YYFZBJS Inhibits Colorectal Tumorigenesis by Remodeling Gut Microbiota and Influence on M2 Macrophage Polarization <i>in vivo</i> and <i>in vitro</i>

Abstract

Background: The occurrence of CRC is believed to be related to a variety of factors. Accumulating evidence shows that microbiota can influence the outcome of cancer immunotherapy. Our previous studies indicated that the extract of Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS), had potent anticancer activities by significantly inhibiting intestinal tumor development in ApcMin/+ mice. However, knowledge regarding the mechanism and effect of YYFZBJS in the prevention of colorectal cancer is limited. Methods: In this study, we investigated the preventive effects of oral administration of YYFZBJS in enterotoxigenic Bacteroides fragilis (ETBF)-colonized mice with azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis. Here, the tumor load, tumor number, histology, and the severity of disease activity index (DAI) scores were reduced as expected. Results: The intragastric administration of YYFZBJS in AOM/DSS model significantly decreased ETBF abundance, immunity and some M2 macrophage markers, including CD206, Arg-1, IL-10, and TGF-β. Additionally, reversing polarized macrophages, which has been modified by YYFZBJS, could suppressed CRC cell proliferation and infiltration, as demonstrated by decreasing some tumor proliferation-related proteins in a dose-dependent manner, including c-Met, cyclinD1 and MMPs. Importantly, ETBF dysbiosis can contribute to the development of colon tumor by stimulating p-STAT3 medicated M2 macrophages polarization to promote chronic inflammation and adenoma malignant transformation, which effectively constrained by YYFZBJS. Conclusion: Altogether, we demonstrate that ETBF dysbiosis may contribute to M2 macrophages-promoted colon carcinogenesis and progression of CRC cells, and indicating that YYFZBJS could be employed as a promising protective agent against ETBF-mediated colorectal cancer. Funding Statement: This research was supported by the National Natural Science Foundation of China (No. 81874399), the Project of Hospital Development Center in Shanghai (No. SHDC2020CR4047). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All animal protocols were approved by the Institutional Animal Use and Care Committee. All experiments and animal care procedures were approved by the Shanghai Medical Experimental Animal Care Commission and were conducted in accordance with the provisions and general recommendations of the Chinese Experimental Animals Administration Legislation. All animals were received humane care according to the National Institutes of Health (USA) guidelines.