Sudan Journal of Medical Sciences Volume 15, Issue no. 4, DOI 10.18502/sjms.v15i4.8165 Production and Hosting by Knowledge E Research Article The Cross-talk Relationship between Metformin and Gut Microbiota Hyder O. Mirghani. MD, M.Sc. Associate Professor of Internal Medicine and Endocrine, Medical Department, Faculty of Medicine, University of Tabuk, KSA Abstract Background: Metformin is the first-line oral therapy for type 2 diabetes mellitus. However, its mode of action is poorly defined. There is an increasing awareness regarding the cross talk of gut microbiota and metformin. The current review aimed to assess the bidirectional relationship between metformin and gut microbiota. Methods: Electronic search was conducted in Pub Med and the first 100 articles in Google Scholar published until November 2019. However, only randomized controlled trials on humans published in the English language were included. The terms “gut microbiota,” “gut flora ”and “ metformin” were as keywords to perform the search. Although 124 articles were retrieved, only six met the inclusion criteria of the study. Results: Of the six full texts of randomized controlled trials included in the study, two-thirds were published in Europe, one in the USA, and one in China. Six hundred- thirty five patients were included and the duration of the studies ranged from seven days to six months. The studies concluded that microbiota modulates some metformin actions on plasma glucose; while metformin enhances the abundance of microbiota that positively affect insulin resistance and plasma glucose. Conclusion: The current review showed that microbiota dysbiosis may mediate metformin antidiabetic effects. Whereas metformin shifted the gut microbiota toward the beneficial species ameliorating insulin resistance. The present study might provide insights into a novel therapeutic approach to treat type 2 diabetes mellitus. Keywords: gut microbiota, metformin, type 2 diabetes 1. Introduction Over decades of clinical use as the first-line drug for the treatment of diabetes mellitus, metformin has proved to be safe and well tolerated. Metformin enhances insulin action in the liver and skeletal muscles to decrease insulin production and increase non- oxidative disposal of glucose. When taken together, these actions reduce insulin in the hyperglycemic state with little potential for hypoglycemia [1]. However, the mechanism of action of metformin is not completely understood. There is an increasing awareness about the role of the gastrointestinal tract in the regulation of plasma glucose, mainly through microbiota effects on incretins, bile acids, and glucagon-like peptide [2]. How to cite this article: Hyder O. Mirghani. MD, M.Sc. (2020) “The Cross-talk Relationship between Metformin and Gut Microbiota,” Sudan Journal of Medical Sciences, vol. 15, issue no. 4, pages 425–430. DOI 10.18502/sjms.v15i4.8165 Page 425 Corresponding Author: Hyder O. Mirghani; Faculty of Medicine, University of Tabuk, PO Box 3378 Tabuk 51941, Saudi Arabia email: s.hyder63@hotmail.com Received 3 November 2020 Accepted 18 December 2020 Published 31 December 2020 Production and Hosting by Knowledge E Hyder O. Mirghani. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Editor-in-Chief: Prof. Mohammad A. M. Ibnouf http://www.knowledgee.com mailto:s.hyder63@hotmail.com https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Sudan Journal of Medical Sciences Hyder O. Mirghani The inhibition of the mitochondrial respiratory chain mediated by activation of adeno- sine monophosphate-activated protein kinase (AMPK) thought as the center of met- formin action has been challenged and it may account for indirect changes in insulin sensitivity [3]; blocking this pathway is not followed by loss of metformin effects on glucose. In addition, oral metformin is more effective than intravenous, raising the possibility of an important gut role. The gut microbiota is the first protection system of the gastrointestinal tract; it is composed of thousands of species and more than 15,000 kinds of bacteria in weight equal to 1 kg [4]. Recent studies showed that the gut microbiota might play an important role in the pharmacodynamics and pharmacokinetics of metformin, while the drug metformin alters the functional capacity of gut microbiota [5, 6]. The gut microbiota is an area of extensive research due to its associations with various diseases including diabetes mellitus. An interesting recent study conducted among patients with type 2 diabetes mellitus (50%), overweight/obesity (78%), co-morbid psychiatric (65%), and opioid use (45%) disorders in the USA concluded the interaction between metformin, gut microbiota, and opioid use [7]. The current review assessed the role of metformin on the gut microbiota, and whether the gut microbiota mediates the actions of metformin. 2. Methods An electronic search was conducted in Pub Med database and the first 100 articles in Google Scholar for relevant articles in the English language; the search was limited to randomized controlled trial on humans from the first published article to November 2019. The terms “gut flora” “metformin,” and “gut microbiota were used as keywords with protean and/or OR. Articles published in languages other than English and studies on animals were not included. One hundred twenty-four articles were retrieved. The titles and abstracts of the articles were screened for the removal of duplications and irrelevant articles. Only six articles fulfilled the inclusion criteria. Figure 1 illustrates the different phases of the search process. 3. Results The six selected randomized controlled trials (four from Europe, one from the USA, and one from Asia) included 635 patients who received metformin for a duration ranging from seven days to six months, the dose ranged from 1 gr/day to 1.7 gr/day. All studies showed that metformin altered microbiota and improved glucose tolerance. In addition, metformin increased the gut microbiota species with positive effects on insulin resistance and plasma glucose, some studies reported a favorable effect on lipids as well (Table 1). DOI 10.18502/sjms.v15i4.8165 Page 426 Sudan Journal of Medical Sciences Hyder O. Mirghani Records iden!fied through database searching (n = 124) S c r e e n in g In c lu d e d E li g ib il it y Id e n ti fi c a ti o n Addi!onal records iden!fied through other sources (n = 0); no other sources Records a#er duplicates removed (n = 111) Records screened (n = 46) Records excluded (n = 55) Full-text ar!cles assessed for eligibility (n = 46 ) Full-text ar!cles excluded (n = 40) Studies included in the qualita!ve synthesis (n = 6) Figure 1: Flow diagram of the different phases of the systematic review (PRISMA flowchart). 