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, yet their specific roles in gut homeostasis remain elusive. Here, we demonstrate that intestinal epithelial-specific deletion of the DNA demethylase Tet2 leads to structural abnormalities, impaired barrier function, and remarkable reprogramming of the gut microbiota. Mechanistically, Tet2 deficiency downregulated the apical sodium-dependent bile acid transporter ASBT/Slc10a2, resulting in altered bile acid homeostasis with luminal accumulation of hyocholic acid (HCA). This metabolic shift created a favorable niche for the selective expansion of bile salt hydrolase (BSH)-expressing Lactobacillus species. Furthermore, we identified an age-dependent regulatory role of HCA, which promoted Lactobacillus in young mice but enriched Akkermansia in aged animals. Our findings establish an epigenetic-metabolic-microbial axis centered on Tet2-mediated bile acid regulation, providing new insights into how host epigenetic factors shape the gut microbial ecosystem in an age-sensitive manner.IMPORTANCEWhile the gut microbiota is known to influence host physiology, the molecular mechanisms by which the host epigenetically regulates microbial composition remain largely unexplored. Our work reveals that the epigenetic enzyme Tet2 in intestinal epithelial cells acts as a master regulator of gut microbial ecology by modulating bile acid metabolism. The discovery that Tet2 deletion drives hyocholic acid (HCA) accumulation-which exerts age-dependent effects on Lactobacillus and Akkermansia-provides a novel principle for understanding host-microbe interactions across the lifespan. By linking epithelial DNA demethylation to bile acid transport and microbial phenotype, we establish a previously unrecognized Tet2-ASBT-HCA pathway that expands the conceptual framework for microbiota research. These insights open new avenues for therapeutic interventions aimed at reversing microbial dysbiosis through epigenetic or metabolic modulation.