Time-restricted feeding ameliorates type 2 diabetes via gut microbiota–bile acids-liver axis

Time-restricted feeding (TRF) improves metabolic health, yet the pathways linking feeding rhythms to host–microbe metabolic integration remain unclear. Using clinical profiling, humanized mouse models, and network analysis, we characterize a liver-driven metabolic axis mediating TRF’s benefits in type 2 diabetes (T2DM). We show that hepatic HNF4α–CYP8B1 pathway dysregulation contributes to T2DM by increasing 12α-hydroxylated bile acids and altering the gut microbial environment, specifically depleting Parabacteroides distasonis . TRF suppresses this hepatic pathway, shifting the bile acid pool toward non-12α-hydroxylated species like ursodeoxycholic acid (UDCA), thereby creating a permissive niche for the restoration of beneficial gut microbes, including P. distasonis . Although supplementation with P. distasonis or UDCA provides partial metabolic improvements, only TRF corrects the upstream hepatic driver, HNF4α. These findings suggest TRF improves T2DM by realigning the liver–bile acid–microbiota axis, highlighting feeding timing as a regulator of host and microbial metabolism.