Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats.
Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats.
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DOI：
10.1093/ndt/gfv353
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发表时间：
2016-03
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通讯作者：
Ayumi Yoshifuji;S. Wakino;J. Irie;Takaya Tajima;K. Hasegawa;T. Kanda;H. Tokuyama;K. Hayashi;H. Itoh
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文献类型：
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作者：
Ayumi Yoshifuji;S. Wakino;J. Irie;Takaya Tajima;K. Hasegawa;T. Kanda;H. Tokuyama;K. Hayashi;H. Itoh
背景肠道微生物群在慢性肾脏病（CKD）进展中的作用尚未完全阐明。方法采用5/6肾切除术（Nx）建立6周龄自发性高血压大鼠肾功能衰竭模型。我们分析了肠道微生物群，以确定可能参与诱导肾损伤的相关物种。人结肠Caco-2细胞被用来描绘参与Nx大鼠肠道中分子变化的机制。结果与假手术组相比，Nx组大鼠肝组织中类杆菌（Bacteroides，Bact）数量增加，乳酸杆菌（Lactobacillus，Lact）数量减少。乳酸菌群与尿蛋白排泄显著相关，而细菌群与尿蛋白排泄无显著相关。用1 × 10（10）CFU/kg/天Lact治疗Nx大鼠，可改善尿蛋白排泄增加和尿毒症毒素、硫酸吲哚酚和对甲苯硫酸酯以及血清尿素氮水平升高。乳酸菌还减轻全身炎症在Nx大鼠，血清脂多糖，白细胞介素-6和C-反应蛋白水平的评价。在组织学上，Nx大鼠中的肾硬化通过Lact治疗恢复。在Nx大鼠结肠中，Lact减轻了紧密连接蛋白和Toll样受体2（TLR 2）（一种假定的Lact受体）表达的减少。吲哚治疗Caco-2细胞下调紧密连接蛋白的表达，这是取消暴露于乳酸。用TLR抑制剂OxPAPC处理可逆转Lact的作用。同样，Caco-2细胞单层渗透性的增加通过给予Lact逆转。Lact上调Caco-2细胞TLR 2表达。Lact还减弱了Nx大鼠血清硫酸吲哚酚和尿素水平以及尿蛋白排泄的增加，即使在无假菌环境中也是如此。结论：补充Lact可减轻与肾衰竭相关的全身炎症和蛋白尿，表明在肠道微生物群中，Lact对CKD的进展起保护作用。
BACKGROUND The role of gut microbiota in the progression of chronic kidney disease (CKD) has not been fully elucidated. METHODS Renal failure was induced in 6-week-old spontaneously hypertensive rats by 5/6 nephrectomy (Nx). We analyzed the gut microbiota population to identify the relevant species potentially involved in inducing renal damage. Human colon Caco-2 cells were used to delineate the mechanism involved in the molecular changes in the gut of Nx rats. RESULTS Nx rats showed an increase in Bacteroides (Bact) and a decrease in Lactobacillus (Lact) species compared with sham-operated rats. Lact, but not Bact, populations were significantly associated with urinary protein excretion. Treatment of Nx rats with 1 × 10(10) CFU/kg/day Lact ameliorated increased urinary protein excretion and higher serum levels of the uremic toxins, indoxyl sulfate and p-cresyl sulfate, and serum urea nitrogen levels. Lact also attenuated systemic inflammation in Nx rats, as evaluated by serum lipopolysaccharide, interleukin-6 and C-reactive protein levels. Histologically, renal sclerosis in Nx rats was restored by Lact treatment. A reduction in the expression of tight junction proteins and the Toll-like receptor 2 (TLR2), a putative Lact receptor, in the colons of Nx rats were mitigated by Lact. Treatment of Caco-2 cells with indole downregulated tight junction protein expression, which was abolished by exposure to Lact. The effects of Lact were reversed by treatment with OxPAPC, a TLR inhibitor. Similarly, the increase in the permeability of the Caco-2 cell monolayer was reversed by the administration of Lact. Lact upregulated TLR2 expression in Caco-2 cells. Lact also attenuated the increase in serum indoxyl sulfate and urea levels and urinary protein excretion in Nx rats even in the pseudogerm-free environment. CONCLUSIONS Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD.