AccScience Publishing / EJMO / Volume 8 / Issue 1 / DOI: 10.14744/ejmo.2024.53968
REVIEW

Type 2 Diabetes Mellitus and the Gut Microbiota: Charting New Territory for Sodium-Glucose Co-Transporter 2 Inhibitors

Natalia Stepanova1
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1 Professor of Medicine, Medical Director of the Medical Center LLC “Nephrocenter” Dovzhenka 3 Kyiv, Ukraine
Submitted: 24 November 2023 | Accepted: 11 February 2024 | Published: 6 March 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract

The gut microbiome is a dynamic microecosystem within us that actively influences health beyond digestion. It impacts energy regulation, the immune response, and even drug metabolism. People with type 2 diabetes mellitus (T2DM) exhibit variations in the gut microbiota, linking gut dysbiosis to metabolic dysfunction. In the pursuit of novel therapeutic strategies for T2DM, the intricate interplay between sodium-glucose co-transporter 2 (SGLT2) inhibitors and the gut microbiota emerges as a promising frontier. Renowned for their effectiveness in glycemic control, SGLT2 inhibitors have a range of benefits, including renoprotection, weight loss, blood pressure reduction, and cardiovascular protection. Although the exact mechanisms responsible for these multifaceted advantages remain unclear, recent evidence indicates that SGLT2 inhibitors potentially affect the gut microbiota. This review sheds light on the potential benefits of SGLT2 inhibitors mediated by their influence on the gut microbiota in the management of T2DM by examining the current understanding and developments in this field of research.

Keywords
Type 2 diabetes mellitus
gut microbiota
sodium-glucose co-transporter-2 (SGLT2) inhibitors
treatment
prevention
Conflict of interest
None declared.
References

1. Unnikrishnan R, Pradeepa R, Joshi SR, Mohan V. Type 2 diabetes: Demystifying the global epidemic. Diabetes 2017;66:1432–42.
2. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of type 2 diabetes - global burden of disease and forecasted trends. J Epidemiol Glob Health 2020;10:107–11.
3. Demikhova N, Chernatska O, Mazur T, Bokova S, Rudenko T, Bumeister L, et al. Markers of cardiovascular complications in patients with type 2 diabetes mellitus and arterial hypertension. Bangladesh J Med Sci 2018;17:319–22.
4. Mambiya M, Shang M, Wang Y, Li Q, Liu S, Yang L, et al. The play of genes and non-genetic factors on type 2 diabetes. Front Public Health 2019;7:349.
5. Kolb H, Martin S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BMC Med 2017;15:131.
6. Shifris I. Diabetic status, comorbidity and survival in patients with chronic kidney disease stage VD: A cohort study. Probl Endocr Pathol 2020;72:95–103.
7. Chernatska O, Demikhova N. Improvement of treatment in persons with arterial hypertension and type 2 diabetes mellitus. Georgian Med News 2018;11:47–51.
8. Tat V, Forest CP. The role of SGLT2 inhibitors in managing type 2 diabetes. JAAPA 2018;31:35–40.
9. Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovasc Diabetol 2022;21:83.
10. Cani PD. Human gut microbiome: Hopes, threats and promises. Gut 2018;67:1716–25.
11. Iatcu CO, Steen A, Covasa M. Gut microbiota and complications of type-2 diabetes. Nutrients 2021;14:166.
12. Zhou Z, Sun B, Yu D, Zhu C. Gut microbiota: An important player in type 2 diabetes mellitus. Front Cell Infect Microbiol 2022;12:834485.
13. de Vos WM, Tilg H, Van Hul M, Cani PD. Gut microbiome and health: Mechanistic insights. Gut 2022;71:1020–32.
14. Madhogaria B, Bhowmik P, Kundu A. Correlation between human gut microbiome and diseases. Infectious Med 2022;1:180–91.
15. Vijay A, Valdes AM. Role of the gut microbiome in chronic diseases: A narrative review. Eur J Clin Nutr 2022;76:489–501.
