Microbiota-induced obesity requires farnesoid X receptor

TLDR

The gut microbiota is linked to obesity, with bile acid alterations and farnesoid X receptor (FXR) signaling implicated in metabolic dysfunction. This study examined whether microbiota‑driven obesity and related traits are mediated through FXR. Wild‑type and Fxr‑/‑ mice, both germ‑free and conventionally raised, were fed a high‑fat diet for 10 weeks while weight, glucose metabolism, microbiota, bile acids, beta‑cell mass, adipose macrophages, liver steatosis, and target gene expression were monitored, and microbiota were transferred to germ‑free wild‑type mice. Microbiota promoted weight gain and hepatic steatosis in an FXR‑dependent manner, with altered bile acid profiles and increased beta‑cell mass, adipose inflammation, steatosis, and lipid‑uptake gene expression, and the obese phenotype was transferable via caecal microbiota transplantation, indicating FXR’s role in obesity through microbiota modulation.

Abstract

Objective The 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. Design We 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. Results The 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. Conclusions Our 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.