Microbiota-induced obesity requires farnesoid X receptor

Abstract

ObjectiveThe gut microbiota has been implicated as an environmental factor that modulates obesity, and recent evidence suggests that microbiota-mediated changes in bile acid profiles and signalling through the bile acid nuclear receptor farnesoid X receptor (FXR) contribute to impaired host metabolism. Here we investigated if the gut microbiota modulates obesity and associated phenotypes through FXR.DesignWe fed germ-free (GF) and conventionally raised (CONV-R) wild-type and Fxr−/− mice a high-fat diet (HFD) for 10 weeks. We monitored weight gain and glucose metabolism and analysed the gut microbiota and bile acid composition, beta-cell mass, accumulation of macrophages in adipose tissue, liver steatosis, and expression of target genes in adipose tissue and liver. We also transferred the microbiota of wild-type and Fxr-deficient mice to GF wild-type mice.ResultsThe gut microbiota promoted weight gain and hepatic steatosis in an FXR-dependent manner, and the bile acid profiles and composition of faecal microbiota differed between Fxr−/− and wild-type mice. The obese phenotype in colonised wild-type mice was associated with increased beta-cell mass, increased adipose inflammation, increased steatosis and expression of genes involved in lipid uptake. By transferring the caecal microbiota from HFD-fed Fxr−/− and wild-type mice into GF mice, we showed that the obesity phenotype was transferable.ConclusionsOur results indicate that the gut microbiota promotes diet-induced obesity and associated phenotypes through FXR, and that FXR may contribute to increased adiposity by altering the microbiota composition.

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

“…Interestingly, transient low-dose antibiotic treatment in early life is sufficient to evoke changes in the composition of the gut microbiota, inducing sustained effects on body composition and enhancing diet-induced obesity [35]. Colonization experiments with germ-free mouse models revealed that this host-microbiota metabolic interaction, promoting diet-induced obesity, is a transferrable trait [35,36]. In more detailed mechanistic studies with germ-free mice lacking the bile acid sensing farnesoid X nuclear receptor, signaling effects of microbiota-derived secondary bile acids were proposed as a central metabolic hub that is responsible for the contribution of gut microbiota in the development of diet-induced obesity [36,37].…”

“…Colonization experiments with germ-free mouse models revealed that this host-microbiota metabolic interaction, promoting diet-induced obesity, is a transferrable trait [35,36]. In more detailed mechanistic studies with germ-free mice lacking the bile acid sensing farnesoid X nuclear receptor, signaling effects of microbiota-derived secondary bile acids were proposed as a central metabolic hub that is responsible for the contribution of gut microbiota in the development of diet-induced obesity [36,37]. The so far identified microbiotadriven mechanisms, contributing to obesity by modulating host energy balance, were recently reviewed [38].…”

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…Recent evidence indicates that these changes occur in NAFLD and have potentially adverse effects on liver physiology. Altered intestinal bile acid metabolism impairs hepatic and extrahepatic signaling pathways that include the farnesoid X receptor (FXR) and the G-protein-coupled bile salt receptor TGR5, which normally mediate anti-steatotic, anti-inflammatory, and anti-fibrotic effects [65,66]. Moreover, weakening of the intestinal epithelial barrier may promote translocation of PAMPs into the portal circulation, stimulating the liver inflammatory response and disturbing sinusoidal homeostasis [48].…”

Farnesoid X receptor (FXR) as a potential therapeutic target in nonalcoholic fatty liver disease and associated syndromes

“…Желчные кислоты могут влиять на состав микробиома как напрямую, реа-лизуя свою антимикробную функцию, так и при помощи FXR-индуцируе мой продукции антимикробных пепти-дов, таких как ангиогенин [6,7]. Исследования, прове-денные на гнотобионтных мышах дикого типа и мышах с генетическими дефектами в FXR, продемонстрировали, что изменения в составе желчных кислот, обусловлен-ные микробиотой кишечника, предрасполагают к разви-тию ожирения, НАЖБП и НАСГ [7].…”