Blocking MyD88 signaling with MyD88 inhibitor prevents colitis-associated colorectal cancer development by maintaining colonic microbiota homeostasis

Purpose: Intestinal microbiota appears to positively correlate with tumorigenesis of CAC. It is proven that blocking MyD88 signaling can prevent colitis-associated colorectal cancer (CAC) development in mice. We are aim to reveal the role of MyD88 signaling of maintaining colonic microbiota homeostasis for preventing CAC development. Methods: . We here analyzed the landscape of gut microbiome in the mice model of AOM/DSS-induced CAC with MyD88 inhibitor treatment. Results: . PCoA revealed significant reduction in Lactobacillus load and increase in Escherichia load in the mucosal microbial composition of mice with CAC, compared with normal controls (NCs). Inhibitor-treatment led to almost undetectable Proteobacteria (Escherichia) and the retention of the dominance of Firmicutes and Bacteroidota (Muribaculaceae) in the mucosa. RNA sequencing analysis identified genes were up-regulated (Hp, SAA3 and IL-1F9) and down-regulated (CYP3A44, SLC30A10, GPNMB and OTC) in Inhibitor-treated mice ( vs. CAC). Meanwhile, Inhibitor-treated mice had higher percentage of MUC2-positive area in colon sections ( vs . CAC, which was less than NCs) by IF staining and decreased Escherichia in the mucus layer ( vs . CAC) by FISH. And intestinal microbiota from mice with MyD88 inhibitor treatment could lessen the outcome of CAC by fecal microbiota transplantation. Conclusions: . The development of CAC was involved in the increasing and ectopic Escherichia in the decreasing colonic mucus layer. MyD88 signaling blockade may maintain the host-microbiota homeostasis by up-regulating MUC2 production, increasing probiotics and their protective effects, and inhibiting the reproduction of Escherichia .