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Genetic locus controls bacteria-induced colitis and associated cancer

▸ Boulard O, Kirchberger S, Royston DJ, et al. Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation. J Exp Med 2012;209:1309–24.

While many genetic studies have identified pathways that contribute to inflammatory bowel disease (IBD) susceptibility, the genetic factors involved in progression from colon inflammation to colitis-associated colorectal cancer (CAC) are not known. In this study by Boulard et al, the authors identify a major susceptibility locus for Helicobacter hepaticus-induced innate colitis and CAC in the 129S6.Rag−/− mouse strain. The locus, designated Hiccs, renders susceptible mice resistant to colitis and reduces colon tumour formation. Hiccs was mapped to a 1.71-Mb interval on chromosome 3, and found to include altered expression of three genes and differences in non-synonymous single nucleotide polymorphisms between resistant and susceptible strains. Analysis of colonic lamina propria leukocytes showed that resistance to colitis correlates with reduced secretion of pro-inflammatory cytokines. Bone marrow chimaera experiments demonstrated that Hiccs acts specifically in innate haematopoietic cells to confer resistance to H hepaticus-induced colitis. Innate inflammation without proper immune regulation plays a key role in inflammation-induced cancer. In order to identify how Hiccs controls the early inflammatory response, kinetic analyses of the innate response following H hepaticus infection were performed. Inflammatory cytokine production (TNF, IL-1β, and IFN-γ) and granulocyte recruitment driven by innate lymphoid cells are both controlled by Hiccs. The authors used a novel tumour induction protocol combining administration of the carcinogen azoxymethane with H hepaticus infection to explore whether the Hiccs locus is involved in CAC development. The Hiccs locus dramatically reduced frequency of colitis-associated invasive adenocarcinoma from 75% to 29%. This study along with further research on molecular pathways involved in increasing susceptibility to colitis and CAC could promote new insights …

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