Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations

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

doi:10.1016/j.celrep.2023.112199

Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	112199
Journal	Cell Reports
Volume	42
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2023.112199
Publication status	Published - 28 Mar 2023

Keywords

antibiotics
bacterial metabolite
colorectal epithelium
CP: Microbiology
genotoxin
gut microbiota
intestinal stem cell
necrotizing enterocolitis
somatic mutation frequency

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

Fields of Expertise

Human- & Biotechnology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2023.112199Licence: CC BY 4.0

Cite this

Pöltl, L., Kitsera, M., Raffl, S., Schild, S., Cosic, A., Kienesberger, S., Unterhauser, K., Raber, G., Lembacher-Fadum, C., Breinbauer, R., Gorkiewicz, G., Sebastian, C., Hoefler, G., & Zechner, E. L. (2023). Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations. Cell Reports, 42(3), Article 112199. https://doi.org/10.1016/j.celrep.2023.112199

@article{1b9aa3acfd65476cb20efb67cfb3ef31,

title = "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.",

keywords = "antibiotics, bacterial metabolite, colorectal epithelium, CP: Microbiology, genotoxin, gut microbiota, intestinal stem cell, necrotizing enterocolitis, somatic mutation frequency",

author = "Lisa P{\"o}ltl and Maksym Kitsera and Sandra Raffl and Stefan Schild and Amar Cosic and Sabine Kienesberger and Katrin Unterhauser and Georg Raber and Christian Lembacher-Fadum and Rolf Breinbauer and Gregor Gorkiewicz and Carlos Sebastian and Gerald Hoefler and Zechner, {Ellen L.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = mar,

day = "28",

doi = "10.1016/j.celrep.2023.112199",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations

AU - Pöltl, Lisa

AU - Kitsera, Maksym

AU - Raffl, Sandra

AU - Schild, Stefan

AU - Cosic, Amar

AU - Kienesberger, Sabine

AU - Unterhauser, Katrin

AU - Raber, Georg

AU - Lembacher-Fadum, Christian

AU - Breinbauer, Rolf

AU - Gorkiewicz, Gregor

AU - Sebastian, Carlos

AU - Hoefler, Gerald

AU - Zechner, Ellen L.

PY - 2023/3/28

Y1 - 2023/3/28

N2 - 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.

AB - 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.

KW - antibiotics

KW - bacterial metabolite

KW - colorectal epithelium

KW - CP: Microbiology

KW - genotoxin

KW - gut microbiota

KW - intestinal stem cell

KW - necrotizing enterocolitis

KW - somatic mutation frequency

UR - http://www.scopus.com/inward/record.url?scp=85150044777&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.112199

DO - 10.1016/j.celrep.2023.112199

M3 - Article

C2 - 36870054

AN - SCOPUS:85150044777

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 112199

ER -

Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations

Abstract

Keywords

ASJC Scopus subject areas

Fields of Expertise

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this