AI-guided discovery and expansion of the human bile acid landscape.

MetLLM and MetSpace expanded the human bile acid landscape by generating 3,900 prioritized candidates, with LC-HRMS in human feces confirming newly detected, structurally novel bile acids including MS2141 and MS1281.

• Why it matters: The human bile acid metabolome is largely uncharted because analytical limitations can obscure potentially thousands of biologically active bile acid species in cells and biofluids.
• What they did: A transformer-based MetLLM learned bile acid modification patterns to prioritize analogs, which were compiled into MetSpace; LC-HRMS then analyzed human feces, followed by in vitro testing of MS2141 in human iPSC-derived cardiomyocytes.
• The result: MS2141 modulates M2 receptor-associated Gi/o signaling and alters electrophysiological parameters in human induced pluripotent stem cell-derived cardiomyocytes, supporting a computational framework for systematic bile acid discovery.