Abstract
Gut dysbiosis is associated with colitis-associated colorectal carcinogenesis, and the genetic deficiency of the Muc2 gene causes spontaneous development of colitis and colorectal cancer. Whether there are changes of gut microbiota and a linkage between the changes of microbiota and intestinal pathology in Muc2−/− mice are unclear. Muc2−/− and Muc2+/+ mice were generated by backcrossing from Muc2+/− mice, and the fecal samples were collected at different dates (48th, 98th, 118th, 138th, and 178th day). Gut microbiota were analyzed by high-throughput sequencing with the universal 16S rRNA primers (V3–V5 region). All mice were sacrificed at day 178 to collect colonic tissue and epithelial cells for the analysis of histopathology and inflammatory cytokines. On the 178th day, Muc2−/− mice developed colorectal chronic colitis, hyperplasia, adenomas and adenocarcinomas, and inflammatory cytokines (e.g., cyclooxygenase 2 (COX-2), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin 1 β (IL-1β), i-kappa-B-kinase β (IKKβ)) were significantly increased in colonic epithelial cells of Muc2−/− mice. In general, structural segregation of gut microbiota was observed throughout the experimental time points between the Muc2−/− and Muc2+/+ mice. Impressively, in Muc2−/− mice, Alpha diversities reflected by Shannon and Chao indexes were higher, the phylum of Firmicutes was enriched and Bacteroidetes was decreased, and Desulfovibrio, Escherichia, Akkermansia, Turicibacter, and Erysipelotrichaceae were significantly increased, but Lactobacilli and Lachnospiraceae were significantly decreased. Moreover, the abundance of Ruminococcaceae and butyrate-producing bacteria was significantly higher in the Muc2−/− mice. There were significant differences of gut microbiota between Muc2−/− and Muc2+/+ mice. The dynamic changes of microbiota might contribute to the development of colitis and colitis-associated colorectal carcinogenesis. Therefore, this study revealed specific functional bacteria in the development of colitis and colitis-associated colorectal carcinogenesis, which will benefit the development of preventive and therapeutic strategies for chronic inflammation and its malignant transformation.
Highlights
Colorectal cancer (CRC) is the third most common and the second most deadly cancer in the world, and there are about 1.2 million new cases of CRC annually [1]
Intestinal dysbiosis or the changes of gut microbe has been reported to play a crucial role in the development of colitis and malignant transformation to CRC [7], but the dynamic changes of gut microbiota during lesions progression are unclear
The present study provided direct evidence that the alterations of intestinal microbiota correlated with colonic lesions and progression
Summary
Colorectal cancer (CRC) is the third most common and the second most deadly cancer in the world, and there are about 1.2 million new cases of CRC annually [1]. Recent studies have shown that gut bacteria drive intestinal inflammation and further increase the risk for CRC [4,5,6,7,8]. Genetic deficiency of the Muc gene results in 90% reduction in mucus and increased exposure of the intestinal epithelial cells to the luminal contents, causing spontaneous colitis and CRC [17,18]. Gut microbiome could contribute to the development of CRC in Muc2−/− mice by regulating metabolic and inflammatory conditions. Morampudi et al demonstrated that the goblet cell mediator resistin-like molecule-β (RELM-β) drives colitis in Muc2−/− mice by depleting protective commensal microbes [20]. The changes of gut microbiota in Muc2−/− mice might contribute to the development of chronic colitis and colorectal tumor formation
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