The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites.
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.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Gerard E
GE
Kaiko
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Stacy H
SH
Ryu
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Olivia I
OI
Koues
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Patrick L
PL
Collins
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Lilianna
L
Solnica-Krezel
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Edward J
EJ
Pearce
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Erika L
EL
Pearce
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Eugene M
EM
Oltz
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: stappenb@wustl.edu.
Thaddeus S
TS
Stappenbeck
D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D002087:Butyrates / Q000378:metabolism*; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology* / Q000382:microbiology*; D000069196:Gastrointestinal Microbiome; D007421:Intestine, Small / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D000069452:Pathogen-Associated Molecular Pattern Molecules / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015027:Zebrafish
D002087:Butyrates; D000069452:Pathogen-Associated Molecular Pattern Molecules; D042964:Acyl-CoA Dehydrogenase