Bile acid is a significant host factor shaping the gut microbiome of diet-induced obese mice

TLDR

Bile acids influence gut microbiota through antimicrobial activity and regulation of bile acid homeostasis via FXR signaling. The study sought to elucidate how bile acids interact with the gut microbiome and shape microbial composition. Bile acids emerged as the most potent factor driving microbiota alterations; a high‑fat diet rapidly increased intestinal bile acids and shifted microbial communities, BA supplementation induced an obese phenotype and obesity‑associated microbiota, and inhibition of bile acid synthesis or microbiota suppression alleviated obesity‑related changes.

Abstract

Intestinal bacteria are known to regulate bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulation of the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way.We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that BAs were the most significant factor correlated with microbial alterations among all types of endogenous metabolites. A high-fat diet (HFD) intervention resulted in a rapid and significant increase in the intestinal BA pool within 12 h, followed by an alteration in microbial composition at 24 h, providing supporting evidence that BAs are major dietary factors regulating gut microbiota. Feeding mice with BAs along with a normal diet induced an obese phenotype and obesity-associated gut microbial composition, similar to HFD-fed mice. Inhibition of hepatic BA biosynthesis under HFD conditions attenuated the HFD-induced gut microbiome alterations. Both inhibition of BAs and direct suppression of microbiota improved obese phenotypes.Our study highlights a liver-BA-gut microbiome metabolic axis that drives significant modifications of BA and microbiota compositions capable of triggering metabolic disorders, suggesting new therapeutic strategies targeting BA metabolism for metabolic diseases.