Oxygen concentration modulates colibactin production

Up to 25% of the E. coli strains isolated from the feces of healthy humans harbor the pks genomic island encoding the synthesis of colibactin, a genotoxic metabolite. Evidence is accumulating for an etiologic role of colibactin in colorectal cancer. Little is known about the conditions of expression of colibactin in the gut. The intestine is characterized by a unique oxygenation profile, with a steep gradient between the physiological hypoxic epithelial surface and the anaerobic lumen, which favors the dominance of obligate anaerobes. Here, we report that colibactin production is maximal under anoxic conditions and decreases with increased oxygen concentration. We show that the aerobic respiration control (ArcA) positively regulates colibactin production and genotoxicity of pks+ E. coli in response to oxygen availability. Thus, colibactin synthesis is inhibited by oxygen, indicating that the pks biosynthetic pathway is adapted to the anoxic intestinal lumen and to the hypoxic infected or tumor tissue.

Automated summary

Up to 25% of healthy human feces-derived E. coli strains carry the pks genomic island, which is responsible for synthesizing colibactin, a genotoxic compound implicated in colorectal cancer. However, the expression conditions of colibactin in the gut remain poorly understood. In this study, it is demonstrated that colibactin production is highest under anoxic conditions and decreases with increased oxygen concentration. The positive regulation of colibactin production and genotoxicity by the aerobic respiration control (ArcA) in response to oxygen availability suggests that the pks biosynthetic pathway is adapted for the anoxic intestinal lumen and hypoxic infected or tumor tissue.