Gut microbiota from colorectal cancer patients enhances the progression of intestinal adenoma in Apcmin/+ mice

Lu Li; Xiaofei Li; Weilong Zhong; Min Yang; Mengque Xu; Yue Sun; Jiaheng Ma; Tianyu Liu; Xueli Song; Wenxiao Dong; Xiang Liu; Yange Chen; Yi Liu; Zaripa Abla; Wentian Liu; Bangmao Wang; Kui Jiang; Hailong Cao

doi:10.1016/j.ebiom.2019.09.021

Gut microbiota from colorectal cancer patients enhances the progression of intestinal adenoma in Apc^min/+ mice

EBioMedicine. 2019 Oct:48:301-315. doi: 10.1016/j.ebiom.2019.09.021. Epub 2019 Oct 5.

Authors

Lu Li¹, Xiaofei Li¹, Weilong Zhong¹, Min Yang¹, Mengque Xu², Yue Sun¹, Jiaheng Ma¹, Tianyu Liu¹, Xueli Song¹, Wenxiao Dong¹, Xiang Liu¹, Yange Chen¹, Yi Liu³, Zaripa Abla⁴, Wentian Liu¹, Bangmao Wang⁵, Kui Jiang⁶, Hailong Cao⁷

Affiliations

¹ Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.
² Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
³ Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China; Department of Gastroenterology and Hepatology, Hotan District People's Hospital, Xinjiang Uygur Autonomous Region, Xinjiang, China.
⁴ Department of Gastroenterology and Hepatology, Hotan District People's Hospital, Xinjiang Uygur Autonomous Region, Xinjiang, China.
⁵ Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. Electronic address: tjmughgi@hotmail.com.
⁶ Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. Electronic address: kjiang@tmu.edu.cn.
⁷ Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China; Department of Gastroenterology and Hepatology, Hotan District People's Hospital, Xinjiang Uygur Autonomous Region, Xinjiang, China. Electronic address: caohailong@tmu.edu.cn.

Abstract

Background: Accumulating evidence points to a close relationship between gut dysbiosis and colorectal cancer (CRC). As >90% of CRC develop from adenoma, we aimed to investigate the crucial role of imbalanced gut microbiota on the progression of intestinal adenoma.

Methods: The Apc^min/+ mice gavage with phosphate-buffered saline (PBS), feces from healthy controls or CRC patients after antibiotic cocktails. The intestinal tissues were isolated for histopathology, western blotting, and RNA-seq. The microbiota of feces and short-chain fatty acids (SCFAs) were analysed by 16S rDNA Amplicon Sequencing and gas chromatography.

Findings: The Apc^min/+mice gavaged by feces from CRC patients had more intestinal tumours compared with those fed with feces from healthy controls or PBS. Administration of feces from CRC patients increased tumour proliferation and decreased apoptosis in tumour cells, accompanied by impairment of gut barrier function and up-regulation the pro-inflammatory cytokines profile. The up-regulated the expression of β-catenin and cyclinD1 further indicating the activation of Wnt signalling pathway. The abundance of pathogenic bacteria was increased after FMT, while producing SCFAs bacteria and SCFAs production were decreased.

Interpretation: Gut microbiota of CRC patients disrupted intestinal barrier, induced low-grade inflammation and dysbiosis. The altered gut microbiota enhanced the progression of intestinal adenomas in Apc^min/+mice, suggesting that a new strategy to target gut microbiota against CRC could be noted. FUND: The study was supported by the National Natural Science Foundation of China, Tianjin Research Programme of Application Foundation and Advanced Technology of China, and China Postdoctoral Science Foundation.

Keywords: Apc(min/+) mice; Colorectal cancer; Fecal microbiota transplantation; Gut microbiota; Wnt signalling pathway.