Toll-like receptor 4 prevents AOM/DSS-induced colitis-associated colorectal cancer in Bacteroides fragilis gnotobiotic mice

• Published in: Human & experimental toxicology Vol. 40; no. 4; pp. 622 - 633
• Main Authors: Lee, Yen-Peng, Huang, Wen-Ching, Lin, Tien-Jen, Chiu, Chien-Chao, Wang, Yu-Chih, Chen, Yi-Hsun, Hung, Shao-Wen, Chuang, Hsiao-Li, Chen, Ter-Hsin
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.04.2021; Sage Publications Ltd
• Subjects: Animal models; Animals; Azoxymethane; Bacteroides fragilis; beta Catenin - metabolism; Cancer; Cell proliferation; Colitis; Colitis - chemically induced; Colitis - metabolism; Colitis - microbiology; Colitis - pathology; Colitis-Associated Neoplasms - metabolism; Colitis-Associated Neoplasms - microbiology; Colitis-Associated Neoplasms - pathology; Colon - metabolism; Colon - microbiology; Colon - pathology; Colonization; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - etiology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - microbiology; Colorectal Neoplasms - pathology; Cyclooxygenase 2 - metabolism; Dextran; Dextran Sulfate; Dextrans; Disease Models, Animal; Germ-Free Life; Germfree; Gnotobiotic; Immune system; Immunohistochemistry; Inflammation; Inflammatory bowel disease; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Proliferating cell nuclear antigen; Proliferating Cell Nuclear Antigen - metabolism; Receptors; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-like receptors; Tumors; β-Catenin; gnotobiotic; mono-colonization; Bacteroides fragilis; colitis-associated colorectal cancer; Toll-like receptor 4
• DOI: 10.1177/0960327120954249
• ISSN: 0960-3271; 1477-0903

Bacteroides fragilis (BF) plays a critical role in developing and maintaining the mammalian immune system. We previously found that BF colonization could prevent inflammation and tumor formation in a germ-free (GF) colitis-associated colorectal cancer (CAC) mouse model. The role of Toll-like receptor 4 (TLR4) in CAC development has not been clearly elucidated in BF mono-colonized gnotobiotic mice. The wild-type (WT) and TLR4 knockout (T4K) germ-free mice were raised with or without BF colonization for 28 days (GF/WT, GF/T4K, BF/WT, and BF/T4K) and then CAC was induced under azoxymethane (AOM)/dextran sulfate sodium (DSS) administration. The results showed that tumor formation and tumor incidence were significantly inhibited in the BF/WT group compared to those observed in the GF/WT group. However, the tumor prevention effect was not observed in the BF/T4K group unlike in the BF/WT group. Moreover, the CAC histological severity of the BF/WT group was ameliorated, but more severe lesions were found in the GF/WT, GF/T4K, and BF/T4K groups. Immunohistochemistry showed decreased cell proliferation (PCNA, β-catenin) and inflammatory markers (iNOS) in the BF/WT group compared to those in the BF/T4K group. Taken together, BF mono-colonization of GF mice might prevent CAC via the TLR4 signal pathway.