The enterohepatic bile acid axis: from perinatal programming to metabolic collapse

The enterohepatic bile acid system undergoes profound developmental and adaptive changes that remain incompletely defined. Here, we profiled bile acid metabolism genes across hepatic ontogeny, tissue distribution, acute fasted-refed, and four chronic MASH models. Classic bile acid synthesis genes were activated in a perinatal-to-weaning wave, with the FXR-SHP feedback loop being functional from birth. In adults, synthesis and FXR-SHP regulation were strictly hepatic, while active reabsorption and FGF15 signaling were ileal, establishing clear spatial compartmentalization. Acute fasting revealed metabolic flexibility, with Shp elevation persisting even after Fxr had returned to baseline. In chronic MASH, this flexibility was lost in a model-specific manner, ranging from FXR-SHP uncoupling to transcriptional collapse. These findings establish that the bile acid metabolic program is precisely wired across development and space, flexibly tuned to acute nutritional status, and progressively dismantled under chronic metabolic injury-a transition that may represent an early event in MASH pathogenesis.