Gut microbiota drives the metabolic dysregulation in obesity-prone individuals by impairing GDCA-mediated activation of brown adipose thermogenesis and ileal GLP-1 secretion

Obesity-prone (OP) individuals exhibit an intrinsic predisposition to obesity and associated metabolic disorders, and early intervention in this population holds significant clinical value; however, the underlying mechanisms driving this susceptibility remain largely obscure. This study enrolled 46 OP subjects without diagnosed metabolic diseases and 35 healthy controls. Our findings revealed that, despite not reaching obesity diagnoses, OP subjects exhibited significant metabolic disturbances strongly associated with gut microbiota dysbiosis. They also displayed disturbed bile acid (BA) profiles, with depleted glycodeoxycholic acid (GDCA) identified as the most potent discriminator between the OP and healthy controls. Fecal microbiota transplantation (FMT) recapitulated metabolic dysfunction and BA pool remodeling, mediated by dysregulated hepatic expression of BA synthesis genes of <i>Cyp8a1</i>, <i>Cyp7a1</i>, and <i>Cyp7b1</i>. Notably, FMT-OP mice also phenocopied the diminished GDCA levels observed in OP subjects. GDCA supplementation in obese mice markedly improved body weight, hepatic steatosis, and metabolic dysfunction. Mechanistically, GDCA exerted anti-obesity effects by activating the TGR5 signaling, which enhanced brown adipose tissue (BAT) thermogenesis and stimulated ileal glucagon-like peptide-1 (GLP-1) secretion, thereby ameliorating obesity and associated metabolic dysregulation. Thus, these findings indicate that gut microbiota-driven dysregulation of BA signaling, particularly impaired TGR5 activation due to diminished GDCA, underlies glycolipid metabolic dysfunction in OP individuals.