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Canagliflozin protects the cardiovascular system through effects on the gut environment in non-diabetic
Ayumi Matsui1, Ayumi Yoshifuji1, Junichiro Irie1,2
1Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjyuku-Ku, Tokyo, 160-8584, Japan.
Background:
The gut produces toxins that contribute to the cardiovascular complications of chronic kidney disease. Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor that is used as an anti-diabetic drug, has a weak inhibitory effect against SGLT1 and may affect the gut glucose concentration and environment.
Methods:
Here, we determined the effect of canagliflozin on the gut microbiota and the serum gut-derived uremic toxin concentrations in 5/6th nephrectomized (Nx) rats.
Results:
Canagliflozin increased the colonic glucose concentration and restored the number of Lactobacillus bacteria, which was low in Nx rats. In addition, the expression of tight junction proteins in the ascending colon was low in Nx rats, and this was partially restored by canagliflozin. Furthermore, the serum concentrations of gut-derived uremic toxins were significantly increased by Nx and reduced by canagliflozin. Finally, the wall of the thoracic aorta was thicker and there was more cardiac interstitial fibrosis in Nx rats, and these defects were ameliorated by canagliflozin.
Conclusions:
The increases in colonic glucose concentration, Lactobacillus numbers and tight junction protein expression, and the decreases in serum uremic toxin concentrations and cardiac interstitial fibrosis may have been caused by the inhibition of SGLT1 by canagliflozin because similar effects were not identified in tofogliflozin-treated rats.
Insights
Canagliflozin improved gut health and reduced cardiovascular damage in chronic kidney disease rats. It increased beneficial bacteria and decreased harmful toxins, potentially by inhibiting SGLT1.
Area of Science:
- Nephrology
- Microbiology
- Cardiovascular Medicine
Background:
- Chronic kidney disease (CKD) is linked to gut-derived toxins contributing to cardiovascular complications.
- Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, may influence the gut environment due to weak SGLT1 inhibition.
Purpose of the Study:
- To investigate the impact of canagliflozin on gut microbiota and uremic toxin levels in a rat model of CKD.
- To assess canagliflozin's effects on gut barrier function and cardiovascular changes in CKD.
Main Methods:
- Utilized a 5/6th nephrectomized (Nx) rat model to simulate CKD.
- Administered canagliflozin and analyzed gut microbiota, colonic glucose, tight junction proteins, serum uremic toxins, and aortic/cardiac tissue.
Main Results:
- Canagliflozin increased colonic glucose and Lactobacillus, while restoring tight junction protein expression in Nx rats.
- Serum concentrations of gut-derived uremic toxins were reduced by canagliflozin treatment.
- Cardiovascular parameters, including aortic wall thickness and cardiac fibrosis, were improved by canagliflozin.
Conclusions:
- Canagliflozin's beneficial effects on gut environment and cardiovascular health in CKD may stem from SGLT1 inhibition.
- These findings suggest a potential therapeutic role for canagliflozin in managing CKD-associated cardiovascular complications via gut modulation.
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