Drug Discovery Opinion

Just as Helicobacter pylori, which causes stomach ulcers and gastric cancers, is being eradicated from many developed countries, Johns Hopkins scientists have shown that bacteria that cause diarrhoea may also lead to some colon cancers. Enterotoxigenic strains of Bacteroides fragilis (ETBF) asymptomatically colonise a proportion of the human population but can also cause inflammatory diarrhoea in both children and adults. An earlier study in Turkey had linked ETBF infection to colon cancer and, to further understand this association, the Johns Hopkins team have carried out a study in multiple intestinal neoplasia (Min) mice. These animals carry mutations in the APC (adenomatosis polyposis coli) gene and spontaneously develop multiple small intestinal adenomas as well as more sporadic colonic adenomas. Mutations in the tumour-suppressing APC gene are also associated with human colon cancer. The present study showed that, although both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonise mice, only ETBF causes diarrhoea and inflammation and induces colonic tumours. The diarrhoea resolved quickly but the mice developed colitis within 7 days and, after 4 weeks, had numerous colonic tumours. ETBF was found to strongly activate Stat3 in the colon, leading to a dramatic (100-fold higher than normal) and selective T_H17 response. Blocking IL-17 as well as the receptor for IL-23, a key cytokine amplifying T_H17 responses, inhibited the colitis, colonic hyperplasia and tumour formation triggered by ETBF. The study, which is published in the August 23^rd issue of Nature Medicine, provides new mechanistic insights into the development of human colon cancers and may lead to the development of vaccines or improved therapies.

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