High-Fat Diet-Induced Gut Dysbiosis Promotes Intestinal Adenoma-Adenocarcinoma Sequence Through Activation of MCP-1/CCR2 Axis

Abstract

Background: High-fat diet (HFD) is a well-known risk factor for gut microbiota dysbiosis and colorectal cancer (CRC). However, evidence relating HFD, gut microbiota and carcinogenesis is limited. Our study aimed to demonstrate that HFD-induced gut dysbiosis promoted intestinal adenoma-adenocarcinoma sequence. Methods: Apcmin/ mice model was used to determine the association between HFD-induced dysbiosis and monocyte chemoattractant protein 1/CC chemokine receptor 2 (MCP-1/CCR2) axis in intestinal carcinogenesis, and clinical data were used to further validate the potential mechanisms. Findings: HFD consumption could induce gut dysbiosis and promote intestinal carcinogenesis in Apcmin/ mice, accompanying with activation of MCP-1/CCR2 axis that recruited and polarized M2 tumor-associated macrophages (TAMs). Interestingly, transfer of fecal microbiota from HFD-fed mice to another batch of Apcmin/ mice in the absence of HFD could also enhance carcinogenesis without significant body weight gain, and induced MCP-1/CCR2 axis activation. HFD-induced dysbiosis could also be transmitted. Meanwhile, antibiotics cocktail treatment was sufficient to inhibit HFD-induced carcinogenesis, indicating the vital role of dysbiosis in cancer development. In addition, clinical data showed that HFD increased the incidence of advanced colorectal neoplasia (AN), and activated the MCP-1/CCR2 axis in CRC patients with HFD in daily life. Interpretation: Our data indicated that HFD-induced dysbiosis accelerated intestinal adenoma-adenocarcinoma sequence through activation of MCP-1/CCR2 axis, which would provide new insight into better understanding of the mechanisms and prevention for HFD-related CRC. Funding Statement: This study is supported by the grants (81741075, 81570478 and 81700456) from the National Natural Science Foundation of China, the grant (17JCYBJC24900) from Natural Science Foundation of Tianjin and the grant (YJSCX201801) from Postgraduate Innovation Fund of ‘13th Five-Year comprehensive investment’, Tianjin Medical University. Declaration of Interests: The authors of this paper declare that they have no competing interests. Ethics Approval Statement: Informed consents were signed by all patients, and ethical approval was obtained from the Ethics Committee of General Hospital, Tianjin Medical University, China.