People with diabetes and obesity have altered gut microbiomes, with more detrimental Firmicutes at the expense of beneficial Bacteroidetes1,2. Firmicutes are proinflammatory, promote harvesting and storage of fat and can cause glucose intolerance3. It is now recognised that the microbiome is a significant contender in the pathogenesis of many chronic diseases, including metabolic ones like diabetes4.

People who undergo gastric bypass surgery often experience significant metabolic changes which cannot be attributed to weight loss alone5. Recent research into this puzzling phenomenon suggests these patients develop a more diverse microbiome, which could help explain the dramatic improvements in glucose and lipid metabolism.

As a pharmacist, Metformin would have to be my favourite drug and it keeps on delivering. It has stood the test of time and, despite promising new drugs on the market, remains first line for type 2 diabetes6. It has a proven track record and is safe and well-tolerated by most patients. The funny thing is, despite being so widely prescribed for over 50 years, its mechanism of action has remained relatively unclear. Recent findings have revealed its long-kept secret.

The bioavailability of Metformin is about 50%, which means, when taken orally, only half the drug actually reaches the systemic circulation7. The remaining 50% concentrates in the gut mucosa at concentrations 30 to 300 times greater than in the plasma8. Moreover, when given intraveneously, it is not particularly effective at reducing blood sugar levels9. A recent study found that, when a delayed release oral metformin dose was given – so that the medication was released only when it reached the lower part of the gastrointestinal tract – it was more effective at lowering blood sugar levels than conventional tablets, despite lower plasma concentrations10.

Researchers then hypothesised that if Metformin’s mechanism of action resides in the gut, perhaps it is due to alterations in the gut microbiome. This is exactly what they found: metformin does in fact shift the gut microbiota, promoting more beneficial microbes11. These beneficial microbes produce anti-inflammatory short chain fatty acids (SCFA) and promote the integrity of the gut lining, which explains part of its glucose lowering and anti-inflammatory effects12.

To prove cause and effect, researchers transferred a faecal transplant from individuals treated with metformin into germ-free mice (no microbiomes) and found that two out of three recipients showed improved glucose tolerance13. This further supports the notion that Metformin’s glucose-lowering effect is partly due to its microbiome-altering properties.

Armed with this insight into Metformin’s anti-inflammatory and pleiotropic effects, researchers are now studying its effectiveness in a range of conditions, including cardiovascular disease, cancer and aging, with promising results14,15,16. What we should really take away from this research is the power of the microbiome!

We know that diet and lifestyle are pivotal for a healthy, blossoming microbiome and, combined, can be more powerful than any drug. A recent study demonstrated how dietary fibre increased the relative abundance of SCFA producing microbiota which resulted in reduced HbA1c17. The greater the variety and abundance of these SCFA producing microbes, the greater the reduction in HbA1c.

Educating patients about the tiny life-forms that reside in our gut can be both eye-opening and empowering. When they learn that these microbes are at the mercy of our lifestyle habits and behaviours, many feel a sense of control and optimism. For me, this is another tool in my toolbox for provoking informed behaviour change.

