2. Academic Validation
  3. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites

Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites

  • Science. 2022 Oct 28;378(6618):eabm3233. doi: 10.1126/science.abm3233.
Yiyun Cao 1,  Joonseok Oh 2 3,  Mengzhao Xue 2,  Won Jae Huh 4,  Jiawei Wang 5,  Jaime A Gonzalez-Hernandez 1,  Tyler A Rice 1,  Anjelica L Martin 1,  Deguang Song 1,  Jason M Crawford 2 3 6,  Seth B Herzon 2 7,  Noah W Palm 1
Affiliations

Affiliations

  • 1 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
  • 2 Department of Chemistry, Yale University, New Haven, CT 06520, USA.
  • 3 Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA.
  • 4 Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 5 Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06510, USA.
  • 6 Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
  • 7 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
PMID: 36302024 DOI: 10.1126/science.abm3233
Abstract

Microbiota-derived metabolites that elicit DNA damage can contribute to colorectal Cancer (CRC). However, the full spectrum of genotoxic chemicals produced by indigenous gut microbes remains to be defined. We established a pipeline to systematically evaluate the genotoxicity of an extensive collection of gut commensals from inflammatory bowel disease patients. We identified isolates from divergent phylogenies whose metabolites caused DNA damage and discovered a distinctive family of genotoxins-termed the indolimines-produced by the CRC-associated species Morganella morganii. A non-indolimine-producing M. morganii mutant lacked genotoxicity and failed to exacerbate colon tumorigenesis in mice. These studies reveal the existence of a previously unexplored universe of genotoxic small molecules from the microbiome that may affect host biology in homeostasis and disease.

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