The intestinal microbiota programs DNA methylation to control tissue homeostasis and inflammation

Although much research has been done on the diversity of gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelial cells. In this study we present a completely new sequencing-based analysis to demonstrate the impact of commensal bacteria on epigenetic DNA methylation landscapes of mouse intestinal cells under normal and acute inflammatory conditions. We show that exposure to microbiota under physiological conditions is associated with extensive alterations in DNA methylation at regulatory elements, which culminates in transcriptional activation of a set of “early sentinel” response genes that play a role in the normal intestinal homeostasis. We further show that exposure to microbiota in acute inflammation results in profound changes in DNA methylation and chromatin accessibility at regulatory elements, which culminate in alterations in expression of genes enriched in colitis and cancer. Our studies provide a new mechanistic understanding of the dual role microbiota plays in the intestine. In health, it generates colonic homeostasis via epigenetic programming, while in acute inflammation microbiota impacts a deleterious chromatin programming.