Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations.

Abstract

The DNA-alkylating metabolite tilimycin is a microbial genotoxin. Intestinal accumulation of tilimycin in individuals carrying til+ Klebsiella spp. causes apoptotic erosion of the epithelium and colitis. Renewal of the intestinal lining and response to injury requires the activities of stem cells located at the base of intestinal crypts. This study interrogates the consequences of tilimycin-induced DNA damage to cycling stem cells. We charted the spatial distribution and luminal quantities of til metabolites in Klebsiella-colonized mice in the context of a complex microbial community. Loss of marker gene G6pd function indicates genetic aberrations in colorectal stem cells that became stabilized in monoclonal mutant crypts. Mice colonized with tilimycin-producing Klebsiella displayed both higher frequencies of somatic mutation and more mutations per affected individual than animals carrying a non-producing mutant. Our findings imply that genotoxic til+ Klebsiella may drive somatic genetic change in the colon and increase disease susceptibility in human hosts.

• Authors: Lisa Pöltl, Maksym Kitsera, Sandra Raffl, Stefan Schild, Amar Cosic, Sabine Kienesberger, Katrin Unterhauser, Georg Raber, Christian Lembacher-Fadum, Rolf Breinbauer, Gregor Gorkiewicz, Carlos Sebastian, Gerald Hoefler, Ellen L Zechner
• Journal: Cell reports (Cell Rep) Vol. 42 Issue 3 Pg. 112199 (03 28 2023) ISSN: 2211-1247 [Electronic] United States
• PMID: 36870054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• tilimycin
• Mutagens

Topics

• Humans
• Mice
• Animals
• Mutagens (metabolism)
• Colon (metabolism)
• Mutation (genetics)
• Microbiota
• Stem Cells
• Intestinal Mucosa