16. Stepanova N. The gut-peritoneum axis in peritoneal dialysis and peritoneal fibrosis. Kidney Med 2023;5:100645.
17. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res 2020;30:492–506.
18. İlhan N. Gut microbiota and metabolism. Int J Med Biochem 2018;1:115–28.
19. Fusco W, Lorenzo MB, Cintoni M, Porcari S, Rinninella E, Kaitsas F, et al. Short-chain fatty-acid-producing bacteria: Key components of the human gut microbiota. Nutrients 2023;15:2211.
20. Yoo JY, Groer M, Dutra SVO, Sarkar A, McSkimming DI. Gut microbiota and immune system interactions. Microorganisms 2020;8:1587.
21. Hou K, Wu ZX, Chen XY, Wang JQ, Zhang D, Xiao C, et al. Microbiota in health and diseases. Signal Transduct Target Ther 2022;7:135.
22. Scheithauer TPM, Rampanelli E, Nieuwdorp M, Vallance BA, Verchere CB, van Raalte DH, et al. Gut microbiota as a trigger for metabolic inflammation in obesity and type 2 diabetes. Front Immunol 2020;11:571731.
23. Zhang L, Chu J, Hao W, Zhang J, Li H, Yang C, et al. Gut microbiota and type 2 diabetes mellitus: Association, mechanism, and translational applications. Mediators Inflamm 2021;2021:5110276.
24. Zhou YD, Liang FX, Tian HR, Luo D, Wang YY, Yang SR. Mechanisms of gut microbiota-immune-host interaction on glucose regulation in type 2 diabetes. Front Microbiol 2023;14:1121695.
25. Barone M, D'Amico F, Brigidi P, Turroni S. Gut microbiomemicronutrient interaction: The key to controlling the bioavailability of minerals and vitamins? Biofactors 2022;48:307–14.
26. Rowland I, Gibson G, Heinken A, Scott K, Swann J, Thiele I, et al. Gut microbiota functions: Metabolism of nutrients and other food components. Eur J Nutr 2018;57:1–24.
27. Stepanova N. How advanced is our understanding of the role of intestinal barrier dysfunction in the pathogenesis of recurrent urinary tract infections. Front Pharmacol 2022;13:780122.
28. 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;50:224–34.
29. Manor O, Dai CL, Kornilov SA, Smith B, Price ND, Lovejoy JC, et al. Health and disease markers correlate with gut microbiome composition across thousands of people. Nat Commun 2020;11:5206.
30. Senghor B, Sokhna C, Ruimy R, Lagier JC. Gut microbiota diversity according to dietary habits and geographical provenance. Hum Microb J 2018;7–8:1–9.
31. Letchumanan G, Abdullah N, Marlini M, Baharom N, Lawley B, Omar MR, et al. Gut microbiota composition in prediabetes and newly diagnosed type 2 diabetes: A systematic review of observational studies. Front Cell Infect Microbiol 2022;12:943427.
32. Maskarinec G, Raquinio P, Kristal BS, Setiawan VW, Wilkens LR, Franke AA, et al. The gut microbiome and type 2 diabetes status in the Multiethnic Cohort. PLoS One 2021;16:e0250855. 
33. Wang L, Yu X, Xu X, Ming J, Wang Z, Gao B, et al. The fecal microbiota is already altered in normoglycemic individuals who go on to have type 2 diabetes. Front Cell Infect Microbiol 2021;11:598672.
34. Chen Z, Radjabzadeh D, Chen L, Kurilshikov A, Kavousi M, Ahmadizar F, et al. Association of insulin resistance and type 2 diabetes with gut microbial diversity: A microbiomewide analysis from population studies. JAMA Netw Open 2021;4:e2118811.
35. Umirah F, Neoh CF, Ramasamy K, Lim SM. Differential gut microbiota composition between type 2 diabetes mellitus patients and healthy controls: A systematic review. Diabetes Res Clin Pract 2021;173:108689.
