Metformin-induced reductions in tumor growth involves modulation of the gut microbiome.

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.

• Authors: 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 Syed, James S V Lally, Amogelang R Raphenya, Marie-Jose Blouin, Michael 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
• Journal: Molecular metabolism (Mol Metab) Vol. 61 Pg. 101498 (07 2022) ISSN: 2212-8778 [Electronic] Germany
• PMID: 35452877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Chemical References

• Metformin

Topics

• Animals
• Colorectal Neoplasms
• Diabetes Mellitus, Type 2
• Diet, High-Fat (adverse effects)
• Gastrointestinal Microbiome (physiology)
• Metformin (pharmacology, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Obesity (drug therapy)