Dysbiosis Triggers ACF Development in Genetically Predisposed Subjects

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-APCMin/+) combining inflammation and genetics. Methods: Gut microbiota profiling was performed on 8-week-old Winnie-APCMin/+ 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 APCMin/+ mice born from wild type mice were investigated by histological analysis at 8 weeks. Results: ACF development in 8-week-old Winnie-APCMin/+ 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 APCMin/+ 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.

The establishment of the gut microbiota in 1-year-aged infants: from birth to family food

“…Furthermore, the absence of competitors, likely Lactobacillaceae and Enterobacteriaceae , for the available substrates within the gut has led to the possibility of overgrowth for Bacteroidaceae . Not all species of Bacteroidaceae are opportunistic pathogens but a great number of them are lipopolysaccharide (LPS) producers [ 45 ] and, due to the strict relationship between LPS and both histone acetylation and methylation processes [ 46 ], some Bacteroidaceae sub-taxa could contribute to the onset of NCDs later in life [ 47 ]. This is an additional point of view concerning the strength of breastfeeding and its immunoglobulin content, which directly acts as a major driver of gut microbiota composition favoring the growth of health promoting bacteria and indirectly avoiding the overgrowth of potentially pathogenic microbes [ 48 ].…”

Polyphenol Enriched Diet Administration During Pregnancy and Lactation Prevents Dysbiosis in Ulcerative Colitis Predisposed Littermates

“…Using a murine model of ulcerative colitis called Winnie, we previously compared the microbiome compositions of homozygous mutant mice (Winnie -/- ) with their C57BL/6 littermates, after weaning from heterozygote Winnie +/- breeders. Heterozygote breeders transmitted dysbiotic microbiota to APC +/Min offspring, resulting in higher rate of CRC development if compared to C57BL/6 breeders ( De Santis et al., 2021 ). We demonstrated that the Winnie offspring displayed significant dysbiosis as early as 4 weeks of age compared with their C57BL/6 littermates ( Liso et al., 2019 ).…”

“…In conclusion, although our results indicate that prolonged dietary intervention with polyphenol enriched nutritional regimes does not significantly impact the offspring microbiota, we observed significant dysbiosis reduction mainly at weaning time, indicating that the reduction of mothers’ dysbiosis may beneficially affect babies’ microbiota and help preventing/reducing IBD development. Nutrition should become a common adjuvant therapy for dysbiosis mediated inflammatory disorders that may evolve in intestinal or extraintestinal disorders ( Ianiro et al., 2020 ; De Santis et al., 2021 ; Xu et al., 2021 ). Based on these results, the present study can contribute to pave the way for future studies based on nutritional interventions designed for IBD mothers.…”

“…ER stress caused the activation of the innate and adaptive immune response, resulting in a spontaneous and severe mucosal inflammation of the distal colon, resembling UC ( Eri et al., 2011 ). Heterozygote mice do not show UC like phenotype, but present mild dysbiosis transmittable to the offspring ( De Santis et al., 2021 ). The breeding strategy was based on co-housing heterozygote breeders to obtain both Winnie -/- and C57BL/6 littermates from the same mother.…”

Microbiota: An Emerging Biomarker in Colorectal Cancer

“…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 [ 6 ]. In all the above indicators of the involvement of microbiota dysbiosis in CRC carcinogenesis, one common characteristic is the induction of local or systemic inflammation caused by a plethora of inflammatory mediators secreted by both immune and tumor cells.…”