Metformin elicits antitumour effect by modulation of the gut microbiota and rescues Fusobacterium nucleatum-induced colorectal tumourigenesis.

Abstract 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).