Enterotoxigenic Bacteroides fragilis Induces Host Genotype-Specific Colonic Epithelial and Immune Responses in Mice.

BACKGROUND: Colorectal cancer pathogenesis involves complex interactions between multiple risk factors including somatic mutations and microbial dysbiosis. A number of individual microbiota members have been implicated in colorectal cancer, including enterotoxigenic strains of Bacteroides fragilis (ETBF). Enterotoxigenic Bacteroides fragilis promotes inflammation in mouse models, which has been mechanistically linked to colon tumorigenesis. We hypothesized that ETBF would promote distinct patterns of colonic damage and inflammation in mice expressing different oncogenic mutations.

METHODS: Mice expressing mutations in the Apc tumor suppressor gene or the BRAF or Kras oncogenes were colonized with ETBF to induce acute colitis. Seven days after colonization, tissues and stools were collected to assess for colonization, epithelial damage, and local and systemic immune responses.

RESULTS: Despite uniform colonization of ETBF across all genotypes and some common features of colitis across groups, Apc, BRAF, and Kras mutations were associated with distinct patterns of colonic epithelial cell injury and goblet cell loss in response to ETBF. RNA sequencing analysis revealed varied transcriptional profiles based on mouse genotype and colon region. Flow cytometry of intra-epithelial leukocytes revealed differential recruitment of myeloid cells based on oncogenic mutation. In particular, mutant BRAF expression was uniquely associated with more systemic inflammation, resistance to goblet cell loss, an interferon gamma gene signature, and recruitment of a macrophage-like polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) population in the midproximal colon.

CONCLUSIONS: Enterotoxigenic Bacteroides fragilis promotes acute colitis in mice expressing different oncogenic mutations, but with distinct patterns of colonic epithelial cell damage and inflammation dependent on host oncogene context.