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The microbiota programs DNA methylation to control intestinal homeostasis and inflammation

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The intestinal microbiota regulates intestinal physiology by modifying host gene expression throughout the intestine, but the underlying mechanisms have remained uncharacterized. Using whole genome technologies, we have analyzed the impact of commensal (normally existing) bacteria on the epigenetic landscapes of mouse intestinal epithelial cells. We discovered that exposure to commensal microbiota induces activation of a set of response genes that maintain intestinal homeostasis (wellbeing) and prime the intestinal cells for future challenges. Therefore, mice that have never been exposed to microbiota are much more sensitive to acute inflammation than regular mice which have been exposed. We showed that the microbiota changes the chromatin in DNA regions which regulate expression of genes involved in anti-bacterial response. We also demonstrated that exposure to the microbiota in acute inflammation results in profound epigenetic changes (DNA methylation, chromatin accessibility) leading to alterations in gene expression program which is enriched in colitis- and colon-cancer-associated functions. Furthermore, we deciphered the molecular mechanism underlying the microbiota-induced epigenetic changes and showed that it is necessary for proper intestinal vigor.