Deng Le, Yang Yang, Xu Gaosi
Department of Nephrology, the Second Affiliated Hospital of Nanchang University, Jiangxi 330006, China.
Department of Nephrology, the Second Affiliated Hospital of Nanchang University, Jiangxi 330006, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Dec;1867(12):159234. doi: 10.1016/j.bbalip.2022.159234. Epub 2022 Sep 19.
The dysregulation of gut microbiota can be found in patients with type 2 diabetes mellitus (T2DM)-related diabetic nephropathy (DN). Inhibitors of sodium-glucose co-transporter 2 (SGLT2) were reported to affect gut microbiota. This study aimed to identify whether empagliflozin (EMPA) attenuated DN via regulating gut microbiota.
The high-fat diet (HFD) combining streptozocin (STZ) injection was performed to induce DN in mice. The therapeutic effects of EMPA were observed by staining of renal tissues and urine albumin/creatinine ratio (UACR). Mouse feces were collected for 16S rRNA sequencing. Fecal short-chain fatty acids (SCFAs) and fecal and serum lipopolysaccharide (LPS) were determined. An antibiotic-ablated model was established to confirm the role of the gut microbiota in the actions of EMPA.
EMPA reduced the elevation of blood glucose and UACR caused by HFD/STZ. It inhibited the thickening of the colonic crypt and restored goblet cells and the expressions of ZO-1 and Occludin. The 16S rRNA sequencing showed that the diversity of gut microbiota was reduced after HFD/STZ treatment, while it was restored after EMPA treatment. The LPS-producing bacteria, Oscillibacter, and the SCFA-producing bacteria, Bateroid and Odoribacter, were changed after EMPA administration. The therapeutic effects of EMPA on ABX-treated mice were reduced. Meanwhile, the level of fecal SCFAs was decreased, while the levels of fecal and serum LPS were elevated, in T2DM mice, and they were negated by the administration of EMPA.
EMPA ameliorates T2DM-related DN via altering the gut microbiota, especially reducing LPS-producing bacteria and increasing SCFA-producing bacteria.
2型糖尿病（T2DM）相关糖尿病肾病（DN）患者存在肠道微生物群失调。据报道，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂会影响肠道微生物群。本研究旨在确定恩格列净（EMPA）是否通过调节肠道微生物群来减轻糖尿病肾病。
采用高脂饮食（HFD）联合链脲佐菌素（STZ）注射诱导小鼠糖尿病肾病。通过肾组织染色和尿白蛋白/肌酐比值（UACR）观察EMPA的治疗效果。收集小鼠粪便进行16S rRNA测序。测定粪便短链脂肪酸（SCFA）以及粪便和血清脂多糖（LPS）水平。建立抗生素清除模型以证实肠道微生物群在EMPA作用中的作用。
EMPA降低了HFD/STZ引起的血糖升高和UACR。它抑制了结肠隐窝增厚，恢复了杯状细胞以及紧密连接蛋白1（ZO-1）和闭合蛋白的表达。16S rRNA测序显示，HFD/STZ处理后肠道微生物群多样性降低，而EMPA处理后恢复。给予EMPA后，产LPS细菌振荡杆菌属以及产SCFA细菌拟杆菌属和嗜臭杆菌属发生了变化。EMPA对经抗生素处理小鼠的治疗效果降低。同时，T2DM小鼠粪便SCFA水平降低，而粪便和血清LPS水平升高，给予EMPA可使其恢复正常。
EMPA通过改变肠道微生物群，特别是减少产LPS细菌和增加产SCFA细菌来改善T2DM相关糖尿病肾病。
