Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations.

Autor:	Pöltl L; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria., Kitsera M; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria., Raffl S; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria., Schild S; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria., Cosic A; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria., Kienesberger S; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria., Unterhauser K; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria., Raber G; Institute of Chemistry, University of Graz, 8010 Graz, Austria., Lembacher-Fadum C; Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria., Breinbauer R; BioTechMed-Graz, 8010 Graz, Austria; Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria., Gorkiewicz G; BioTechMed-Graz, 8010 Graz, Austria; Diagnostic and Research Institute of Pathology, Medical University of Graz, 8036 Graz, Austria., Sebastian C; Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Italy; Departament de Biologia Cellular, Fisiologia i Immunologia, Facultad de Biologia, Universitat de Barcelona (UB), 08028 Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain., Hoefler G; Diagnostic and Research Institute of Pathology, Medical University of Graz, 8036 Graz, Austria., Zechner EL; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria. Electronic address: ellen.zechner@uni-graz.at.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Mar 28; Vol. 42 (3), pp. 112199. Date of Electronic Publication: 2023 Mar 03.
DOI:	10.1016/j.celrep.2023.112199
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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