Microbial-Derived Metabolites Regulate the Colonic Crypt Niche

In the mammalian intestine, crypts of Leiberkühn house intestinal epithelial stem /progenitor cells at their base. We found that the presence of this structure was supported by the physiologic role of a prominent bacterial metabolite, butyrate. This bacterially-produced short chain fatty acid inhibited intestinal epithelial proliferation at physiologic concentrations. During homeostasis, butyrate did not suppress epithelial stem proliferation because it was metabolized by differentiated colonocytes. Provision of butyrate access to stem/progenitor cells either through mucosal injury or application to a crypt-less host led to inhibition of proliferation. The mechanism was dependent on HDAC inhibition in stem cells and the transcription factor Foxo3. Thus, the mammalian crypt unit structure provides energy for differentiated cells at a distance from the crypt base and this action prevents suppression of stem/progenitor proliferation.