Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD
Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD
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DOI：
10.1681/asn.2014060530
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发表时间：
2015-08-01
影响因子：
13.6
通讯作者：
Abe, Takaaki
中科院分区：
文献类型：
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作者：
Mishima, Eikan;Fukuda, Shinji;Abe, Takaaki
尿毒症毒素的积聚参与了CKD的进展。各种尿毒症毒素来源于肠道微生物区系，肠道微生物区系失衡或生态失调与肾功能衰竭有关。然而，肠道微生物区系与肾功能衰竭之间的关系的病理生理机制仍不清楚。使用腺嘌呤诱导的小鼠肾功能衰竭模型，我们评估了CIC-2氯通道激活剂路比前列酮(通常用于治疗便秘)对慢性肾脏病的影响。口服鲁比前列酮(500微克/千克/天)可改变肾功能衰竭小鼠的粪便和肠道性质。此外，鲁比前列酮治疗可降低升高的血尿素氮，保护肾小管间质损伤、肾纤维化和炎症。对肾衰小鼠肠道16S rRNA基因进行的肠道微生物组分析表明，路比前列酮治疗改变了它们的微生物组成，尤其是恢复了乳杆菌科和普氏杆菌属的水平，而在肾衰小鼠中这两种微生物的水平显著降低。此外，基于毛细管电泳质谱的代谢组分析表明，路比前列酮治疗降低了尿毒症毒素的血浆水平，如源自肠道微生物区系的吲哚硫酸盐和马尿酸盐，以及最近发现的尿毒症毒素反式乌头酸酯。这些结果表明，鲁比前列酮通过改善肠道微生物区系和肠道环境来改善CKD的进展和尿毒症毒素的积聚。
The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the CIC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 mu g/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.