TY - JOUR
T1 - SGLT-1-specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine-induced renal failure
AU - Ho, Hsin Jung
AU - Kikuchi, Koichi
AU - Oikawa, Daiki
AU - Watanabe, Shun
AU - Kanemitsu, Yoshitomi
AU - Saigusa, Daisuke
AU - Kujirai, Ryota
AU - Ikeda-Ohtsubo, Wakako
AU - Ichijo, Mariko
AU - Akiyama, Yukako
AU - Aoki, Yuichi
AU - Mishima, Eikan
AU - Ogata, Yoshiaki
AU - Oikawa, Yoshitsugu
AU - Matsuhashi, Tetsuro
AU - Toyohara, Takafumi
AU - Suzuki, Chitose
AU - Suzuki, Takehiro
AU - Mano, Nariyasu
AU - Kagawa, Yoshiteru
AU - Owada, Yuji
AU - Katayama, Takane
AU - Nakayama, Toru
AU - Tomioka, Yoshihisa
AU - Abe, Takaaki
N1 - Funding Information:
This work was supported in part by a National Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18H02822, 20K20604, 21H02932), and the Japan Agency for Medical Research and Development (AMED) 20ek0210133h0001, 20ak0101127h0001, and J21000294 and Taisho Pharmaceutical Co. The authors thank Fumiko Date, Miki Yoshizawa, and Naoko Shibata (Histological platform, Tohoku University School of Medicine) for their histological assistance.
Funding Information:
This work was supported in part by a National Grant‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18H02822, 20K20604, 21H02932), and the Japan Agency for Medical Research and Development (AMED) 20ek0210133h0001, 20ak0101127h0001, and J21000294 and Taisho Pharmaceutical Co.
Publisher Copyright:
© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85121718855&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121718855&partnerID=8YFLogxK
U2 - 10.14814/phy2.15092
DO - 10.14814/phy2.15092
M3 - Article
C2 - 34921520
AN - SCOPUS:85121718855
SN - 2051-817X
VL - 9
JO - Physiological Reports
JF - Physiological Reports
IS - 24
M1 - e15092
ER -
