Abstract

Bile acids (BAs) have emerged as pleiotropic signaling molecules that connect gut microbiota, liver, intestine, 
and peripheral metabolic tissues. Beyond their classical role in lipid absorption, BAs act as endocrine regulators 
via receptors such as the farnesoid X receptor (FXR) and the G-protein–coupled receptor TGR5, shaping 
glucose and lipid metabolism, energy expenditure, and inflammation. Gut microbes profoundly remodel the BA 
pool through bile salt hydrolase (BSH) and other enzymes, altering receptor affinity and signaling bias. 
Dysbiosis in obesity (OB) and type 2 diabetes (T2D) perturbs this “microbiota–BA axis,”, contributing to insulin 
resistance, fatty liver, and impaired incretin responses. This review frames gut microbial BA signaling as a 
shared therapeutic axis in OB and T2D. We summarize BA synthesis and microbial transformations, then detail 
how BA receptors integrate microbial cues to control hepatic gluconeogenesis, adipose and muscle insulin 
sensitivity, incretin (GLP-1) secretion, and energy expenditure. We highlight human and preclinical data 
linking altered BA profiles and receptor activity to metabolic disease, including mechanistic insights from 
bariatric surgery, BA sequestrants, and FXR/TGR5-targeted drugs. We further discuss next-generation 
strategies that exploit microbiota-derived BA species or receptor-selective agonists, including microbial amino 
acid–conjugated BAs that stimulate GLP-1 via novel G-protein–coupled receptors. Finally, we outline 
biomarker and precision-medicine opportunities based on BA and microbiome signatures, and key knowledge 
gaps for safely manipulating this axis in chronic metabolic disease. Understanding and harnessing gut microbial 
BA signaling may allow convergent treatments that simultaneously tackle OB, T2D, and associated liver 
disease.