Guggulsterone as a modulator of the microbiota-bile acid-FXR axis: Molecular mechanisms and therapeutic potential in metabolic ageing.

Cholesterol biosynthesis and bile acid metabolism are tightly controlled by the Farnesoid X receptor (FXR), which integrates bile acid signaling with lipid, glucose, and inflammatory pathways to maintain metabolic homeostasis. Gut microbiota dysbiosis alters bile acid composition, increasing secondary bile acids that can chronically overactivate FXR, contributing to inflammatory bowel disease, metabolic syndrome, and liver-related disorders. Guggulsterone (GGS), a steroidal bioactive from Commiphora mukul, antagonizes FXR, restores bile acid synthesis via CYP7A1 induction, and modulates interconnected nuclear receptors involved in lipid metabolism and inflammation. Beyond FXR antagonism, GGS influences fat digestion and absorption and counteracts FXR-driven metabolic disturbances, highlighting its systems-level, pleiotropic mode of action. Targeted FXR antagonism guided by bile acid and microbiota profiling potentially combined with probiotics or bile acid receptor modulators positions GGS as a nutraceutical bridge toward precision medicine for dysbiosis-associated metabolic diseases.