Gut Microbiota-Dependent Choline Metabolism Drives Mammary Gland Lipid Redistribution via Microbial Metabolites

The mechanisms governing lipid allocation to the mammary gland (MG) during lactation remain poorly understood, particularly across mammalian species. Here, we identify choline-an essential nutrient with established roles in liver and brain function but uncharacterized effects on lactation-as a key regulator of mammary lipid metabolism through gut microbiota and their metabolites. Using complementary yak observational studies and mouse intervention models, we show that choline supplementation and yak-derived fecal microbiota transplantation (FMT) similarly enrich the abundance of Akkermansia muciniphila (A. muciniphila), increasing lysophosphatidylcholine (LPC) and phosphatidylcholine (PC) levels. These metabolites enhance lipid accumulation in the MG of pregnant mice through CD36-mediated lipid uptake while modulating intestinal anti-inflammatory pathways, mirroring metabolic adaptations observed during human lactation. Our multi-omics analyses reveal a coordinated metabolic and immunological regulation through which gut microbiota translate dietary choline into MG lipid redistribution. These insights provide fundamental insights that bridge the gap between animal models and potential human applications, suggesting new avenues for investigating choline's role in mammalian lactation biology and nutritional interventions.