Modification of the gut microbiome in response to metformin and other antidiabetic drugs
https://doi.org/10.62751/2713-0177-2025-6-3-06
Abstract
Currently, there is a rapid increase in the study of the relationship of the gut microbiota (GM) with the pharmacokinetics and pharmacodynamics of drugs, including hypoglycemic ones. The review describes possible mechanisms by which GM can influence the efficacy and safety of various hypoglycemic drugs (HDs). Moreover, intestinal bacteria affecting the pharmacokinetics of HDs are described. Despite the fact that data on the relationship of GM with the effectiveness and development of side effects of HDs are sharply limited, using the example of metformin, it was determined that the presence in GM of a high number of Short-chain fatty acids (SCFAs) producers and genera associated with bile acid metabolism is associated with high drug efficacy and the development of side effects. The fact is that SCFAs and primary bile acids are triggers for the secretion of glucagon-like peptide-1, which, on the one hand, contributes to the improvement of glycemic indices through the incretin effect and the operation of the “intestine – brain – perif” mechanism.
About the Authors
K. G. Lobanova
Pirogov Russian National Research Medical University
Russian Federation
Russian Federation
Kristina G. Lobanova – C. Sci. (Med.), assistant at the Department of Endocrinology, Institute of Clinical Medicine
Moscow
A. S. Teplova
Pirogov Russian National Research Medical University
Russian Federation
Russian Federation
Anna S. Teplova – Assistant of the Department of Endocrinology of the Medical Faculty Pirogov
Moscow
V. V. Titova
Pirogov Russian National Research Medical University
Russian Federation
Russian Federation
Victoria V. Titova – assistant of the department of endocrinology medical faculty
Moscow
References
1. Pottegard A, Andersen JH, Sondergaard J, Thomsen RW, Vilsboll T. Changes in the use of glucose-lowering drugs: A Danish nationwide study. Diabetes Obes Metab. 2023;25(4):1002–10. doi: 10.1111/dom.14947.
2. Zhang X, Han Y, Huang W, Jin M, Gao Z. The infl of the gut microbiota on the bioavailability of oral drugs. Acta Pharm Sin B. 2021;11(7):1789–812. doi: 10.1016/j.apsb.2020.09.013.
3. Dhurjad P, Dhavaliker C, Gupta K, Sonti R. Exploring drug metabolism by the gut microbiota: Modes of metabolism and experimental approaches. Drug Metab Dispos. 2022;50(3):224–34. doi: 10.1124/dmd.121.000669.
4. Bashiardes S, Christodoulou C. Orally Administered drugs and their complicated relationship with our gastrointestinal tract. Microorganisms. 2024;12(2):242. doi: 10.3390/microorganisms12020242.
5. Balaich J., Estrella M., Wu G., et al. The human microbiome encodes resistance to the antidiabetic drug acarbose. Nature. 2021 Dec;600(7887):110-115. doi: 10.1038/s41586-021-04091-0
6. Pavlovic N, Golocorbin-Kon S, Danic M, Stanimirov B, Al-Salami H, Stankov K, Mikov M. Bile acids and their derivatives as potential modifiers of drug release and pharmacokinetic profiles. Front Pharmacol. 2018;9:1283. doi: 10.3389/fphar.2018.01283.
7. Drozdzik M, Czekawy I, Oswald S, Drozdzik A. Intestinal drug transporters in pathological states: An overview. Pharmacol Rep. 2020;72(5):1173–94. doi: 10.1007/s43440-020-00139-6.
8. Bocci G, Oprea TI, Benet LZ. State of the art and uses for the Biopharmaceutics Drug Disposition Classification System (BDDCS): New additions, revisions, and citation references. AAPS J. 2022;24(2):37. doi: 10.1208/s12248-022-00687-0.
9. Cheng M, Ren L, Jia X, Wang J, Cong B. Understanding the action mechanisms of metformin in the gastrointestinal tract. Front Pharmacol. 2024;15:1347047. doi: 10.3389/fphar.2024.1347047.
10. Lee Y, Kim AH, Kim E, Lee S, Yu KS, Jang IJ et al. Changes in the gut microbiome influence the hypoglycemic effect of metformin through the altered metabolism of branched-chain and nonessential amino acids. Diabetes Res Clin Pract. 2021;178:108985. doi: 10.1016/j.diabres.2021.108985.
11. Li R, Shokri F, Rincon AL, Rivadeneira F, Medina-Gomez C, Ahmadizar F. Bi-directional interactions between glucose-lowering medications and gut microbiome in patients with type 2 diabetes mellitus: A systematic review. Genes (Basel). 2023;14(8):1572. doi: 10.3390/genes14081572.
12. Elbere I, Silamikelis I, Dindune II, Kalnina I, Briviba M, Zaharenko L et al. Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients. PLoS One. 2020;15(10):e0241338. doi: 10.1371/journal.pone.0241338.
