Maternal cold exposure improves offspring metabolic health via a milk lithocholic acid-microbiota-Th17 axis

Metabolic diseases are rising with a trend toward earlier onset, yet effective preventive strategies remain limited. While cold exposure improves metabolic health in adults, its role during pregnancy in shaping offspring metabolic outcomes remains unknown. Herein, we demonstrate that maternal cold exposure in early pregnancy markedly improved offspring glucose tolerance, insulin sensitivity, and hepatic lipid metabolism when challenged with a Western diet, and the benefits persisted into late adulthood. Transcriptomic and immunophenotyping analyses revealed that offspring with cold-exposed dams exhibited suppressed Th17 activity and IL-17 signaling. Cross-fostering and metabolomics identified elevated lithocholic acid (LCA) in maternal milk as a critical mediator of these effects. LCA supplementation recapitulates these benefits through gut microbiota-dependent conversion to 3-oxo-LCA. Furthermore, Clostridium scindens supplementation enhanced 3-oxo-LCA production, suppressed Th17 responses, and alleviated diet-induced hepatic steatosis. Clinically, analysis of the UK Biobank cohort showed that winter conception was associated with a lower risk of metabolic dysfunction-associated steatotic liver disease in offspring. A similar association was observed in the CHARLS cohort in colder northern China. Together, these results identify a maternal cold-microbiota-bile acid-Th17 axis that programs offspring metabolic health and highlight microbial bile acid metabolism as a potential therapeutic target for metabolic diseases.