Kidney Node Laboratory, The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
J Am Soc Nephrol. 2020 Jun;31(6):1267-1281. doi: 10.1681/ASN.2019101029. Epub 2020 May 1.
Studies have reported "dysbiotic" changes to gut microbiota, such as depletion of gut bacteria that produce short-chain fatty acids (SCFAs) through gut fermentation of fiber, in CKD and diabetes. Dietary fiber is associated with decreased inflammation and mortality in CKD, and SCFAs have been proposed to mediate this effect.
To explore dietary fiber's effect on development of experimental diabetic nephropathy, we used streptozotocin to induce diabetes in wild-type C57BL/6 and knockout mice lacking the genes encoding G protein-coupled receptors GPR43 or GPR109A. Diabetic mice were randomized to high-fiber, normal chow, or zero-fiber diets, or SCFAs in drinking water. We used proton nuclear magnetic resonance spectroscopy for metabolic profiling and 16S ribosomal RNA sequencing to assess the gut microbiome.
Diabetic mice fed a high-fiber diet were significantly less likely to develop diabetic nephropathy, exhibiting less albuminuria, glomerular hypertrophy, podocyte injury, and interstitial fibrosis compared with diabetic controls fed normal chow or a zero-fiber diet. Fiber beneficially reshaped gut microbial ecology and improved dysbiosis, promoting expansion of SCFA-producing bacteria of the genera and , which increased fecal and systemic SCFA concentrations. Fiber reduced expression of genes encoding inflammatory cytokines, chemokines, and fibrosis-promoting proteins in diabetic kidneys. SCFA-treated diabetic mice were protected from nephropathy, but not in the absence of GPR43 or GPR109A. , SCFAs modulated inflammation in renal tubular cells and podocytes under hyperglycemic conditions.
Dietary fiber protects against diabetic nephropathy through modulation of the gut microbiota, enrichment of SCFA-producing bacteria, and increased SCFA production. GPR43 and GPR109A are critical to SCFA-mediated protection against this condition. Interventions targeting the gut microbiota warrant further investigation as a novel renoprotective therapy in diabetic nephropathy.
研究报告称，在慢性肾脏病（CKD）和糖尿病患者中，肠道微生物群发生了“失调”变化，例如通过纤维的肠道发酵而产生短链脂肪酸（SCFA）的肠道细菌减少。膳食纤维与 CKD 中的炎症和死亡率降低有关，并且已经提出 SCFAs 介导了这种作用。
为了探索膳食纤维对实验性糖尿病肾病发展的影响，我们使用链脲佐菌素诱导野生型 C57BL/6 和缺乏编码 G 蛋白偶联受体 GPR43 或 GPR109A 基因的基因敲除小鼠发生糖尿病。将糖尿病小鼠随机分为高纤维、正常饲料或无纤维饮食，或 SCFAs 饮用水。我们使用质子核磁共振波谱进行代谢谱分析和 16S 核糖体 RNA 测序来评估肠道微生物组。
与接受正常饲料或无纤维饮食的糖尿病对照相比，给予高纤维饮食的糖尿病小鼠发生糖尿病肾病的可能性明显降低，表现为白蛋白尿、肾小球肥大、足细胞损伤和间质纤维化减少。纤维有益地重塑了肠道微生物生态，改善了肠道失调，促进了产 SCFA 细菌属 和 的扩张，增加了粪便和系统 SCFA 浓度。纤维减少了糖尿病肾脏中编码炎症细胞因子、趋化因子和纤维化促进蛋白的基因表达。用 SCFA 治疗的糖尿病小鼠可预防肾病，但在缺乏 GPR43 或 GPR109A 的情况下则不行。在高血糖条件下， 和 SCFAs 调节了肾小管细胞和足细胞中的炎症。
膳食纤维通过调节肠道微生物群、富集产 SCFA 细菌和增加 SCFA 产生来预防糖尿病肾病。GPR43 和 GPR109A 对 SCFA 介导的对这种疾病的保护作用至关重要。针对肠道微生物群的干预措施作为糖尿病肾病的一种新型肾脏保护治疗方法值得进一步研究。
