Abstract
Inflammatory bowel disease (IBD) involves chronic inflammation, loss of epithelial integrity, and gastrointestinal microbiota dysbiosis, resulting in the development of a colon cancer known as colitis-associated colorectal cancer (CAC). In this study, we evaluated the effects of corylin in a mouse model of dextran sodium sulfate (DSS)-induced colitis. The results showed corylin could improved the survival rate and colon length, maintained body weight, and ameliorated the inflammatory response in the colon. Then, we further identified the possible antitumor effects after 30-day treatment of corylin on an azoxymethane (AOM)/DSS-induced CAC mouse model. Biomarkers associated with inflammation, the colon tissue barrier, macrophage polarization (CD11c, CCR7, CD163, and CD206), and microbiota dysbiosis were monitored in the AOM/DSS group versus corylin groups. Corylin downregulated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) mRNA expression and inflammatory signaling-associated markers (TLR4, MyD88, AP-1, CD11b, and F4/80). In addition, a colon barrier experiment revealed that epithelial cell proliferation of the mucus layer (Lgr5, Cyclin D1, and Olfm4) was downregulated and tight junction proteins (claudin-1 and ZO-1) were upregulated. Furthermore, the Firmicutes/Bacteroidetes ratio changed with corylin intervention, and the microbial diversity and community richness of the AOM/DSS mice were improved by corylin. The comparative analysis of gut microbiota revealed that Bacteroidetes, Patescibacteria, Candidatus Saccharimonas, Erysipelatoclostridium, and Enterorhabdus were significantly increased but Firmicutes, Turicibacter, Romboutsia, and Blautia decreased after corylin treatment. Altogether, corylin administration showed cancer-ameliorating effects by reducing the risk of colitis-associated colon cancer via regulation of inflammation, carcinogenesis, and compositional change of gut microbiota. Therefore, corylin could be a novel, potential health-protective, natural agent against CAC.
Highlights
Colorectal cancer (CRC) is the most commonly diagnosed malignancy and the leading cause of cancer mortality worldwide [1]
Our results show that corylin significantly alleviated weight loss and the survival rate scores in dextran sodium sulfate (DSS)-induced colitis mice and reduced the infiltration of macrophages
This may partially explain the enhanced expression of zona occludens (ZO)-1 and claudin-1, since the overproduction of IL-6 and TNF-α was considered to participate in enhancing intestinal epithelial permeability [33]
Summary
Colorectal cancer (CRC) is the most commonly diagnosed malignancy and the leading cause of cancer mortality worldwide [1]. Chronic inflammation has been suggested to be one of the hallmarks of IBD and cancer development. A causal relationship between chronic inflammation and CRC carcinogenesis has already been well established [2]. Colitis-associated cancer (CAC) represents a relatively ideal model in tumor biology to unravel how inflammatory responses activate tumorigenesis in the normal colonic mucosa [5]. The demand for more effective and safer natural agents to prevent colon cancer has, increased. Chronic inflammation is thought to contribute to cancer initiation by the persistent release of reactive oxygen and nitrogen species, leading to genome damage and carcinogenesis. There is an urgent need to characterize the possible mechanisms involved in IBD and inflammation-driven colon tumorigenesis. It is essential to explore alternative approaches to managing IBD and help prevent CAC
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