Abstract
Background:
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.
Results:
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.
Conclusions:
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.
Keywords:
Bile acids, High-fat diet, Gut microbiota, Obesity, Microbe-metabolite interaction
