Microbial Metabolites Regulate Intestinal Stem Cells During Tissue Repair

Studies in germ-free and antibiotic-treated mice reveal important cross-talk between the microbiota and intestinal epithelium but the mechanisms in many cases remain unknown. Intestinal stem cells (ISCs) are the master control unit of the epithelial barrier, however to date there is no evidence for a direct effect of specific microbes or microbial components on ISCs. As the mucus layer for the most part keeps bacteria separated from the epithelium, we investigated whether microbial-derived metabolites may act as soluble effectors and influence the function of ISCs. Using primary mouse cultures of ISCs, we conducted a large scale screen of the effect of all known mouse intestinal microbial-derived metabolites and microbial-associated molecular patterns. We discovered 8 microbial metabolites that significantly inhibited ISC proliferation in vitro, the most potent of which was the short chain fatty acid butyrate. Similarly, in vivo we demonstrated that elevated luminal butyrate suppressed both ISC proliferation and healing in crypts adjacent to areas of ulceration. In contrast, elevated luminal butyrate did not affect ISC proliferation in areas where the epithelial barrier was intact (non-ulcerated regions). In uninjured tissue terminally differentiated colonocytes actively metabolized butyrate, thus preventing it from reaching the stem cell compartment and exerting its inhibitory effect on proliferation. The mechanism underlying the direct impact of butyrate on ISCs was dependent on histone acetylation and independent of GPCR signalling. Importantly, differentiated colonocytes were resistant to this butyrate-induced histone remodelling. This study suggests that microbial-derived metabolites directly regulate the repair of the intestinal epithelial barrier during tissue damage.