Matsui Ayumi, Yoshifuji Ayumi, Irie Junichiro, Tajima Takaya, Uchiyama Kiyotaka, Itoh Tomoaki, Wakino Shu, Itoh Hiroshi
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjyuku-Ku, Tokyo, 160-8584, Japan.
AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.
Clin Exp Nephrol. 2023 Apr;27(4):295-308. doi: 10.1007/s10157-022-02312-y. Epub 2023 Jan 7.
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.
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.
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.
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.
肠道会产生毒素，这些毒素会导致慢性肾病的心血管并发症。卡格列净是一种用作抗糖尿病药物的钠葡萄糖协同转运蛋白（SGLT）2抑制剂，对SGLT1具有微弱的抑制作用，可能会影响肠道葡萄糖浓度和环境。
在此，我们测定了卡格列净对5/6肾切除（Nx）大鼠肠道微生物群和血清中源自肠道的尿毒症毒素浓度的影响。
卡格列净提高了结肠葡萄糖浓度，并恢复了Nx大鼠中数量较低的乳酸杆菌数量。此外，Nx大鼠升结肠中紧密连接蛋白的表达较低，而卡格列净可部分恢复这一表达。此外，源自肠道的尿毒症毒素的血清浓度在Nx大鼠中显著升高，而在卡格列净作用下降低。最后，Nx大鼠的胸主动脉壁更厚，心脏间质纤维化更严重，而这些缺陷在卡格列净作用下得到改善。
结肠葡萄糖浓度、乳酸杆菌数量和紧密连接蛋白表达的增加，以及血清尿毒症毒素浓度和心脏间质纤维化的降低，可能是由于卡格列净对SGLT1的抑制作用所致，因为在托格列净治疗的大鼠中未发现类似效果。
