Maternal diet shapes milk bile acids to regulate neonatal growth through TGR5

Maternal diet is critical in shaping neonatal metabolism and long-term health by governing breast milk composition. Although bile acids are present in breast milk, their functional role in infant development is not well understood. We identify enteromammary trafficking as the primary source of milk bile acids and show that this pool is modifiable by maternal diet. We also find that maternal bile acids regulate infant growth and levels of the growth-promoting hormone insulin-like growth factor 1 (IGF-1). Remarkably, maternal bile acid sequestration completely prevents excess weight gain in offspring nursed by dams on a high-fat diet. Supplementation with a bile acid or an agonist of the bile acid receptor TGR5 restores growth. Furthermore, TGR5-deficient pups phenocopy the maternal sequestration phenotype, supporting the model that maternal milk bile acids activate neonatal TGR5 to promote infant growth. Altogether, these findings reveal milk bile acids as active metabolic signals with potential for nutritional intervention in early-life programming.