Metformin-induced reductions in tumor growth involves modulation of the gut microbiome
Lindsay A. Broadfield, Amna Saigal, Jake C. Szamosi, Joanne A. Hammill, Ksenia Bezverbnaya, Dongdong Wang, Jaya Gautam, Evangelia E. Tsakiridis, Fiorella Di Pastena, Jamie McNicol, Jianhan Wu, Saad A. Syed, James Lally, Amogelang R. Raphenya, Marie‐José Blouin, Michaël Pollak, Andrea Sacconi, Giovanni Blandino, Andrew G. McArthur, Jonathan D. Schertzer, Michael G. Surette, Stephen M. Collins, Jonathan L. Bramson, Paola Muti, Theodoros Tsakiridis, Gregory R. Steinberg
Abstract
BACKGROUND/PURPOSE: Type 2 diabetes and obesity increase the risk of developing colorectal cancer. Metformin may reduce colorectal cancer but the mechanisms mediating this effect remain unclear. In mice and humans, a high-fat diet (HFD), obesity and metformin are known to alter the gut microbiome but whether this is important for influencing tumor growth is not known. METHODS: Mice with syngeneic MC38 colon adenocarcinomas were treated with metformin or feces obtained from control or metformin treated mice. RESULTS: We find that compared to chow-fed controls, tumor growth is increased when mice are fed a HFD and that this acceleration of tumor growth can be partially recapitulated through transfer of the fecal microbiome or in vitro treatment of cells with fecal filtrates from HFD-fed animals. Treatment of HFD-fed mice with orally ingested, but not intraperitoneally injected, metformin suppresses tumor growth and increases the expression of short-chain fatty acid (SCFA)-producing microbes Alistipes, Lachnospiraceae and Ruminococcaceae. The transfer of the gut microbiome from mice treated orally with metformin to drug naïve, conventionalized HFD-fed mice increases circulating propionate and butyrate, reduces tumor proliferation, and suppresses the expression of sterol response element binding protein (SREBP) gene targets in the tumor. CONCLUSION: These data indicate that in obese mice fed a HFD, metformin reduces tumor burden through changes in the gut microbiome.