Gut Microbial Metabolism Drives Transformation of MSH2-deficient Colon Epithelial Cells

Cell. 2014 Jul 17;158(2):288-299. doi: 10.1016/j.cell.2014.04.051.

Abstract

The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APC(Min/+)MSH2(-/-) mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2(-/-) colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. PAPERCLIP:

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Animals
  • Butyrates / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Colonic Polyps / metabolism
  • Colonic Polyps / microbiology
  • Colonic Polyps / pathology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / microbiology
  • Colorectal Neoplasms / pathology*
  • DNA Mismatch Repair
  • Dietary Carbohydrates / metabolism*
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / microbiology
  • Mice
  • Mice, Inbred C57BL
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics
  • MutS Homolog 2 Protein / metabolism*
  • Nuclear Proteins / metabolism
  • Specific Pathogen-Free Organisms
  • beta Catenin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein
  • Butyrates
  • Dietary Carbohydrates
  • Mlh1 protein, mouse
  • Nuclear Proteins
  • beta Catenin
  • Msh2 protein, mouse
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein