Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis

Abstract

Inflammation and microbiota are critical components of intestinal tumorigenesis. To dissect how the microbiota contributes to tumor distribution, we generated germ-free (GF) <i>Apc^Min/+</i> and <i>Apc^Min/+</i> ;<i>Il10^-/-</i> mice and exposed them to specific-pathogen-free (SPF) or colorectal cancer-associated bacteria. We found that colon tumorigenesis significantly correlated with inflammation in SPF-housed <i>Apc^Min/+</i> ;<i>Il10^-/-</i> , but not in <i>Apc^Min/+</i> mice. In contrast, small intestinal neoplasia development significantly correlated with age in both <i>Apc^Min/+</i> ;<i>Il10^-/-</i> and <i>Apc^Min/+</i> mice. GF <i>Apc^Min/+</i> ;<i>Il10^-/-</i> mice conventionalized by an SPF microbiota had significantly more colon tumors compared with GF mice. Gnotobiotic studies revealed that while <i>Fusobacterium nucleatum</i> clinical isolates with FadA and Fap2 adhesins failed to induce inflammation and tumorigenesis, <i>pks</i>⁺<i>Escherichia coli</i> promoted tumorigenesis in the <i>Apc^Min/+</i> ;<i>Il10^-/-</i> model in a colibactin-dependent manner, suggesting colibactin is a driver of carcinogenesis. Our results suggest a distinct etiology of cancers in different locations of the gut, where colon cancer is primarily driven by inflammation and the microbiome, while age is a driving force for small intestine cancer. <i>Cancer Res; 77(10); 2620-32. ©2017 AACR</i>.