4. Discussion In the present review of randomized controlled studies, Napolitano et al. [8] assessed 14 patients on metformin 1000 mg/day and followed them up for three months. The study assessed gut microbiota, gut hormones including glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine, glucose-dependent insulinotropic peptide), and blood and fecal bile acids at four points (baseline, after metformin withdrawal, when the fasting plasma glucose was 25% above normal, and after the drugs were reintroduced. The researcher observed an increased level of GLP-1 and reduction in bile acids with DOI 10.18502/sjms.v15i4.8165 Page 427 Sudan Journal of Medical Sciences Hyder O. Mirghani TABLE 1: The relationship between metformin and gut microbiota. Author Year Country Number of patients Study duration Results Napolitano et al. 2014 UK 14 Three months on metformin 1000 mg/day Metformin changed gut microbes ( phylum Firmicutes and Bacteroidetes abundance) in patients with type 2 diabetes Burton et al. 2015 USA 14 Two weeks on 1500 mg/day with microbiome modulator Microbiome modulator (NM504) in addition to metformin increased efficacy and tolerability of the drug Pendersen et al. 2016 UK 29 patients Prebiotics for 21 weeks No effect of prebiotics on microbiota proposed that metformin may play a role Wu et al. 2017 Sweden 120 days on metformin or placebo with a washout period Microbiota mediates some metformin antidiabetic effects; moreover, fecal transplantation from metformin-treated patients improved glycemia among mice Albere et al. 2018 Latvia 18 Metformin 850 twice daily for seven days Metformin had an immediate effect on gut microbiota Tong et al. 2018 China 400 12 weeks Metformin shifted the gut microbiota (the abundance of the Blautia spp. that improved insulin resistance), ameliorated hyperlipidemia, and improved glycemic control metformin, while the reverse happened with metformin withdrawal. Furthermore, the researchers observed that the abundance of Bacteroidetes was negatively correlated with changes in cholic acid and conjugates, while phylum Firmicutes abundance was positively correlated. These results imply that metformin exerts gut-based pharmacol- ogy. A study published in the United States [9] found that the addition of microbiome modulator to metformin increased both efficacy and tolerability in the form of glucose profile improvement and lesser gastrointestinal manifestations (the most common side effects of metformin). The aforementioned findings supported the previous observations regarding the role of gut microbiota on metformin. Also, it may pave the way for more use of this essential first-line antidiabetic medication. Pendersen et al. [10] assessed the effects of prebiotics on gut microbiota and found no positive results. However, the authors proposed that metformin might play a role. A study [11] with a long period of follow-up (120 days) observed that microbiota mediates some metformin antidia- betic effects; moreover, fecal transplantation from metformin-treated patients improved glycemia among mice. This observation suggested that metformin may play a major role in fecal transplantation, and supporting the previous finding, fecal transplantation was an effective measure including diabetes mellitus, autism, and inflammatory bowel disease among various diseases [12–14]. It is interesting to note that metformin had an immediate effect on the gut microbiota starting from the first 24 hr [15], a study with a relatively large sample size [16] showed that metformin shifted the gut microbiota, ameliorated hyperlipidemia, and improved glycemic control. DOI 10.18502/sjms.v15i4.8165 Page 428 Sudan Journal of Medical Sciences Hyder O. Mirghani 5. Conclusion The current review showed that microbiota dysbiosis might mediate the antidiabetic effects of metformin. While metformin shifted the gut microbiota toward the beneficial species, the current review showed that gut microbiota might serve as a promising target for diabetes control, which has become a worldwide public health threat. Acknowledgements The author would like to acknowledge Dr. Abdullah Hammad EL-Temani, Associate Professor of Family Medicine, Department of Family Medicine, Faculty of Medicine, University of Tabuk, Saudi Arabia for revising this manuscript Ethical considerations The study has been approved by the University of Tabuk, Saudi Arabia. Competing interests The author declares that there are no conflicts of interest. Availability of data and material The data included in the study is available upon reasonable request Funding None References [1] Hostalek, U., Gwilt, M., and Hildemann, S. (2015). Therapeutic use of metformin in prediabetes and dia- betes prevention. Drugs, vol. 75, no. 10, pp. 1071–1094. doi:10.1007/s40265-015-0416-8 [2] Sansome, D. 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Canadian Journal of Diabetes, vol. 43, no. 3, pp. 224–231. doi:10.1016/j.jcjd.2019.01.007 DOI 10.18502/sjms.v15i4.8165 Page 429 Sudan Journal of Medical Sciences Hyder O. Mirghani [7] Barengolts, E., Green, S. J., Eisenberg, Y., et al. (2018). Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease. PLOS ONE, vol. 13, no. 3, p. e0194171. doi:10.1371/journal.pone.0194171 [8] Napolitano, A., Miller, S., Nicholls, A. W., et al. (2014). Novel gut-based pharmacology of met- formin in patients with type 2 diabetes mellitus. PLOS ONE, vol. 9, no. 7, p. e100778. doi:10.1371/journal.pone.0100778 [9] Burton, J. H., Johnson, M., Johnson, J., et al. (2015). Addition of a gastrointestinal microbiome modulator to metformin improves metformin tolerance and fasting glucose levels. 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MBio, vol. 9, no. 3, pii: e02392-17. doi:10.1128/mBio.02392-17 DOI 10.18502/sjms.v15i4.8165 Page 430 Introduction Methods Results Discussion Conclusion Acknowledgements Ethical considerations Competing interests Availability of data and material Funding References