IMPACTS OF ADDITIVE FOOD E171 (TITANIUM DIOXIDE) ON THE GUT MICROBIOTA AND COLORECTAL CARCINOGENESIS IN APCMIN/+ MURINE MODEL
Résumé
Background and aim: Contaminant molecules could play a key role in the initiation and/or promotion of colorectal cancer (CRC) which is the second leading cause of cancer worldwide. Among the different pollutants, titanium dioxide (TiO2) is a white natural metal oxide which is particularly monitored. It is one of the most widely used engineered nanomaterials in daily consumer products, including food. Long-term inhalation studies with TiO2 nanoparticles (NPs) in rats reported development of lung tumors leading to classify this compound as a possible carcinogen for humans by International Agency for Research on Cancer. The food additive TiO2, referred to as E171 in the European Union, is commonly used as a whitening and brightening agent in sugar confectionary, sauces, ice creams and pastries. The gastro-intestinal tract may be an important absorption route for TiO2 NPs and additive E171 could be involved in the CRC etiology. Thus, this project aimed to assess the impact of chronic exposure of food additive E171 in CRC development using APCmin/+ mouse model which spontaneously develop intestinal tumors. Because intestinal microbiota play a role in colorectal carcinogenesis, carcinogenic properties of TiO2 will be evaluated in association with microbiota dysbiosis.
Methods: Additive E171 composition was characterized by X-ray diffraction (XRD) and thermogravimetric analysis (TGA). APCmin/+ mice were chronically exposed (twice per week) to E171 (1 and 10 mg/kg of body weight (BW)) or vehicle (water) for 28 days via intragastric gavage. Micro-inflammation was assessed by the quantification of fecal lipocalin-2 (LCN-2) marker. At the end of the experimental protocol, macroscopic and histologic examinations of colon were performed and colonic mucosa-associated microbiota was analyzed by quantitative PCR.
Results: As shown by the TGA analysis, the E171 compound is purely mineral and the size of NPs administrated to mice in this study did not exceed 28 nm (XRD analysis). No significant body weight loss was observed between mice groups suggesting no toxicity in our experimental conditions. However macroscopic and histological observations showed a more advanced tumor development in mice receiving the additive E171 (at a dose of 10 mg/kg of BW) compared to control animals. At the end of the experiment, high level of fecal LCN-2 concentration correlated with increase of tumoral volume. Mice with adenocarcinoma within this group also exhibit an increase of Bacteroides and Akkermansia as well as a higher prevalence of Escherichia coli and a decrease of Bifidobacterium.
Conclusion: Additive E171 promotes colonic tumorigenesis and induces change in gut microbiota composition. Underlying carcinogenic mechanisms focusing on microbiota dysbiosis implication are in progress. This study supports the carcinogenic properties of TiO2 in the context of colorectal cancer.