Pro-mutagenic effects of the gut microbiota in a Lynch syndrome mouse model

The gut microbiota strongly impacts the development of sporadic colorectal cancer (CRC), but it is largely unknown how the microbiota affects the pathogenesis of mismatch-repair-deficient CRC in the context of Lynch syndrome. In a mouse model for Lynch syndrome, we found a nearly complete loss of in...

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Published in:Gut microbes Vol. 14; no. 1; p. 2035660
Main Authors: Pieters, Wietske, Hugenholtz, Floor, Kos, Kevin, Cammeraat, Maxime, Moliej, Teddy C., Kaldenbach, Daphne, Klarenbeek, Sjoerd, Davids, Mark, Drost, Lisa, de Konink, Charlotte, Delzenne-Goette, Elly, de Visser, Karin E., te Riele, Hein
Format: Journal Article
Language:English
Published: United States Taylor & Francis 31.12.2022
Taylor & Francis Group
Subjects:
Animals
colorectal cancer
Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
Colorectal Neoplasms, Hereditary Nonpolyposis - pathology
Disease Models, Animal
Gastrointestinal Microbiome
Lynch syndrome
Mice
microbiota
mismatch repair
Mutagenesis
Mutagens
MutS Homolog 2 Protein - genetics
Research Paper
microbiota
mismatch repair
colorectal cancer
mutagenesis
Lynch syndrome
ISSN:1949-0976, 1949-0984, 1949-0984
Online Access:Get full text
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Summary:The gut microbiota strongly impacts the development of sporadic colorectal cancer (CRC), but it is largely unknown how the microbiota affects the pathogenesis of mismatch-repair-deficient CRC in the context of Lynch syndrome. In a mouse model for Lynch syndrome, we found a nearly complete loss of intestinal tumor development when animals were transferred from a conventional "open" animal facility to specific-pathogen-free (SPF) conditions. Using 16S sequencing we detected large changes in microbiota composition between the two facilities. Transcriptomic analyses of tumor-free intestinal tissues showed signs of strong intestinal inflammation in conventional mice. Whole exome sequencing of tumors developing in Msh2-Lynch mice revealed a much lower mutational load in the single SPF tumor than in tumors developing in conventional mice, suggesting reduced epithelial proliferation in SPF mice. Fecal microbiota transplantations with conventional feces altered the immune landscape and gut homeostasis, illustrated by increased gut length and elevated epithelial proliferation and migration. This was associated with drastic changes in microbiota composition, in particular increased relative abundances of different mucus-degrading taxa such as Desulfovibrio and Akkermansia, and increased bacterial-epithelial contact. Strikingly, transplantation of conventional microbiota increased microsatellite instability in untransformed intestinal epithelium of Msh2-Lynch mice, indicating that the composition of the microbiota influences the rate of mutagenesis in MSH2-deficient crypts.
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ISSN:1949-0976
1949-0984
1949-0984
DOI:10.1080/19490976.2022.2035660