Ionizing radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, and cerebrovascular injuries. We investigated a population of mice that recovered from high-dose radiation to live normal life spans. These “elite-survivors” harbored distinct gut microbiota that developed after radiation and protected against radiation-induced damage and death in both germ-free and conventionally housed recipients. Elevated abundances of members of the bacterial taxa Lachnospiraceae and Enterococcaceae were associated with postradiation restoration of hematopoiesis and gastrointestinal repair. These bacteria were also found to be more abundant in leukemia patients undergoing radiotherapy, who also displayed milder gastrointestinal dysfunction. In our study in mice, metabolomics revealed increased fecal concentrations of microbially derived propionate and tryptophan metabolites in elite-survivors. The administration of these metabolites caused long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in proinflammatory responses.

Environmental factors, mucosal permeability and defective immunoregulation drive overactive immunity to a subset of resident intestinal bacteria that mediate multiple inflammatory conditions. GUT-103 and GUT-108, live biotherapeutic products rationally designed to complement missing or underrepresented functions in the dysbiotic microbiome of IBD patients, address upstream targets, rather than targeting a single cytokine to block downstream inflammation responses. GUT-103, composed of 17 strains that synergistically provide protective and sustained engraftment in the IBD inflammatory environment, prevented and treated chronic immune-mediated colitis. Therapeutic application of GUT-108 reversed established colitis in a humanized chronic T cell-mediated mouse model. It decreased pathobionts while expanding resident protective bacteria; produced metabolites promoting mucosal healing and immunoregulatory responses; decreased inflammatory cytokines and Th-1 and Th-17 cells; and induced interleukin-10-producing colonic regulatory cells, and IL-10-independent homeostatic pathways. We propose GUT-108 for treating and preventing relapse for IBD and other inflammatory conditions characterized by unbalanced microbiota and mucosal permeability.

Inflammatory bowel disease (IBD) has stimulated much interest due to its surging incidences and health impacts in the U.S. and worldwide. However, the exact cause of IBD remains incompletely understood, and biomarker is lacking towards early diagnostics and effective therapy assessment. To tackle these, the emerging high-resolution mass spectrometry (HRMS)-based metabolomics shows promise. Here, we conducted a pilot untargeted LC/MS metabolomic profiling in Crohn’s disease, for which serum samples of both active and inactive cases were collected, extracted, and profiled by a state-of-the-art compound identification workflow. Results show a distinct metabolic profile of Crohn’s from control, with most metabolites downregulated. The identified compounds are structurally diverse, pointing to important pathway perturbations ranging from energy metabolism (e.g., β-oxidation of fatty acids) to signaling cascades of lipids (e.g., DHA) and amino acid (e.g., L-tryptophan). Importantly, an integral role of gut microbiota in the pathogenesis of Crohn’s disease is highlighted. Xenobiotics and their biotransformants were widely detected, calling for massive exposomic profiling for future cohort studies as such. This study endorses the analytical capacity of untargeted metabolomics for biomarker development, cohort stratification, and mechanistic interpretation; the findings might be valuable for advancing biomarker research and etiologic inquiry in IBD.

The mammalian gut harbors a complex and dynamic microbial ecosystem: the microbiota. While emerging studies support that microbiota regulates brain function with a few molecular cues suggested, the overall biochemical landscape of the “microbiota-gut-brain axis” remains largely unclear. Here we use high-coverage metabolomics to comparatively profile feces, blood sera, and cerebral cortical brain tissues of germ-free C57BL/6 mice and their age-matched conventionally raised counterparts. Results revealed for all three matrices metabolomic signatures owing to microbiota, yielding hundreds of identified metabolites including 533 altered for feces, 231 for sera, and 58 for brain with numerous significantly enriched pathways involving aromatic amino acids and neurotransmitters. Multicompartmental comparative analyses single out microbiota-derived metabolites potentially implicated in interorgan transport and the gut-brain axis, as exemplified by indoxyl sulfate and trimethylamine-N-oxide. Gender-specific characteristics of these landscapes are discussed. Our findings may be valuable for future research probing microbial influences on host metabolism and gut-brain communication.

