Effect of TiO2, as food additive E171 and as nanoparticules, on colorectal carcinogenesis and colibactin-producing Escherichia coli CoPEC
Résumé
Background: Colorectal cancer (CRC) is the third most common cancer worldwide, and the second leading cause of cancer mortality. Genetic, host susceptibility, immunological and environmental factors all contribute to the initiation, development or/and clinical expression of the disease. Among the environmental contaminants, titanium dioxide (TiO2) particles are of particular concern given their potential carcinogenic effects and their ubiquity in everyday consumer products, especially as a food additive (E171). TiO2 nanoparticles may interact with the intestinal microbiota and facilitate the emergence of pathobionts such as colibactin-producing Escherichia coli (CoPEC), which abnormally colonise the colonic mucosa of CRC patients. The aim of this project is to investigate the impact of titanium dioxide on colorectal carcinogenesis, with a particular focus on its effects on interactions between intestinal epithelial cells and the gut microbiota, including CoPEC. Methods: The growth of 5 CopEC strains was monitored after 24-hour exposure to TiO2 doses equivalent to those reaching the intestine (0.1 and 1 mg.kg-1). Their ability to interact with HT-29 intestinal epithelial cells (IEC) was also measured. Interactions with nanoparticles were observed using scanning electron microscopy coupled with energy dispersive spectroscopy. On the other hand, APCmin/+ mice predisposed to develop CRC were exposed to a human equivalent dose of 10 mg.kg-1 of body weight, twice a week for 27 days and macroscopic, histological and colonic mucosa-associated microbiota analyses were performed. Results: In vitro, compared to a laboratory strain, the doubling time of each CoPEC strain was reduced and adsorption of TiO2 particles was observed on the surface of 11G5 strain. It also showed an increase in 11G5 ability to adhere to and multiply in IEC as well as structural modifications of its pili. In vivo, some of the E171 exposed individuals exhibited more advanced tumour development than the control group (number and total volume of polyps). The “E171 sensitive” mice also exhibited a greater dysbiosis than the “E171 non-sensitive” and “unexposed” ones with several overrepresented taxa that are also more abundant in CRC. Among these 3 groups, PCNA and claudin-2 gene expression appeared to be modified and occludin gene expression was significantly reduced in the sensitive mice. Conclusion: These results collectively suggest that, in some individuals, exposure to TiO2 may play a role in the aetiology of CRC by altering the structure and function of the intestinal microbial ecosystem as well as the host intestinal barrier. This could promote the emergence of pathobionts such as CoPEC, in addition to inducing changes that enhance their ability of colonisation.