Dietary Fiber Protects against Diabetic Nephropathy through Short-Chain Fatty Acid?Mediated Activation of G Protein?Coupled Receptors GPR43 and GPR109A
Dietary Fiber Protects against Diabetic Nephropathy through Short-Chain Fatty Acid?Mediated Activation of G Protein?Coupled Receptors GPR43 and GPR109A
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DOI：
10.1681/asn.2019101029
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发表时间：
2020-06-01
影响因子：
13.6
通讯作者：
Wu, Huiling
中科院分区：
文献类型：
--
作者：
Li, Yan Jun;Chen, Xiaochen;Wu, Huiling
意义陈述 肠道微生物群及其代谢物，特别是源自肠道微生物的短链脂肪酸？纤维发酵是全身炎症和代谢疾病（包括糖尿病肾病）的新兴治疗靶点。作者报告说，高纤维饮食或补充短链脂肪酸（乙酸盐、丁酸盐或丙酸盐）可以预防糖尿病小鼠患肾病。膳食纤维恢复了肠道微生物生态，纠正了“生态失调”。变化，并增加短链脂肪酸的产量。缺乏代谢物感应 G 蛋白偶联受体 GPR43 或 GPR109A 的小鼠不受短链脂肪酸的保护，表明保护作用是通过下游与这些受体的结合介导的。通过饮食挖掘肠道微生物群的代谢潜力可能会提供一种解决糖尿病肾病的新方法。背景研究报道了“生态失调”。 CKD 和糖尿病中肠道微生物群的变化，例如通过肠道纤维发酵产生短链脂肪酸 (SCFA) 的肠道细菌被耗尽。膳食纤维与 CKD 炎症和死亡率的降低有关，而 SCFA 已被提出可以介导这种作用。 方法 为了探讨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在野生型 C57BL/6 和缺乏编码 G 蛋白偶联受体 GPR43 或 GPR43 的基因的敲除小鼠中诱导糖尿病。 GPR109A。糖尿病小鼠被随机分配到高纤维、正常食物或零纤维饮食，或饮用水中的 SCFA。我们使用质子核磁共振波谱进行代谢分析，并使用 16S 核糖体 RNA 测序来评估肠道微生物群。 结果 与喂食正常食物或普通食物的糖尿病对照组相比，喂食高纤维饮食的糖尿病小鼠患糖尿病肾病的可能性显着降低，表现出较少的蛋白尿、肾小球肥大、足细胞损伤和间质纤维化。 零纤维饮食。纤维有益地重塑了肠道微生物生态并改善了生态失调，促进了普氏菌属和双歧杆菌属产生 SCFA 的细菌的扩张，从而增加了粪便和全身 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的表达。 SCFA 治疗的糖尿病小鼠可以免受肾病的影响，但在缺乏 GPR43 或 GPR109A 的情况下则不然。在体外，SCFA 在高血糖条件下调节肾小管细胞和足细胞的炎症。结论膳食纤维通过调节肠道微生物群、富集 SCFA 产生细菌和增加 SCFA 产量来预防糖尿病肾病。 GPR43 和 GPR109A 对于 SCFA 介导的针对这种情况的保护至关重要。针对肠道微生物群的干预措施值得进一步研究，作为糖尿病肾病的新型肾脏保护疗法。
Significance Statement The gut microbiota and its metabolites, in particular short-chain fatty acids derived from gut microbes? fermentation of fiber, are emerging therapeutic targets for systemic inflammatory and metabolic diseases, including diabetic nephropathy. The authors report that high-fiber diets or supplementation with short-chain fatty acids (acetate, butyrate, or propionate) afforded protection against development of kidney disease in diabetic mice. Dietary fiber restored gut microbial ecology, corrected ?dysbiotic? changes, and increased production of short-chain fatty acids. Mice deficient in the metabolite-sensing G protein?coupled receptors GPR43 or GPR109A were not protected by short-chain fatty acids, suggesting that protection was mediated by downstream binding to these receptors. Tapping into the metabolic potential of the gut microbiota through diet may offer a novel approach to address diabetic nephropathy.Background 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.Methods 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.Results 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 Prevotella and Bifidobacterium, 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. In vitro, SCFAs modulated inflammation in renal tubular cells and podocytes under hyperglycemic conditions.Conclusions 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.