Graboski Amanda L, Redinbo Matthew R
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
Departments of Chemistry, Biochemistry, Microbiology and Genomics, University of North Carolina, Chapel Hill, NC 27599-3290, USA.
Toxins (Basel). 2020 Sep 11;12(9):590. doi: 10.3390/toxins12090590.
Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.
慢性肾脏病（CKD）在全球折磨着超过5亿人，是全球死亡率增长最快的原因之一。当肾小球滤过率开始下降时，尿毒症毒素在血清中蓄积，显著增加心血管疾病和其他原因导致的死亡风险。几种最有害的尿毒症毒素是由肠道微生物群产生的。此外，许多此类毒素与蛋白质结合，因此难以通过透析清除。我们综述了肠道来源的、与蛋白质结合的尿毒症毒素（PBUTs）的产生及病理机制。我们进一步概述了肾脏疾病与肠道生态失调之间新出现的关系，包括改变的细菌分类群、微生物尿毒症毒素产生基因的调控及其下游的生理和神经学后果。最后，我们讨论了用于减少PBUTs的肠道靶向治疗策略。我们得出结论，通过阻断透析无法清除的PBUTs在血清中的蓄积，靶向肠道微生物群是治疗CKD的一种有前景的方法。
