Abstract
Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of Escherichia coli within the gut-associated microbial community through aerobic respiration. An aerobic expansion of colibactin-producing E. coli was required for the cancer-inducing activity of this pathobiont in a mouse model of colitis-associated colorectal cancer formation. We conclude that increased epithelial oxygenation in the colon is associated with an expansion of a prooncogenic driver species, thereby increasing the cancer-inducing activity of the microbiota.IMPORTANCE One of the environmental factors important for colorectal cancer formation is the gut microbiota, but the habitat filters that control its cancer-inducing activity remain unknown. Here, we show that chemically induced colitis elevates epithelial oxygenation in the colon, thereby driving an expansion of colibactin-producing Escherichia coli, a prooncogenic driver species. These data suggest that elevated epithelial oxygenation is a potential risk factor for colorectal cancer formation because the consequent changes in the gut habitat escalate the cancer-inducing activity of the microbiota.
Highlights
Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown
Inoculation of dextran sulfate sodium (DSS)-treated mice with a commensal E. coli isolate of phylogroup B2 (E. coli Nissle 1917 wild type) revealed that colitis drove a marked expansion of this facultative anaerobic bacterium (Fig. 1C), modeling the expansion of Enterobacteriaceae observed in patients with inflammatory bowel disease (IBD) [9]
Since limited oxygen availability is thought to maintain a microbial community dominated by obligate anaerobic bacteria in the colon [13], we investigated whether an expansion of facultative anaerobic E. coli was linked to a disruption in anaerobiosis [8]
Summary
Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. We show that chemically induced colitis elevates epithelial oxygenation in the colon, thereby driving an expansion of colibactinproducing Escherichia coli, a prooncogenic driver species. These data suggest that elevated epithelial oxygenation is a potential risk factor for colorectal cancer formation because the consequent changes in the gut habitat escalate the cancerinducing activity of the microbiota. One prime candidate for environmental factors is an altered colonic microbiota [2] Consistent with this idea, tumorigenic bacteria, such as colibactin-producing Escherichia coli, are found in significantly higher percentages in patients with colorectal cancer than in healthy controls [3]. Solicited external reviewers: Michael Sigal, Max Planck Institute, Berlin; Xavier Nassif, Universite Paris Descartes Faculte de medecine Necker / INSERM U1002
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