Role of autophagy in the host response to infection by pathogenic Escherichia coli associated with colorectal cancer.

International audience

Английский. Background: In patients with colorectal cancer (CRC), intestinal dysbiosis has been observed, with abnormal colonization of the colonic mucosa by pathogenic Escherichia coli strains producing a cyclomodulin named cytotoxic necrotizing factor (CNF). Cyclomodulins are bacterial toxins capable of altering the cell cycle of the infected cell. One of the mechanisms involved in host defence against pathogens and in carcinogenesis is autophagy. However, the role of autophagy in the host response to the infection by CNF-producing E. coli, designated as CyPEC, has not yet been described. Aims: Thus, the aim of this study was to investigate the role of autophagy in colorectal carcinogenesis in the context of CyPEC infection. Methods: Mice predisposed to CRC development with autophagy deficiency specifically intestinal epithelial cells (ApcMin/+/Atg16l1ΔIEC mice) and their control littermates with functional autophagy (ApcMin/+ mice) were infected with the clinical CyPEC strain 21F8. Tumor size and number were determined using a dissecting microscope. The mouse colons were collected and used for histological score assessment, and to analyse the levels of markers of autophagy, cell proliferation, apoptosis and inflammation by immunoblot, immunohistochemical staining and ELISA. Results: We showed that in ApcMin/+/Atg16l1ΔIEC mice, infection with the CyPEC 21F8 strain led to increases in the number and the size of colonic tumours, compared with the uninfected condition. However, this was not observed in ApcMin/+ mice. The increase in tumorigenesis in ApcMin/+/Atg16l1ΔIEC mice upon 21F8 infection versus uninfected condition was associated with increased pro-inflammatory cytokine production, enhanced cellular proliferation and decreased apoptosis in colonic epithelial cells. Conclusion: Our results suggest that autophagy is necessary to limit the pro-carcinogenesis effects of the CyPEC 21F8 strain, thereby decreasing colorectal tumorigenesis. In another word, autophagy deficiency could be a susceptibility factor for the development of CRC in a host with colonization by CyPEC strains.