role in ruminant production, contributes to human nutrition and food security. A thorough knowledge of the genetic potential of rumen microbes will provide opportunities for improving the sustainability of ruminant production systems. The availability of gene reference catalogs from gut microbiomes has advanced the understanding of the role of the microbiota in health and disease in humans and other mammals. In this work, we established a catalog of reference prokaryote genes from the bovine rumen. RESULTS: Using deep metagenome sequencing we identified 13,825,880 non-redundant prokaryote genes from the bovine rumen. Compared to human, pig, and mouse gut metagenome catalogs, the rumen is larger and richer in functions and microbial species associated with the degradation of plant cell wall material and production of methane. Genes encoding enzymes catalyzing the breakdown of plant polysaccharides showed a particularly high richness that is otherwise impossible to infer from available genomes or shallow metagenomics sequencing. The catalog expands the dataset of carbohydrate-degrading enzymes described in the rumen. Using an independent dataset from a group of 77 cattle fed 4 common dietary regimes, we found that only <0.1% of genes were shared by all animals, which contrast with a large overlap for functions, i.e., 63% for KEGG functions. Different diets induced differences in the relative abundance rather than the presence or absence of genes, which explains the great adaptability of cattle to rapidly adjust to dietary changes. CONCLUSIONS: These data bring new insights into functions, carbohydrate-degrading enzymes, and microbes of the rumen to complement the available information on microbial genomes. The catalog is a significant biological resource enabling deeper understanding of phenotypes and biological processes and will be expanded as new data are made available.

A reference gene catalogue of the pig gut microbiome.

The pig is a major species for livestock production and is also extensively used as the preferred model species for analyses of a wide range of human physiological functions and diseases1. The importance of the gut microbiota in complementing the physiology and genome of the host is now well recognized2. Knowledge of the functional interplay between the gut microbiota and host physiology in humans has been advanced by the human gut reference catalogue3,4. Thus, establishment of a comprehensive pig gut microbiome gene reference catalogue constitutes a logical continuation of the recently published pig genome5. By deep metagenome sequencing of faecal DNA from 287 pigs, we identified 7.7 million non-redundant genes representing 719 metagenomic species. Of the functional pathways found in the human catalogue, 96% are present in the pig catalogue, supporting the potential use of pigs for biomedical research. We show that sex, age and host genetics are likely to influence the pig gut microbiome. Analysis of the prevalence of antibiotic resistance genes demonstrated the effect of eliminating antibiotics from animal diets and thereby reducing the risk of spreading antibiotic resistance associated with farming systems.

Stress responses in lactic acid bacteria.

Lactic acid bacteria (LAB) constitute a heterogeneous group of bacteria that are traditionally used to produce fermented foods. The industrialization of food bio-transformations increased the economical importance of LAB, as they play a crucial role in the development of the organoleptique and hygienic quality of fermented products. Therefore, the reliability of starter strains in terms of quality and functional properties (important for the development of aroma and texture), but also in terms of growth performance and robustness has become essential. These strains should resist to adverse conditions encountered in industrial processes, for example during starter handling and storage (freeze-drying, freezing or spray-drying). The development of new applications such as life vaccines and probiotic foods reinforces the need for robust LAB since they may have to survive in the digestive tract, resist the intestinal flora, maybe colonize the digestive or uro-genital mucosa and express specific functions under conditions that are unfavorable to growth (for example, during stationary phase or storage). Also in nature, the ability to quickly respond to stress is essential for survival and it is now well established that LAB, like other bacteria, evolved defense mechanisms against stress that allow them to withstand harsh conditions and sudden environmental changes. While genes implicated in stress responses are numerous, in LAB the levels of characterization of their actual role and regulation differ widely between species. The functional conservation of several stress proteins (for example, HS proteins, Csp, etc) and of some of their regulators (for example, HrcA, CtsR) renders even more striking the differences that exist between LAB and the classical model micro-organisms. Among the differences observed between LAB species and B. subtilis, one of the most striking is the absence of a sigma B orthologue in L. lactis ssp. lactis as well as in at least two streptococci and probably E. faecalis. The overview of LAB stress responses also reveals common aspects of stress responses. As in other bacteria, adaptive responses appear to be a usual mode of stress protection in LAB. However, the cross-protection to other stress often induced by the expression of a given adaptive response, appears to vary between species. This observation suggests that the molecular bases of adaptive responses are, at least in part, species (or even subspecies) specific. A better understanding of the mechanisms of stress resistance should allow to understand the bases of the adaptive responses and cross protection, and to rationalize their exploitation to prepare LAB to industrial processes. Moreover, the identification of crucial stress related genes will reveal targets i) for specific manipulation (to promote or limit growth), ii) to develop tools to screen for tolerant or sensitive strains and iii) to evaluate the fitness and level of adaptation of a culture. In this context, future genome and transcriptome analyses will undoubtedly complement the proteome and genetic information available today, and shed a new light on the perception of, and the response to, stress by lactic acid bacteria.