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 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

doi:10.1016/j.molmet.2022.101498

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

Mol Metab. 2022 Jul:61:101498. doi: 10.1016/j.molmet.2022.101498. Epub 2022 Apr 20.

Authors

Lindsay A Broadfield¹, Amna Saigal², Jake C Szamosi³, Joanne A Hammill⁴, Ksenia Bezverbnaya⁴, Dongdong Wang¹, Jaya Gautam¹, Evangelia E Tsakiridis¹, Fiorella Di Pastena¹, Jamie McNicol⁴, Jianhan Wu¹, Saad Syed⁵, James S V Lally¹, Amogelang R Raphenya⁶, Marie-Jose Blouin⁷, Michael Pollak⁷, Andrea Sacconi⁸, Giovanni Blandino⁸, Andrew G McArthur⁹, Jonathan D Schertzer¹⁰, Michael G Surette¹¹, Stephen M Collins¹², Jonathan L Bramson⁴, Paola Muti¹³, Theodoros Tsakiridis¹³, Gregory R Steinberg¹⁴

Affiliations

¹ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada.
² Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.
³ Farncombe Family Digestive Research Institute, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
⁴ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
⁵ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada; Farncombe Family Digestive Research Institute, McMaster University, Hamilton, ON, Canada.
⁶ Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
⁷ Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital; Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada.
⁸ Oncogenomic and Epigenetic Unit, Italian National Cancer Institute "Regina Elena", Rome, Italy.
⁹ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
¹⁰ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Farncombe Family Digestive Research Institute, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
¹¹ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada; Farncombe Family Digestive Research Institute, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
¹² Department of Medicine, McMaster University, Hamilton, ON, Canada; Farncombe Family Digestive Research Institute, McMaster University, Hamilton, ON, Canada.
¹³ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Oncology, McMaster University, Hamilton, ON, Canada.
¹⁴ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada. Electronic address: gsteinberg@mcmaster.ca.

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.

Keywords: Colon cancer; Gut microbiome; High-fat diet; Metformin; Obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Metformin

Abstract

Publication types

MeSH terms

Substances

Grants and funding