13. Ke H, Li F, Deng W, Li Z, Wang S, Lv P, Chen Y. Metformin exerts anti-inflammatory and mucus barrier protective eff by enriching Akkermansia muciniphila in mice with ulcerative colitis. 2021. Front Pharmacol. 2021;12:726707. doi: 10.3389/fphar.2021.726707.
14. Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018;24(12):1919–29. doi: 10.1038/s41591-018-0222-4
15. Danic M, Stanimirov B, Pavlovic N, Vukmirovic S, Lazic J, Al-Salami H, Mikov M. Transport and biotransformation of gliclazide and the effect of deoxycholic acid in a probiotic bacteria model. Front Pharmacol. 2019;10:1083. doi: 10.3389/fphar.2019.01083.
16. Madsen MSA, Gronlund RV, Eid J, Christensen-Dalsgaard M, Sommer M, Rigbolt K et al. Characterization of local gut microbiome and intestinal transcriptome responses to rosiglitazone treatment in diabetic db/db mice. Biomed Pharmacother. 2021;133:110966. doi: 10.1016/j.biopha.2020.110966.
17. Nepelska M, de Wouters T, Jacouton E, et al. Commensal gut bacteria modulate phosphorylation-dependent PPARγ transcriptional activity in human intestinal epithelial cells. Sci Rep. 2017 Mar 7;7:43199. doi: 10.1038/srep43199.
18. Kasahara N, Imi Y, Amano R, Shinohara M, Okada K, Hosokawa Y et al. A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF-β signaling in hepatic stellate cells. Sci Rep. 2023;13(1):18983. doi: 10.1038/s41598-023-46404-5.
19. Wang K, Zhang Z, Hang J, et al. Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target. Science. 2023 Aug 4;381(6657):eadd5787. doi: 10.1126/science.add5787.
20. Olivares M, Hernandez-Calderon P, Cardenas-Brito S, Liebana-Garcia R, Sanz Y, Benitez-Paez A. Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation. Genome Biol. 2024;25(1):174. doi: 10.1186/s13059-024-03325-4.
21. Zhang X, Ren H, Zhao C, et al. Metagenomic analysis reveals crosstalk between gut microbiota and glucose-lowering drugs targeting the gastrointestinal tract in Chinese patients with type 2 diabetes: a 6 month, two-arm randomised trial. Diabetologia. 2022 Oct;65(10):1613-1626. doi: 10.1007/s00125-022-05768-5.
22. Tsai CY, Lu HC, Chou YH, et al. Gut Microbial Signatures for Glycemic Responses of GLP-1 Receptor Agonists in Type 2 Diabetic Patients: A Pilot Study. Front Endocrinol (Lausanne). 2022 Jan 10;12:814770. doi: 10.3389/fendo.2021.814770
23. Martchenko SE, Martchenko A, Cox BJ, et al. Circadian GLP-1 Secretion in Mice Is Dependent on the Intestinal Microbiome for Maintenance of Diurnal Metabolic Homeostasis. Diabetes. 2020 Dec;69(12):2589-2602. doi: 10.2337/db20-0262.
24. Zhang Y, Xie P, Li Y, Chen Z, Shi A. Mechanistic evaluation of the inhibitory eff of four SGLT-2 inhibitors on SGLT 1 and SGLT 2 using physiologically based pharmacokinetic (PBPK) modeling approaches. Front Pharmacol. 2023;14:1142003. doi: 10.3389/fphar.2023.1142003.
25. Klemets A, Reppo I, Liis Krigul K, Volke V, Aasmets O, Org E. Fecal microbiome predicts treatment response after the initiation of semaglutide or empagliflozin uptake. medRxiv. 2024.07.19.24310611. Preprint. doi: 10.1101/2024.07.19.24310611.
26. Li F, Dong YZ, Zhang D, Zhang XM, Lin ZJ, Zhang B. Molecular mechanisms involved in drug-induced liver injury caused by urate-lowering Chinese herbs: A network pharmacology study and biology experiments. PLoS One. 2019;14(5):e0216948. doi: 10.1371/journal.pone.0216948.
27. Bryrup T, Thomsen CW, Kern T, Allin KH, Brandslund I, Jorgensen NR 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(6):1024–35. doi: 10.1007/s00125-019-4848-7.
28. Zhang H, Lai J, Zhang L, Zhang W, Liu X, Gong Q et al. The co-regulation of the gut microbiome and host genes might play essential roles in metformin gastrointestinal intolerance. Toxicol Appl Pharmacol. 2023;481:116732. doi: 10.1016/j.taap.2023.116732.
Review
For citations:
Lobanova K.G., Teplova A.S., Titova V.V. Modification of the gut microbiome in response to metformin and other antidiabetic drugs. FOCUS. Endocrinology. 2025;6(3):86-95. (In Russ.) https://doi.org/10.62751/2713-0177-2025-6-3-06
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