Obesity-enriched gut microbe degrades myo-inositol and promotes lipid absorption.

Numerous studies have reported critical roles for the gut microbiota in obesity. However, the specific microbes that causally contribute to obesity and the underlying mechanisms remain undetermined. Here, we conducted shotgun metagenomic sequencing in a Chinese cohort of 631 obese subjects and 374 normal-weight controls and identified a Megamonas-dominated, enterotype-like cluster enriched in obese subjects. Among this cohort, the presence of Megamonas and polygenic risk exhibited an additive impact on obesity. Megamonas rupellensis possessed genes for myo-inositol degradation, as demonstrated in vitro and in vivo, and the addition of myo-inositol effectively inhibited fatty acid absorption in intestinal organoids. Furthermore, mice colonized with M. rupellensis or E. coli heterologously expressing the myo-inositol-degrading iolG gene exhibited enhanced intestinal lipid absorption, thereby leading to obesity. Altogether, our findings uncover roles for M. rupellensis as a myo-inositol degrader that enhances lipid absorption and obesity, suggesting potential strategies for future obesity management.

Gut microbiota regulates postprandial GLP-1 response via ileal bile acid-TGR5 signaling.

The gut microbiota interacts with intestinal epithelial cells through microbial metabolites to regulate the release of gut hormones. We investigated whether the gut microbiota affects the postprandial glucagon-like peptide-1 (GLP-1) response using antibiotic-treated mice and germ-free mice. Gut microbiome depletion completely abolished postprandial GLP-1 response in the circulation and ileum in a lipid tolerance test. Microbiome depletion did not influence the GLP-1 secretory function of primary ileal cells in response to stimulators in vitro, but dramatically changed the postprandial dynamics of endogenous bile acids, particularly ω-muricholic acid (ωMCA) and hyocholic acid (HCA). The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) but not farnesoid X receptor (FXR), participated in the regulation of postprandial GLP-1 response in the circulation and ileum, and ωMCA or HCA stimulated GLP-1 secretion via TGR5. Finally, fecal microbiota transplantation or ωMCA and HCA supplementation restored postprandial GLP-1 response. In conclusion, gut microbiota is indispensable for maintaining the postprandial GLP-1 response specifically in the ileum, and bile acid (ωMCA and HCA)-TGR5 signaling is involved in this process. This study helps to understand the essential interplay between the gut microbiota and host in regulating postprandial GLP-1 response and opens the foundation for new therapeutic targets.

Fasting and refeeding triggers specific changes in bile acid profiles and gut microbiota.

BACKGROUND: Bile acids (BAs) are closely related to nutrient supply and modified by gut microbiota. Gut microbiota perturbations shape BA composition, which further affects host metabolism. METHODS: We investigated BA profiles in plasma, feces, and liver of mice fed ad libitum, fasted for 24 h, fasted for 24 h and then refed for 24 h using ultraperformance liquid chromatography coupled to tandem mass spectrometry. Gut microbiota was measured by 16S rRNA gene sequencing. Expressions of BA biosynthesis-related genes in the liver and BA reabsorption-related genes in the ileum were analyzed. FINDINGS: Compared with the controls, unconjugated primary BAs (PBAs) and unconjugated secondary BAs (SBAs) in plasma were decreased whereas conjugated SBAs in plasma, unconjugated PBAs, unconjugated SBAs and conjugated SBAs in feces, and unconjugated SBAs in liver were increased in the fasting mice. The expression of BA biosynthesis-related genes in the liver and BA reabsorption-related genes in the ileum were decreased in the fasting mice compared with the controls. Compared with the controls, Akkermansia, Parabacteroides, Muribaculum, Eubacterium_coprostanoligenes and Muribaculaceae were increased in the fasting mice whereas Lactobacillus and Bifidobacterium were decreased. All these changes in BAs and gut microbiota were recovered under refeeding. Akkermansia was negatively correlated with plasma levels of unconjugated PBAs, unconjugated SBAs and glucose, whereas it was positively correlated with plasma conjugated SBAs, fecal unconjugated PBAs, and fecal unconjugated SBAs. CONCLUSIONS: We characterized the BA profiles, gut microbiota, and gene expression responsible for BA biosynthesis and intestinal reabsorption to explore their rapid changes in response to food availability. Our study highlighted the rapid effect of nutrient supply on BAs and gut microbiota.

CTNNB1/ß-catenin dysfunction contributes to adiposity by regulating the cross-talk of mature adipocytes and preadipocytes.

Overnutrition results in adiposity and chronic inflammation with expansion of white adipose tissue (WAT). However, genetic factors controlling fat mass and adiposity remain largely undetermined. We applied whole-exome sequencing in young obese subjects and identified rare gain-of-function mutations in CTNNB1/ß-catenin associated with increased obesity risk. Specific ablation of ß-catenin in mature adipocytes attenuated high-fat diet-induced obesity and reduced sWAT mass expansion with less proliferated Pdgfrα+ preadipocytes and less mature adipocytes. Mechanistically, ß-catenin regulated the transcription of serum amyloid A3 (Saa3), an adipocyte-derived chemokine, through ß-catenin-TCF (T-Cell-Specific Transcription Factor) complex in mature adipocytes, and Saa3 activated macrophages to secrete several factors, including Pdgf-aa, which further promoted the proliferation of preadipocytes, suggesting that ß-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of ß-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/ß-catenin pathway to combat obesity.

Commensal Bacteria-Dependent CD8αß+ T Cells in the Intestinal Epithelium Produce Antimicrobial Peptides.

The epithelium of the intestine functions as the primary "frontline" physical barrier for protection from enteric microbiota. Intraepithelial lymphocytes (IELs) distributed along the intestinal epithelium are predominantly CD8+ T cells, among which CD8αß+ IELs are a large population. In this investigation, the proportion and absolute number of CD8αß+ IELs decreased significantly in antibiotic-treated and germ-free mice. Moreover, the number of CD8αß+ IELs was correlated closely with the load of commensal microbes, and induced by specific members of commensal bacteria. Microarray analysis revealed that CD8αß+ IELs expressed a series of genes encoding potent antimicrobial peptides (AMPs), whereas CD8αß+ splenocytes did not. The antimicrobial activity of CD8αß+ IELs was confirmed by an antimicrobial-activity assay. In conclusion, microbicidal CD8αß+ IELs are regulated by commensal bacteria which, in turn, secrete AMPs that have a vital role in maintaining the homeostasis of the small intestine.