SGLT-1-specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine-induced renal failure.

Abstract

Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol-producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low-absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases.

• Authors: Hsin-Jung Ho, Koichi Kikuchi, Daiki Oikawa, Shun Watanabe, Yoshitomi Kanemitsu, Daisuke Saigusa, Ryota Kujirai, Wakako Ikeda-Ohtsubo, Mariko Ichijo, Yukako Akiyama, Yuichi Aoki, Eikan Mishima, Yoshiaki Ogata, Yoshitsugu Oikawa, Tetsuro Matsuhashi, Takafumi Toyohara, Chitose Suzuki, Takehiro Suzuki, Nariyasu Mano, Yoshiteru Kagawa, Yuji Owada, Takane Katayama, Toru Nakayama, Yoshihisa Tomioka, Takaaki Abe
• Journal: Physiological reports (Physiol Rep) Vol. 9 Issue 24 Pg. e15092 (12 2021) ISSN: 2051-817X [Electronic] United States
• PMID: 34921520 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• Blood Glucose
• SGL5213
• Slc5a1 protein, mouse
• Sodium-Glucose Transporter 1
• Sorbitol
• Adenine

Topics

• Adenine (toxicity)
• Animals
• Blood Glucose (drug effects, metabolism)
• Gastrointestinal Microbiome (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Renal Insufficiency (chemically induced, drug therapy, metabolism)
• Sodium-Glucose Transporter 1 (antagonists & inhibitors)
• Sorbitol (analogs & derivatives, pharmacology, therapeutic use)