Bile Acid Metabolism as a Unifying Readout for Diet, Microbiome Function, and Gastrointestinal Disease

Bile acid biology has advanced through significant conceptual shifts. Once understood primarily as biological detergents, bile acids are now recognized as signaling molecules and, more recently, as a chemically diverse set of host- and microbe-derived metabolites. The 2020 discovery of microbially conjugated bile acids (MCBAs) and the expansion of the recognized catalog from approximately 20 species to more than 200 mark a new phase in this trajectory. Clinical translation has not kept up. Direct farnesoid X receptor (FXR) agonism failed twice in trials for non-alcoholic steatohepatitis, later received a serious liver injury safety communication from the U.S. Food and Drug Administration, and was voluntarily withdrawn from the United States market. The standard of care for bile acid diarrhea and post-cholecystectomy diarrhea still relies largely on chemical binding with drugs introduced in the 1960s and 1970s. This Perspective argues that the gap between bile acid biology and bile acid medicine persists in part because the field has not been organized around the bile acid pool as a shared measurable output. Researchers studying dietary modulators of the gut microbiome have worked in separate communities around fiber, fermented foods, polyphenols, protein, and dietary fat. Each of these inputs can shape bile acid metabolism, yet many intervention studies do not measure it. The most immediately implementable bile acid-targeted strategy is specified dietary intervention designed with measurable bile acid outcomes and evaluated with the precision of pharmacological therapy. Four recommendations follow: intervention studies should routinely measure bile acid outcomes; clinicians should test bile acid metabolism in conditions involving dysregulation; regulators should develop a framework for multicomponent dietary therapies; and researchers should build infrastructure for population-scale longitudinal monitoring.