Although artificial sweeteners are widely used in food industry, their effects on human health remain a controversy. It is known that the gut microbiota plays a key role in human metabolism and recent studies indicated that some artificial sweeteners such as saccharin could perturb gut microbiome and further affect host health, such as inducing glucose intolerance. Neotame is a relatively new low-caloric and high-intensity artificial sweetener, approved by FDA in 2002. However, the specific effects of neotame on gut bacteria are still unknown. In this study, we combined high-throughput sequencing and gas chromatography–mass spectrometry (GC-MS) metabolomics to investigate the effects of neotame on the gut microbiome and fecal metabolite profiles of CD-1 mice. We found that a four-week neotame consumption reduced the alpha-diversity and altered the beta-diversity of the gut microbiome. Firmicutes was largely decreased while Bacteroidetes was significantly increased. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis also indicated that the control mice and neotame-treated mice have different metabolic patterns and some key genes such as butyrate synthetic genes were decreased. Moreover, neotame consumption also changed the fecal metabolite profiles. Dramatically, the concentrations of multiple fatty acids, lipids as well as cholesterol in the feces of neotame-treated mice were consistently higher than controls. Other metabolites, such as malic acid and glyceric acid, however, were largely decreased. In conclusion, our study first explored the specific effects of neotame on mouse gut microbiota and the results may improve our understanding of the interaction between gut microbiome and neotame and how this interaction could influence the normal metabolism of host bodies.

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ObjectiveConflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient (mdr2−/−) mice and microbial profiles in PSC patient cohorts.DesignWe measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2−/− mice and targeted metagenomic analysis in PSC patients.ResultsGF mdr2−/− mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2−/− mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2−/− mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients’ clinical severity by Mayo risk scores.ConclusionsWe identified novel functionally protective and detrimental resident bacterial species in mdr2−/− mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.

Background:Arsenic-induced liver X receptor/retinoid X receptor (LXR/RXR) signaling inhibition is a potential mechanism underlying the cardiovascular effects caused by arsenic. The gut microbiota can influence arsenic toxic effects.Objective:We aimed to explore whether gut microbiota play a role in arsenic-induced LXR/RXR signaling inhibition and the subsequent lipid and cholesterol dysbiosis.Methods:Conventional and antibiotic-treated mice (AB-treated mice) were exposed to 0.25  ppm and 1  ppm arsenic for 2 wk. Hepatic mRNAs were extracted and sequenced. The expression levels of genes associated with LXR/RXR signaling were quantified by quantitative real-time polymerase chain reaction (qPCR), and serum and hepatic cholesterol levels were measured. Liquid chromatography–mass spectrometry (LC-MS)–based lipidomics were used to examine serum and hepatic lipids.Results:Pathway analysis indicated that arsenic exposure differentially influenced the hepatic signaling pathways in conventional and AB-treated mice. The expression of sterol regulatory element-binding protein 1 (Srebp1c), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), and cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), as well as cholesterol efflux genes, including ATP binding cassette subfamily G member 5/8 (Abcg5/8) and cluster of differentiation 36 (Cd36), was lower in arsenic-exposed conventional mice but not in AB-treated mice. Similarly, under arsenic exposure, the hepatic expression of scavenger receptor class B member 1 (Scarb1), which is involved in reverse cholesterol transport (RCT), was lower in conventional mice, but was higher in AB-treated animals compared with controls. Correspondingly, arsenic exposure exerted opposite effects on the serum cholesterol levels in conventional and AB-treated mice, i.e., higher serum cholesterol levels in conventional mice but lower levels in AB-treated mice than in respective controls. Serum lipid levels, especially triglyceride (TG) levels, were higher in conventional mice exposed to 1  ppm arsenic, while arsenic exposure did not significantly affect the serum lipids in AB-treated mice. Liver lipid patterns were also differentially perturbed in a microbiota-dependent manner.Conclusions:Our results suggest that in mice, the gut microbiota may be a critical factor regulating arsenic-induced LXR/RXR signaling perturbation, suggesting that modulation of the gut microbiota might be an intervention strategy to reduce the toxic effects of arsenic on lipid and cholesterol homeostasis. https://doi.org/10.1289/EHP4415