Metformin intolerance in type 2 diabetes mellitus – the possibility of using a multi-strain probiotic
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Students’ Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Poland
Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Poland
Department of Biochemical Science, Pomeranian Medical University, Poland
Submission date: 2023-10-20
Final revision date: 2023-11-02
Acceptance date: 2024-04-05
Publication date: 2024-05-27
Corresponding author
Katarzyna Nabrdalik   

Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Poniatowskiego 15, 40-055, Katowice, Poland
Current Topics in Diabetes 2024;(1):1-6
Metformin is a widely used drug in the management of type 2 diabetes (T2DM); however, its administration is linked with the elevated incidence of gastrointestinal (GI) adverse events (AEs) limiting its use or treatment intensification. The complex interplay between metformin and the gut ecosystem has emerged as a additional of interest, particularly the drug’s impact on the composition and function of the gut microbiota. Therefore, in this review we present the possibility of interfering with microbiota by using multi-strain probiotic to mitigate the GI AEs in patients with metformin intolerance. We synthesise findings from various research studies that explore the modification of gut microbiota as a means to reduce GI AEs in T2DM patients with metformin intolerance. As we discuss the available evidence, the narrative outlines the mechanisms through which probiotics may exert beneficial effects and evaluate the efficacy of different probiotic formulations. The results of research on gut microbiota modification in patients with T2DM and metformin intolerance appear promising in alleviating GI AEs.
International Diabetes Federation. IDF Diabetes Atlas 2022 Reports, Brussels, Belgium 2022.
IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes: recommendations for standard, comprehensive, and minimal care. Diabet Med 2006; 23: 579–593.
Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2022; 65: 1925–10966.
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015; 58: 429–442.
Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002; 137: 25–33.
Florez H, Luo J, Castillo-Florez S, et al. Impact of metformin-induced gastrointestinal symptoms on quality of life and adherence in patients with type 2 diabetes. Postgrad Med 2010; 122: 112–120.
Nabrdalik K, Skonieczna-Żydecka K, Irlik K, et al. Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review, meta-analysis and meta-regression of randomized controlled trials. Front Endocrinol (Lausanne) 2022; 13: 975912.
Bailey CJ, Wilcock C, Scarpello JHB. Metformin and the intestine. Diabetologia 2008; 51: 1552–1553.
Dujic T, Zhou K, Tavendale R, et al. Effect of serotonin transporter 5-HTTLPR polymorphism on gastrointestinal intolerance to metformin: A GoDARTS study. Diabetes Care 2016; 39: 1896–1901.
Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50: 81–98.
DeFronzo R, Fleming GA, Chen K, et al. Metformin-associated lactic acidosis: current perspectives on causes and risk. Metabolism 2016; 65: 20–29.
Cubeddu LX, Bönisch H, Göthert M, et al. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 85–91.
Sun L, Xie C, Wang G, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 2018; 24: 1919–1929.
Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med 1998; 15: 651–656.
Dujic T, Zhou K, Donnelly LA, et al. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes 2015; 64: 1786–1793.
Bouchoucha M, Uzzan B, Cohen R. Metformin and digestive disorders. Diabet Metabol 2011; 37: 90–96.
Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015; 528: 262–266.
Bryrup T, Thomsen CW, Kern T, et al. Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study. Diabetologia 2019; 62: 1024–1035.
Vich Vila A, Collij V, Sanna S, et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat Commun 2020; 11: 362.
Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498: 99–103.
Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490: 55–60.
Hur KY, Lee MS. Gut microbiota and metabolic disorders. Diabetes Metab J 2015; 39: 198–203.
Noureldein MH, Bitar S, Youssef N, et al. Butyrate modulates diabetes-linked gut dysbiosis: epigenetic and mechanistic modifications. J Mol Endocrinol 2020; 64: 29–42.
Khan S, Jena G. The role of butyrate, a histone deacetylase inhibitor in diabetes mellitus: experimental evidence for therapeutic intervention. Epigenomics 2015; 7: 669–680.
