The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites

• Published in: Cell 2016-06, Vol.165 (7), p.1708-1720
• Main Authors: Kaiko, Gerard E., Ryu, Stacy H., Koues, Olivia I., Collins, Patrick L., Solnica-Krezel, Lilianna, Pearce, Edward J., Pearce, Erika L., Oltz, Eugene M., Stappenbeck, Thaddeus S.
• Format: Article
• Language: English
• Subjects: Acyl-CoA Dehydrogenase - deficiency; Acyl-CoA Dehydrogenase - genetics; Animals; Bacteria - metabolism; Butyrates - metabolism; Cell Proliferation; Colon - cytology; Colon - microbiology; Gastrointestinal Microbiome; Intestine, Small - cytology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Oxidation-Reduction; Pathogen-Associated Molecular Pattern Molecules - metabolism; Stem Cells - cytology; Stem Cells - metabolism; Zebrafish
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.05.018

In the mammalian intestine, crypts of Leiberkühn house intestinal epithelial stem/progenitor cells at their base. The mammalian intestine also harbors a diverse array of microbial metabolite compounds that potentially modulate stem/progenitor cell activity. Unbiased screening identified butyrate, a prominent bacterial metabolite, as a potent inhibitor of intestinal stem/progenitor proliferation at physiologic concentrations. During homeostasis, differentiated colonocytes metabolized butyrate likely preventing it from reaching proliferating epithelial stem/progenitor cells within the crypt. Exposure of stem/progenitor cells in vivo to butyrate through either mucosal injury or application to a naturally crypt-less host organism led to inhibition of proliferation and delayed wound repair. The mechanism of butyrate action depended on the transcription factor Foxo3. Our findings indicate that mammalian crypt architecture protects stem/progenitor cell proliferation in part through a metabolic barrier formed by differentiated colonocytes that consume butyrate and stimulate future studies on the interplay of host anatomy and microbiome metabolism. [Display omitted] •Microbial metabolite screening identifies intestinal stem cell effectors•Butyrate suppresses intestinal stem cell proliferation upon exposure•Crypt structure and colonocytes protect stem/progenitor cells The architecture of intestinal crypts protects the stem cells at their base from a growth-inhibiting metabolite derived from the gut microbiome. Might these findings suggest co-evolution of mammalian anatomy with commensal flora?