36. Polidori I, Marullo L, Ialongo C, Tomassetti F, Colombo R, di Gaudio F, et al. Characterization of gut microbiota composition in type 2 diabetes patients: A population-based study. Int J Environ Res Public Health 2022;19:15913.
37. Cunningham AL, Stephens JW, Harris DA. Gut microbiota influence in type 2 diabetes mellitus (T2DM). Gut Pathog 2021;13:50.
38. Barlow GM, Mathur R. Type 2 diabetes and the microbiome. J Endocr Soc 2022;7:bvac184.
39. Sohail MU, Mashood F, Oberbach A, Chennakkandathil S, Schmidt F. The role of pathogens in diabetes pathogenesis and the potential of immunoproteomics as a diagnostic and prognostic tool. Front Microbiol 2022;13:1042362.
40. Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: Gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol Lausanne 2023;14:1169624.
41. Gurung M, Li Z, You H, Rodrigues R, Jump DB, Morgun A, et al. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine 2020;51:102590.
42. Jian Z, Zeng L, Xu T, Sun S, Yan S, Zhao S, et al. The intestinal microbiome associated with lipid metabolism and obesity in humans and animals. J Appl Microbiol 2022;133:2915–30.
43. Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome. Gut 2020;69:1510–9.
44. Forslund SK, Chakaroun R, Zimmermann-Kogadeeva M, Markó L, Aron-Wisnewsky J, Nielsen T, et al. Combinatorial, additive and dose-dependent drug-microbiome associations. Nature 2021;600:500–5.
45. Patangia DV, Anthony Ryan C, Dempsey E, Paul Ross R, Stanton C. Impact of antibiotics on the human microbiome and consequences for host health. Microbiologyopen 2022;11:e1260.
46. Stepanova N, Akulenko I, Serhiichuk T, Dovbynchuk T, Savchenko S, Tolstanova G. Synbiotic supplementation and oxalate homeostasis in rats: focus on microbiota oxalate-degrading activity. Urolithiasis 2022;50:249–58.
47. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 2018;555:623–8.
48. Liu W, Luo Z, Zhou J, Sun B. Gut microbiota and antidiabetic drugs: Perspectives of personalized treatment in type 2 diabetes mellitus. Front Cell Infect Microbiol 2022;12:853771.
49. Li R, Shokri F, Rincon AL, Rivadeneira F, Medina-Gomez C, Ahmadizar F. Bi-directional interactions between glucoselowering medications and gut microbiome in patients with type 2 diabetes mellitus: A systematic review. Genes Basel 2023;14:1572.
50. Chen R, Pan S. Interaction of anti-diabetic medications and gut microbiota. Front Biosci Landmark Ed 2021;26:673–4.
51. Kant R, Chandra L, Verma V, Nain P, Bello D, Patel S, et al. Gut microbiota interactions with anti-diabetic medications and pathogenesis of type 2 diabetes mellitus. World J Methodol 2022;12:246–57.
52. Hung WW, Hung WC. How gut microbiota relate to the oral antidiabetic treatment of type 2 diabetes. Med Microecol 2020;3:100007.
53. Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, ManneråsHolm L, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 2017;23:850–8.
54. de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velásquez-Mejía EP, Carmona JA, Abad JM, et al. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acidproducing microbiota in the gut. Diabetes Care 2017;40:54–62.
55. Kyriachenko Y, Falalyeyeva T, Korotkyi O, Molochek N, Kobyliak N. Crosstalk between gut microbiota and antidiabetic drug action. World J Diabetes 2019;10:154–68.
56. Zhao L, Chen Y, Xia F, Abudukerimu B, Zhang W, Guo Y, et al. A glucagon-like peptide-1 receptor agonist lowers weight by modulating the structure of gut microbiota. Front Endocrinol Lausanne 2018;9:233.
57. Liao X, Song L, Zeng B, Liu B, Qiu Y, Qu H, et al. Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis. EBioMedicine 2019;44:665–74.
58. Smits MM, Fluitman KS, Herrema H, Davids M, Kramer MHH, Groen AK, et al. Liraglutide and sitagliptin have no effect on intestinal microbiota composition: A 12-week randomized placebo-controlled trial in adults with type 2 diabetes. Diabetes Metab 2021;47:101223.
