Dysbiosis Triggers ACF Development in Genetically Predisposed Subjects

SIMPLE SUMMARY: Colorectal cancer (CRC) is a non-communicable disease resulting from the combination of a genetic predisposition and environmental triggers, possibly including intestinal microbiota composition. However, the relationship between microbiota modulation and other CRC risk factors is still debated. With the intent to shed light on the axis between microbial imbalance and ACF (aberrant crypt foci) development in genetically predisposed individuals, we used the Winnie-APC(Min/+) model combining genetics and inflammation. Our results indicate that the mother’s microbial composition can be a transmittable risk factor favoring the cascade of events finally resulting in ACF development in the offspring. In light of these results, preventive strategies developed to avoid dysbiosis could help to reduce the risk of tumor lesion onset and progression. These preventive approaches may be particularly effective during pregnancy and lactation to reduce a child’s risk of CRC development. ABSTRACT: Background: Colorectal cancer (CRC) is the third most common cancer worldwide, characterized by a multifactorial etiology including genetics, lifestyle, and environmental factors including microbiota composition. To address the role of microbial modulation in CRC, we used our recently established mouse model (the Winnie-APC(Min/+)) combining inflammation and genetics. Methods: Gut microbiota profiling was performed on 8-week-old Winnie-APC(Min/+) mice and their littermates by 16S rDNA gene amplicon sequencing. Moreover, to study the impact of dysbiosis induced by the mother’s genetics in ACF development, the large intestines of APC(Min/+) mice born from wild type mice were investigated by histological analysis at 8 weeks. Results: ACF development in 8-week-old Winnie-APC(Min/+) mice was triggered by dysbiosis. Specifically, the onset of ACF in genetically predisposed mice may result from dysbiotic signatures in the gastrointestinal tract of the breeders. Additionally, fecal transplant from Winnie donors to APC(Min/+) hosts leads to an increased rate of ACF development. Conclusions: The characterization of microbiota profiling supporting CRC development in genetically predisposed mice could help to design therapeutic strategies to prevent dysbiosis. The application of these strategies in mothers during pregnancy and lactation could also reduce the CRC risk in the offspring.