Singh V, Lee G, Son H, et al. Butyrate producers, “The Sentinel of Gut”: their intestinal significance with and beyond butyrate, and prospective use as microbial therapeutics. Front Microbiol 2023; 13: 1103836.
Napolitano A, Miller S, Nicholls AW, et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One 2014; 9: e100778.
Mueller NT, Differding MK, Zhang M, et al. Metformin affects gut microbiome composition and function and circulating short-chain fatty acids: a randomized trial. Diabetes Care 2021; 44: 1462–1471.
Huang Y, Lou X, Jiang C, et al. Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes. Front Endocrinol (Lausanne) 2022; 13: 1044030.
Elbere I, Kalnina I, Silamikelis I, et al. Association of metformin administration with gut microbiome dysbiosis in healthy volunteers. PLoS One 2018; 13: e0204317.
Aydin Ö, Nieuwdorp M, Gerdes V. The gut microbiome as a target for the treatment of type 2 diabetes. Curr Diab Rep 2018; 18: 55.
Gest H. The discovery of microorganisms by Robert Hooke and Antoni Van Leeuwenhoek, fellows of the Royal Society. Notes Rec R Soc Lond 2004; 58: 187–201.
Mullish BH, Quraishi MN, Segal JP, et al. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. J Hosp Infect 2018; 100: S1–31.
Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent clostridium difficile. N En J Med 2013; 368: 407–415.
Gasbarrini G, Bonvicini F, Gramenzi A. Probiotics history. J Clin Gastroenterol 2016; 50: S116.
Hill C, Guarner F, Reid G, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014; 11: 506–514.
Burton JH, Johnson M, Johnson J, et al. Addition of a gastrointestinal microbiome modulator to metformin improves metformin tolerance and fasting glucose levels. J Diabetes Sci Technol 2015; 9: 808–814.
Bolam DN, Sonnenburg JL. Mechanistic insight into polysaccharide use within the intestinal microbiota. Gut Microbes 2011; 2: 86–90.
Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the g-protein-coupled receptor FFAR2. Diabetes 2012; 61: 364–371.
Vendrame S, Guglielmetti S, Riso P, et al. Six-week consumption of a wild blueberry powder drink increases bifidobacteria in the human gut. J Agric Food Chem 2011; 59: 12815–12820.
Memon H, Abdulla F, Reljic T, et al. Effects of combined treatment of probiotics and metformin in management of type 2 diabetes: a systematic review and meta-analysis. Diabet Res Clin Pract 2023; 202: 110806.
Hove KD, Brøns C, Færch K, et al. Effects of 12 weeks of treatment with fermented milk on blood pressure, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind placebo-controlled study. Eur J Endocrinol 2015; 172: 11–20.
Palacios T, Vitetta L, Coulson S, et al. Targeting the intestinal microbiota to prevent type 2 diabetes and enhance the effect of metformin on glycaemia: a randomised controlled pilot study. Nutrients 2020; 12: 2041.
Tonucci LB, Olbrich dos Santos KM, Licursi de Oliveira L, et al. Clinical application of probiotics in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study. Clin Nutr 2017; 36: 85–92.
Kale-Pradhan PB, Jassaly HK, Wilhelm SM. Role of Lactobacillus in the prevention of antibiotic-associated diarrhea: a meta-analysis. Pharmacother 2010; 30: 119–126.
Goodman C, Keating G, Georgousopoulou E, et al. Probiotics for the prevention of antibiotic-associated diarrhoea: a systematic review and meta-analysis. BMJ Open 2021; 11: e043054.
Qu L, Ren J, Huang L, et al. Antidiabetic effects of Lactobacillus casei fermented yogurt through reshaping gut microbiota structure in type 2 diabetic rats. J Agric Food Chem 2018; 66: 12696–12705.
Nabrdalik K, Drożdż K, Kwiendacz H, et al. Clinical trial: probiotics in metformin intolerant patients with type 2 diabetes (ProGasMet). Biomed Pharmacother 2023; 168: 115650.
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