59. Wu J, Chen Y, Yang H, Gu L, Ni Z, Mou S, et al. Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves
diabetic kidney disease (DKD) over time associated with increasing effect on the gut microbiota in db/db mice. Front Endocrinol Lausanne 2023;14:1026040.
60. Wang D, Liu J, Zhou L, Zhang Q, Li M, Xiao X. Effects of oral glucose-lowering agents on gut microbiota and microbial metabolites. Front Endocrinol Lausanne 2022;13:905171.
61. Deng L, Yang Y, Xu G. Empagliflozin ameliorates type 2 diabetes mellitus-related diabetic nephropathy via altering the gut microbiota. Biochim Biophys Acta Mol Cell Biol Lipids 2022;1867:159234.
62. Pereira MJ, Eriksson JW. Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs 2019;79:219–30.
63. Pittampalli S, Upadyayula S, Mekala HM, Lippmann S. Risks vs benefits for SGLT2 inhibitor medications. Fed Pract 2018;35:45–8.
64. Perry RJ, Shulman GI. Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks. J Biol Chem 2020;295:14379–90.
65. Tsushima Y, Lansang MC, Makin V. The role of SGLT-2 inhibitors in managing type 2 diabetes. Cleve Clin J Med 2021;88:47–58.
66. Lee DM, Battson ML, Jarrell DK, Hou S, Ecton KE, Weir TL, et al. SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. Cardiovasc Diabetol 2018;17:62.
67. Oh TJ, Sul WJ, Oh HN, Lee YK, Lim HL, Choi SH, et al. Butyrate attenuated fat gain through gut microbiota modulation in db/db mice following dapagliflozin treatment. Sci Rep 2019;9:20300.
68. Mishima E, Fukuda S, Kanemitsu Y, Saigusa D, Mukawa C, Asaji K, et al. Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model. Am J Physiol Renal Physiol 2018;315:F824–33.
69. Hata S, Okamura T, Kobayashi A, Bamba R, Miyoshi T, Nakajima H, et al. Gut microbiota changes by an SGLT2 inhibitor, Luseogliflozin, alters metabolites compared with those in a low carbohydrate diet in db/db mice. Nutrients 2022;14:3531.
70. Wang X, Wang Z, Liu D, Jiang H, Cai C, Li G, et al. IDDF2021-ABS-0198 Canagliflozin alleviates diabetic cardiovascular disease via lipid lowering, mitochondrial homeostasis, and gut microbiota regulation. Gut 2021;70:A58–9.
71. Wang L, Liang C, Song X, Jia X, Wang X, Zhang Y, et al. Canagliflozin alters the gut, oral, and ocular surface microbiota of patients with type 2 diabetes mellitus. Front Endocrinol Lausanne 2023;14:1256292.
72. Deng X, Zhang C, Wang P, Wei W, Shi X, Wang P, et al. Cardiovascular benefits of Empagliflozin are associated with gut microbiota and plasma metabolites in type 2 diabetes. J Clin Endocrinol Metab 2022;107:1888–96.
73. Yang M, Shi FH, Liu W, Zhang MC, Feng RL, Qian C, et al. Dapagliflozin modulates the fecal microbiota in a type 2 diabetic rat model. Front Endocrinol Lausanne 2020;11:635.
74. Kusunoki M, Hisano F, Matsuda SI, Kusunoki A, Wakazono N, Tsutsumi K, et al. Effects of SGLT2 inhibitors on the intestinal bacterial flora in Japanese patients with type 2 diabetes mellitus. Drug Res Stuttg 2023;73:412–6.
75. van Bommel EJM, Herrema H, Davids M, Kramer MHH, Nieuwdorp M, van Raalte DH. Effects of 12-week treatment with dapagliflozin and gliclazide on faecal microbiome: Results of a double-blind randomized trial in patients with type 2 diabetes. Diabetes Metab 2020;46:164–8.

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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing