Metformin elicits antitumour effect by modulation of the gut microbiota and rescues Fusobacterium nucleatum-induced colorectal tumourigenesis
Xiaowen Huang,
Xialu Hong,
Jilin Wang,
Tiantian Sun,
TaChung Yu,
Yanan Yu,
Jingyuan Fang,
Hua Xiong
Affiliations
Xiaowen Huang
Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai 200001, China
Xialu Hong
Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai 200001, China
Jilin Wang
Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai 200001, China
Tiantian Sun
Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai 200001, China
TaChung Yu
Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai 200001, China
Yanan Yu
Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
Jingyuan Fang
Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai 200001, China; Corresponding author.
Hua Xiong
Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai 200001, China; Corresponding author.
Background: The effect of metformin on gut microbiota has been reported, but whether metformin can suppress colorectal cancer (CRC) by affecting gut microbiota composition and rescue F. nucleatum-induced tumourigenicity remains unclear. Methods: To identify microbiota associated with both CRC occurrence and metformin treatment, first, we reanalyzed the gut microbiome of our previous data on two human cohorts of normal and CRC individuals. Subsequently, we summarized microbiota altered by metformin from published literatures. Several taxa, including Fusobacterium, were associated with both CRC occurrence and metformin treatment. We investigated the effect of metformin on APCMin/+ mice given with or without F. nucleatum. 16S rRNA gene sequencing was performed. Findings: We summarized 131 genera altered by metformin from 18 published literatures. Five genera reported to be changed by metformin, including Bacteroides, Streptococcus, Achromobacter, Alistipes and Fusobacterium, were associated with CRC in both of our human cohorts. Metformin relieved the symptoms caused by F. nucleatum administration in APCMin/+ mice, and showed promise in suppressing intestinal tumour formation and rescuing F. nucleatum-induced tumourigenicity. Administration of F. nucleatum and/or metformin had effect on gut microbiome structure, composition and functions of APCMin/+ mice. Interpretation: This study pioneers in predicting critical CRC-associated taxa contributing to the antitumour effect of metformin, and correlating gut microbiome with the antitumour effect of metformin in experimental animals. We presented a basis for future investigations into metformin's potential effect on suppressing F. nucleatum-induced tumor formation in vivo. Funding: This work was supported by grants from the National Natural Science Foundation of China (31701250).
