A specifically designed synbiotic reduces uremic toxin generation and improves kidney function

Metagenomic data of the intestinal microbiota were collected from mice with and without kidney disease, with or without synbiotic treatment. Chronic Kidney Disease (CKD) is characterized by accumulation of uremic toxins (UTs), such as p-cresyl sulfate and indoxyl sulfate, generated through the transformation of tyrosine and tryptophan by the gut microbiota. We further designed a novel specific synbiotic for CKD (SynCKD) that are able to decrease UTs in silico and in vitro. We tested a specific synbiotic (SynCKD) in a male mouse model of CKD induced by two-step 5/6 nephrectomy at 6 weeks of age. The mice were treated with either a placebo or the synbiotic for 6 weeks. Fecal samples were collected at the end of the treatment period for analysis. The in vivo efficacy of SynCKD was demonstrated by reduced plasma levels of uremic toxins (UTs) and improved kidney function after 6 tweeks of treatment. Finally, metagenomic analyses showed that SynCKD resulted in a lower abundance of microbial genes involved in tryptophan and tyrosine degradation.

本研究收集了患肾病与健康小鼠、经合生元（synbiotic）干预与未干预小鼠的肠道菌群宏基因组数据。慢性肾病（Chronic Kidney Disease, CKD）以尿毒症毒素（uremic toxins, UTs）蓄积为特征，这类毒素包括对甲酚硫酸盐和吲哚酚硫酸盐，均由肠道菌群转化酪氨酸与色氨酸生成。本研究进一步设计了一种针对CKD的新型特异性合生元（SynCKD），经计算机模拟（in silico）与体外实验（in vitro）验证，其可降低尿毒症毒素水平。本研究在6周龄雄性小鼠中构建了两步法5/6肾切除诱导的CKD模型，并在此模型中测试了该特异性合生元（SynCKD）的效果：将小鼠分为两组，分别给予安慰剂或合生元干预，干预周期为6周；于干预结束时收集粪便样本用于后续分析。干预6周后，小鼠血浆尿毒症毒素水平降低、肾功能得到改善，证实了SynCKD的体内（in vivo）干预效果。最终宏基因组分析结果显示，SynCKD可降低参与色氨酸与酪氨酸降解过程的微生物基因丰度。