PMID- 35188867
OWN - NLM
STAT- MEDLINE
DCOM- 20220509
LR  - 20220509
IS  - 1949-0984 (Electronic)
IS  - 1949-0976 (Print)
IS  - 1949-0976 (Linking)
VI  - 14
IP  - 1
DP  - 2022 Jan-Dec
TI  - Pro-mutagenic effects of the gut microbiota in a Lynch syndrome mouse model.
PG  - 2035660
LID - 10.1080/19490976.2022.2035660 [doi]
LID - 2035660
AB  - 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.
FAU - Pieters, Wietske
AU  - Pieters W
AUID- ORCID: 0000-0002-0375-5789
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
FAU - Hugenholtz, Floor
AU  - Hugenholtz F
AD  - Microbiota Center Amsterdam, Amsterdam, The Netherlands.
FAU - Kos, Kevin
AU  - Kos K
AUID- ORCID: 0000-0002-2407-4413
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
FAU - Cammeraat, Maxime
AU  - Cammeraat M
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
FAU - Moliej, Teddy C
AU  - Moliej TC
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
FAU - Kaldenbach, Daphne
AU  - Kaldenbach D
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
FAU - Klarenbeek, Sjoerd
AU  - Klarenbeek S
AUID- ORCID: 0000-0002-1891-1940
AD  - Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The 
      Netherlands.
FAU - Davids, Mark
AU  - Davids M
AD  - Microbiota Center Amsterdam, Amsterdam, The Netherlands.
FAU - Drost, Lisa
AU  - Drost L
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
FAU - de Konink, Charlotte
AU  - de Konink C
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
FAU - Delzenne-Goette, Elly
AU  - Delzenne-Goette E
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
FAU - de Visser, Karin E
AU  - de Visser KE
AUID- ORCID: 0000-0002-0293-868X
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
FAU - Te Riele, Hein
AU  - Te Riele H
AUID- ORCID: 0000-0003-0255-4042
AD  - Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Gut Microbes
JT  - Gut microbes
JID - 101495343
RN  - 0 (Mutagens)
RN  - EC 3.6.1.3 (MutS Homolog 2 Protein)
SB  - IM
MH  - Animals
MH  - *Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis/genetics/pathology
MH  - Disease Models, Animal
MH  - *Gastrointestinal Microbiome
MH  - Mice
MH  - MutS Homolog 2 Protein/genetics
MH  - Mutagenesis
MH  - Mutagens
PMC - PMC8865281
OTO - NOTNLM
OT  - Lynch syndrome
OT  - colorectal cancer
OT  - microbiota
OT  - mismatch repair
OT  - mutagenesis
COIS- No potential conflict of interest was reported by the author(s).
EDAT- 2022/02/22 06:00
MHDA- 2022/05/10 06:00
PMCR- 2022/02/21
CRDT- 2022/02/21 17:09
PHST- 2022/02/21 17:09 [entrez]
PHST- 2022/02/22 06:00 [pubmed]
PHST- 2022/05/10 06:00 [medline]
PHST- 2022/02/21 00:00 [pmc-release]
AID - 2035660 [pii]
AID - 10.1080/19490976.2022.2035660 [doi]
PST - ppublish
SO  - Gut Microbes. 2022 Jan-Dec;14(1):2035660. doi: 10.1080/19490976.2022.2035660.