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SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure
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 th...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683788/ https://www.ncbi.nlm.nih.gov/pubmed/34921520 http://dx.doi.org/10.14814/phy2.15092 |
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author | Ho, Hsin‐Jung Kikuchi, Koichi Oikawa, Daiki Watanabe, Shun Kanemitsu, Yoshitomi Saigusa, Daisuke Kujirai, Ryota Ikeda‐Ohtsubo, Wakako Ichijo, Mariko Akiyama, Yukako Aoki, Yuichi Mishima, Eikan Ogata, Yoshiaki Oikawa, Yoshitsugu Matsuhashi, Tetsuro Toyohara, Takafumi Suzuki, Chitose Suzuki, Takehiro Mano, Nariyasu Kagawa, Yoshiteru Owada, Yuji Katayama, Takane Nakayama, Toru Tomioka, Yoshihisa Abe, Takaaki |
author_facet | Ho, Hsin‐Jung Kikuchi, Koichi Oikawa, Daiki Watanabe, Shun Kanemitsu, Yoshitomi Saigusa, Daisuke Kujirai, Ryota Ikeda‐Ohtsubo, Wakako Ichijo, Mariko Akiyama, Yukako Aoki, Yuichi Mishima, Eikan Ogata, Yoshiaki Oikawa, Yoshitsugu Matsuhashi, Tetsuro Toyohara, Takafumi Suzuki, Chitose Suzuki, Takehiro Mano, Nariyasu Kagawa, Yoshiteru Owada, Yuji Katayama, Takane Nakayama, Toru Tomioka, Yoshihisa Abe, Takaaki |
author_sort | Ho, Hsin‐Jung |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8683788 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86837882021-12-30 SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure Ho, Hsin‐Jung Kikuchi, Koichi Oikawa, Daiki Watanabe, Shun Kanemitsu, Yoshitomi Saigusa, Daisuke Kujirai, Ryota Ikeda‐Ohtsubo, Wakako Ichijo, Mariko Akiyama, Yukako Aoki, Yuichi Mishima, Eikan Ogata, Yoshiaki Oikawa, Yoshitsugu Matsuhashi, Tetsuro Toyohara, Takafumi Suzuki, Chitose Suzuki, Takehiro Mano, Nariyasu Kagawa, Yoshiteru Owada, Yuji Katayama, Takane Nakayama, Toru Tomioka, Yoshihisa Abe, Takaaki Physiol Rep Original Articles 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. John Wiley and Sons Inc. 2021-12-18 /pmc/articles/PMC8683788/ /pubmed/34921520 http://dx.doi.org/10.14814/phy2.15092 Text en © 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Ho, Hsin‐Jung Kikuchi, Koichi Oikawa, Daiki Watanabe, Shun Kanemitsu, Yoshitomi Saigusa, Daisuke Kujirai, Ryota Ikeda‐Ohtsubo, Wakako Ichijo, Mariko Akiyama, Yukako Aoki, Yuichi Mishima, Eikan Ogata, Yoshiaki Oikawa, Yoshitsugu Matsuhashi, Tetsuro Toyohara, Takafumi Suzuki, Chitose Suzuki, Takehiro Mano, Nariyasu Kagawa, Yoshiteru Owada, Yuji Katayama, Takane Nakayama, Toru Tomioka, Yoshihisa Abe, Takaaki SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure |
title | SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure |
title_full | SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure |
title_fullStr | SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure |
title_full_unstemmed | SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure |
title_short | SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure |
title_sort | sglt‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683788/ https://www.ncbi.nlm.nih.gov/pubmed/34921520 http://dx.doi.org/10.14814/phy2.15092 |
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