Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, 980-8578, Japan; Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, 567-0085, Japan.
Biochem Biophys Res Commun. 2020 May 7;525(3):773-779. doi: 10.1016/j.bbrc.2020.02.141. Epub 2020 Mar 5.
In chronic kidney disease, elevated levels of circulating uremic toxins are associated with a variety of symptoms and organ dysfunction. Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are microbiota-derived metabolites and representative uremic toxins. We have previously shown that the oral adsorbent AST-120 profoundly reduced pCS compared to IS in adenine-induced renal failure in mice. However, the mechanisms of the different attenuation effects of AST-120 between IS and pCS are unclear. To clarify the difference of AST-120 on IS and pCS, we investigated the levels of fecal indole and p-cresol, the respective precursors of IS and pCS, and examined the influence on the gut microbiota. Although fecal indole was detected in all groups analyzed, fecal p-cresol was not detected in AST-120 treatment groups. In genus level, a total of 23 organisms were significantly changed by renal failure or AST-120 treatment. Especially, AST-120 reduced the abundance of Erysipelotrichaceae uncultured and Clostridium sensu stricto 1, which have a gene involved in p-cresol production. Our findings suggest that, in addition to the adsorption of the uremic toxin precursors, AST-120 affects the abundance of some gut microbiota in normal and renal failure conditions, thereby explaining the different attenuation effects on IS and pCS.
在慢性肾脏病中，循环尿毒症毒素水平升高与多种症状和器官功能障碍有关。硫酸吲哚酚（IS）和对甲酚硫酸盐（pCS）是微生物衍生的代谢物和代表性尿毒症毒素。我们之前已经表明，与腺嘌呤诱导的小鼠肾衰竭中的 IS 相比，口服吸附剂 AST-120 可显著降低 pCS。然而，AST-120 对 IS 和 pCS 的不同衰减作用的机制尚不清楚。为了阐明 AST-120 在 IS 和 pCS 之间的不同作用机制，我们研究了粪便吲哚和对甲酚的水平，它们分别是 IS 和 pCS 的前体，并检查了它们对肠道微生物群的影响。虽然在所有分析的组中都检测到粪便吲哚，但在 AST-120 治疗组中未检测到粪便对甲酚。在属水平上，肾功能衰竭或 AST-120 治疗总共改变了 23 种微生物。特别是，AST-120 降低了未培养的 Erysipelotrichaceae 和严格梭菌 1 的丰度，它们都具有与对甲酚产生相关的基因。我们的研究结果表明，除了吸附尿毒症毒素前体外，AST-120 还会影响正常和肾功能衰竭条件下某些肠道微生物群的丰度，从而解释了对 IS 和 pCS 的不同衰减作用。
