Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
Maksym Kitsera
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
Sandra Raffl
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
Stefan Schild
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
Amar Cosic
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
Sabine Kienesberger
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
Katrin Unterhauser
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
Georg Raber
Institute of Chemistry, University of Graz, 8010 Graz, Austria
Christian Lembacher-Fadum
Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria
Rolf Breinbauer
BioTechMed-Graz, 8010 Graz, Austria; Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria
Gregor Gorkiewicz
BioTechMed-Graz, 8010 Graz, Austria; Diagnostic and Research Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
Carlos Sebastian
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
Gerald Hoefler
Diagnostic and Research Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
Ellen L. Zechner
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; Corresponding author
Summary: 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.
