ASBT governs neonatal bile acid homeostasis early in life despite its strong ileal repression.

Neonatal bile acid metabolism is distinct from that of adults due to developmental regulation of key transporters and enzymes. The apical sodium-dependent bile acid transporter (ASBT) is transiently repressed in the intestine after birth, yet its role in neonatal bile acid homeostasis remains unclear. Here, we demonstrate that ASBT plays a crucial role in limiting fecal bile acid loss and suppressing hepatic bile acid synthesis in neonates. ASBT-deficient pups exhibited a marked decrease in serum bile acids and concomitant increase in fecal bile acids, accompanied by upregulated hepatic bile acid synthesis genes, including CYP7A1, CYP7B1, and CYP27A1. We also illuminated a tissue-specific distinction in neonatal negative feedback regulation of bile acid synthesis, with intact hepatic regulation but impaired intestinal regulation. Our study identifies ASBT as a key regulator of neonatal bile acid homeostasis despite its strong repression early in life, highlighting its role in bile acid retention and synthesis regulation.NEW & NOTEWORTHY Despite being repressed after birth, ASBT is essential for neonatal bile acid homeostasis. This study reveals that ASBT limits fecal bile acid loss and suppresses hepatic bile acid synthesis in neonates. ASBT-deficient pups showed reduced serum bile acids, increased fecal loss, and upregulation of bile acid synthesis genes. Notably, feedback regulation of bile acid synthesis was intact in the liver but impaired in the intestine, uncovering tissue-specific control mechanisms in early life.