  1. Ley, Ruth E.; Backhed, Fredrik; Turnbaugh, Peter; Lozupone, Catherine A.; Knight, Robin D.; Gordon, Jeffrey I, 2005, Obesity alters gut microbial ecology’, Proceedings of the National Academy of Sciences of the United States, Vol.102(31), p.11070(6)
  2. Larsen N, Vogensen FK, van den Berg FWJ, Nielsen DS, Andreasen AS, et al. (2010) Gut Microbiota in Human Adults with Type 2 Diabetes Differs from Non-Diabetic Adults. PLoS ONE 5(2): e9085. doi:10.1371/journal.pone.0009085
  3. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, et al. (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444: 1027–1131
  4. Baothman, Othman A ; Zamzami, Mazin A ; Taher, Ibrahim ; Abubaker, Jehad ; Abu-Farha, Mohamed, 2016, ‘The role of the gut microbiota in the development of obesity and diabetes’, Lipids in health and disease,  Vol.15, p.108
  5. Kirwan, John P; Münzberg, Heike; Berthoud, Hans-Rudolf, Mechanisms Responsible for Metabolic Improvements of Bariatric Surgeries.,Diabetes, 2018, Vol.67(6), pp.1043-1044
  6. General practice management of type 2 diabetes – 2014–15. Melbourne: The Royal Australian College of General Practitioners and Diabetes Australia, 2014.
  7. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50:81–98
  8. Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia 2008;51: 1552–1553
  9. Enzo Bonora, Massimo Cigolini, Ottavio Bosello, Carlo Zancanaro, Luigi Capretti, Ivana Zavaroni, Carlo Coscelli & Ugo Butturini, 1984, ‘Lack of effect of intravenous metformin on plasma concentrations of glucose, insulin, C-peptide, glucagon and growth hormone in non-diabetic subjects’, Current Medical Research and Opinion, 9:1, 47-51
  10. Buse JB, DeFronzo RA, Rosenstock J, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 2016;39:198–205
  11. Lee, Heetae ; Ko, Gwangpyo ; Griffiths, M. W, 2014,  Effect of Metformin on Metabolic Improvement and Gut Microbiota, Applied and Environmental Microbiology, Vol.80(19), pp.5935-5943
  12. de la Cuesta-Zuluaga, J. et al. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid– producing microbiota in the gut. Diabetes Care 40, 54–62 (2017)
  13. Hao Wu1,12, Eduardo Esteve2–4,12, Valentina Tremaroli1, Muhammad Tanweer Khan1, Robert Caesar1, Louise Mannerås-Holm1, Marcus Ståhlman1, Lisa M Olsson1, Matteo Serino5, Mercè Liping Planas-Fèlix6, Gemma Xifra2–4, Josep M Mercader6, David Torrents6,7, Rémy Burcelin8,9, Wifredo Ricart2–4, Rosie Perkins1, José Manuel Fernàndez-Real2–4 & Fredrik Bäckhed 2017, Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug, nature medicine,  volume 23 | number 7,
  14. Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2012;2:778–790
  15. Olga Moiseeva, Xavier-Deschênes-Simard, Michael Pollak, and Gerardo Ferbeyre, Metformin, aging and cancer,  2013 May; 5(5): 330–331. doi: 10.18632/aging.100556
  16. Rena, C., Graham ; Lang, C., Chim, Repurposing Metformin for Cardiovascular Disease, Circulation, 2018, Vol.137(5), p.422-424
  17. Zhao1,2,*,†, Feng Zhang1,*, Xiaoying Ding3,*, Guojun Wu1,*, Yan Y. Lam2,*, Xuejiao Wang3, Huaqing Fu1, Xinhe Xue1, Chunhua Lu4, Jilin Ma4, Lihua Yu4, Chengmei Xu4, Zhongying Ren4, Ying Xu5, Songmei Xu5, Hongli Shen5, Xiuli Zhu5, Yu Shi6, Qingyun Shen6, Weiping Dong3, Rui Liu1, Yunxia Ling3, Yue Zeng7, Xingpeng Wang7, Qianpeng Zhang1, Jing Wang1, Linghua Wang1, Yanqiu Wu1, Benhua Zeng8, Hong Wei8, Menghui Zhang1, Yongde Peng3,†, Chenhong Zhang1, 2018, Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes, Science, Vol. 359, Issue 6380, pp. 1151-1156, DOI: 10.1126/science.aao5774

This article has been written for the Australasian Society of Lifestyle Medicine (ASLM) by the documented original author. The views and opinions expressed in this article are solely those of the original author and do not necessarily represent the views and opinions of the ASLM or its Board.

Juliet Richards is a Consultant Pharmacist, Credentialed Diabetes Educator and an ASLM-Certified Practitioner in Lifestyle Medicine.

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