Intestinal Epithelial Tet2 Deficiency Reprograms the Gut Microbiota through Bile Acid Metabolic Alterations

Epigenetic mechanisms are increasingly recognized as critical regulators of host-microbiota interactions. Here, we report that intestinal epithelial-specific deletion of Tet2, a key DNA demethylase, leads to structural abnormalities, impaired barrier function, and remarkable reprogramming of the gut microbial community. Mechanistically, Tet2 deficiency significantly downregulated the expression of the apical sodium-dependent bile acid transporter (ASBT/Slc10a2), resulting in altered bile acid homeostasis with specific accumulation of hyocholic acid (HCA) in the intestinal lumen. This metabolic shift created a favorable niche for selective expansion of bile salt hydrolase (BSH)-expressing Lactobacillus species. Furthermore, we identified an age-dependent regulatory role of HCA in shaping microbial composition, promoting Lactobacillus in young mice while enriching Akkermansia in aged animals. Our findings unveil an epigenetic-metabolic-microbial axis centered on Tet2-mediated regulation of bile acid metabolism, providing new insights into how host epigenetic factors shape the gut microbial ecosystem. Overall design: The gut microbiota is shaped by host-derived factors through mechanisms that remain incompletely understood. This study demonstrates that intestinal epithelial Tet2, an epigenetic modulator, plays a pivotal role in determining gut microbial composition through regulation of bile acid metabolism. Tet2 deficiency downregulates ASBT expression, leading to altered bile acid profiles with accumulation of hyocholic acid (HCA), which in turn selectively enriches BSH-expressing Lactobacillus species. Notably, the effects of HCA on microbial communities are age-dependent. Our work establishes Tet2 as a key epigenetic regulator at the host-microbiota interface and reveals a previously unrecognized connection between DNA demethylation, bile acid transport, and microbial ecology. These findings provide a foundation for developing novel therapeutic strategies targeting the epigenetic-metabolic axis to modulate gut microbiota in diseases associated with microbial dysbiosis.