Effects of SGLT2 inhibitors on the intestinal bacterial flora in Japanese patients with type 2 diabetes mellitus

Abstract

Selective inhibitors of sodium glucose co-transporter-2 (SGLT2) suppress renal glucose reabsorption and promote urinary glucose excretion, thereby lowering blood glucose. SGLT2 inhibitors have been reported to reduce body weight. However, the mechanism underlying the reduction in the body weight induced by SGLT2 inhibitor treatment remains to be elucidated. In this study, we investigated the effects of SGLT2 inhibitors on the intestinal bacterial flora. A total of 36 Japanese patients with type 2 diabetes mellitus received a SGLT2 inhibitor (luseogliflozin or dapagliflozin) for 3 months, and the prevalences of balance-regulating bacteria and balance-disturbing bacteria in the feces of the patients before and after SGLT2 inhibitor treatment were determined. SGLT2 inhibitor treatment was associated with a significant increase of the overall prevalence of the 12 types of balance-regulating bacteria. In addition, significant increases in the prevalences of the short-chain fatty acid (SCFAs)-producing bacteria among the balance-regulating bacteria were also observed. Individual analyses of the balance-regulating bacteria revealed that the SGLT2 inhibitor treatment was associated with a significant increase in the prevalence of Ruminococci, which are balance-regulating bacteria classified as SCFAs-producing bacteria. However, SGLT2 inhibitor had no effect on the balance-disturbing bacteria. These results suggested that SGLT2 inhibitor treatment was associated with an overall increase in the prevalence of balance-regulating bacteria. Among the balance-regulating bacteria, the prevalences of SCFAs-producing bacteria increased. SCFAs have been reported to prevent obesity. The results of the present study suggest that SGLT2 inhibitors might induce body weight reduction via their actions on the intestinal bacterial flora.

Key words

SGLT2 inhibitor - intestinal bacterial flora - obesity - balance-regulating bacteria - short-chain fatty acid-producing bacteria

Publication History

Received: 20 November 2022

Accepted: 03 February 2023

Article published online:
26 May 2023

• References

• 1 Wright EM. Glucose transport families SLC5 and SLC50. Med Aspects Med 2013; 34: 183-196
• 2 Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev 2011; 91: 733-794
• 3 Seino Y, Sasaki T, Fukatsu A. et al. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, Phase 3 study. Curr Med Res Opin 2014; 30: 1245-1255
• 4 Turnbaugh PJ, Ley RE, Mahowald MA. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444: 1027-1031
• 5 Goodrich JK, Waters JL, Poole AC. et al. Human genetics shape the gut microbiome. Cell 2014; 159: 789-799
• 6 Gutell RR, Larsen N, Woese CR. Lessons from an evolving rRNA: 16S and 23S rRNA structures from a comparative perspective. Microbiol Rev 1994; 58: 10-26
• 7 Zhou G, Myers R, Li Y. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167-1174
• 8 de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V. 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 2017; 40: 54-62
• 9 Wu H, Esteve E, Tremaroli V. 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: 850-858
• 10 Depommier C, Everard A, Druart C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 2019; 25: 1096-1103
• 11 Everard A, Belzer C, Geurts L. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 2013; 110: 9066-9071
• 12 Naito Y, Uchiyama K, Takagi T. A next-generation beneficial microbe: Akkermansia muciniphila . J Clin Biochem Nutr 2018; 63: 33-35
• 13 Deng X, Zhang C, 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; 16: 1888-1896
• 14 van Bommel EJM, Herrema H, Davids M. et al. 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: 164-168
• 15 Lee DM, Battson ML, Jarrell DK. 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
• 16 Yang M, Shi FH, Liu W. et al. Dapagliflozin in modulates the fecal microbiota in a type 2 diabetic rat model. Front Endocrinol 2020; 11: 635
• 17 Lecamwasam A, Ekinci EI. Novel associations of empagliflozin on the gut microbiome and metabolome in type 2 diabetes. J Clin Endocrinol Metab 2022; 107: e4246-e4247