Molecular Metabolism (Jul 2022)
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
Affiliations
- Lindsay A. Broadfield
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada
- Amna Saigal
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
- Jake C. Szamosi
- Farncombe Family Digestive Research Institute, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Joanne A. Hammill
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- Ksenia Bezverbnaya
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- Dongdong Wang
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada
- Jaya Gautam
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada
- Evangelia E. Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada
- Fiorella Di Pastena
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada
- Jamie McNicol
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- Jianhan Wu
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada
- Saad Syed
- 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
- James S.V. Lally
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada
- Amogelang R. Raphenya
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Marie-Jose Blouin
- Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital; Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
- Michael Pollak
- Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital; Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
- Andrea Sacconi
- Oncogenomic and Epigenetic Unit, Italian National Cancer Institute “Regina Elena”, Rome, Italy
- Giovanni Blandino
- Oncogenomic and Epigenetic Unit, Italian National Cancer Institute “Regina Elena”, Rome, Italy
- Andrew G. McArthur
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Jonathan D. Schertzer
- 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
- Michael G. Surette
- 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
- Stephen M. Collins
- Department of Medicine, McMaster University, Hamilton, ON, Canada; Farncombe Family Digestive Research Institute, McMaster University, Hamilton, ON, Canada
- Jonathan L. Bramson
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- Paola Muti
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Oncology, McMaster University, Hamilton, ON, Canada
- Theodoros Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Oncology, McMaster University, Hamilton, ON, Canada
- Gregory R. Steinberg
- 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; Corresponding author. HSC 4N63, 1280 Main St W, Hamilton, ON, Canada, L8S 4K1.
- Journal volume & issue
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Vol. 61
p. 101498
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.
