Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Tohoku Medical Megabank Organization, Sendai, Japan.
Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
Kidney Int. 2017 Sep;92(3):634-645. doi: 10.1016/j.kint.2017.02.011. Epub 2017 Apr 8.
Gut microbiota is involved in the metabolism of uremic solutes. However, the precise influence of microbiota to the retention of uremic solutes in CKD is obscure. To clarify this, we compared adenine-induced renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles of plasma, feces, and urine using a capillary electrophoresis time-of-flight mass spectrometry-based approach. Mice with renal failure under germ-free conditions demonstrated significant changes in plasma metabolites. Among 183 detected solutes, plasma levels of 11 solutes, including major uremic toxins, were significantly lower in germ-free mice than in SPF mice with renal failure. These 11 solutes were considered microbiota-derived uremic solutes and included indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, γ-guanidinobutyrate, glutarate, 2-hydroxypentanoate, trimethylamine N-oxide, and phenaceturate. Metabolome profiling showed that these solutes were classified into three groups depending on their origins: completely derived from microbiota (indoxyl sulfate, p-cresyl sulfate), derived from both host and microbiota (dimethylglycine), and derived from both microbiota and dietary components (trimethylamine N-oxide). Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Microbiota-derived short-chain fatty acids and efficient amino acid utilization may have a renoprotective effect, and loss of these factors may exacerbate renal damage in germ-free mice with renal failure. Thus, microbiota contributes substantially to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression.
肠道微生物群参与尿毒症溶质的代谢。然而，微生物群对 CKD 中尿毒症溶质潴留的确切影响尚不清楚。为了阐明这一点，我们比较了无菌或特定病原体（SPF）条件下腺嘌呤诱导的肾功能衰竭和对照小鼠，使用毛细管电泳飞行时间质谱分析方法检测血浆、粪便和尿液中的代谢物谱。在无菌条件下患有肾功能衰竭的小鼠的血浆代谢物发生了显著变化。在检测到的 183 种溶质中，11 种溶质（包括主要尿毒症毒素）的血浆水平在无菌小鼠中明显低于 SPF 肾功能衰竭小鼠。这 11 种溶质被认为是微生物群衍生的尿毒症溶质，包括吲哚硫酸酯、对甲酚硫酸酯、苯硫酸酯、胆酸盐、马尿酸、二甲基甘氨酸、γ-胍基丁酸、戊二酸、2-羟基戊酸、三甲胺 N-氧化物和苯乙酰胺。代谢组学分析表明，这些溶质根据其来源分为三组：完全来源于微生物群（吲哚硫酸酯、对甲酚硫酸酯），来源于宿主和微生物群（二甲基甘氨酸），来源于微生物群和膳食成分（三甲胺 N-氧化物）。此外，与 SPF 肾功能衰竭小鼠相比，无菌肾功能衰竭条件导致结肠短链脂肪酸消失、肠道氨基酸利用率降低和更严重的肾脏损伤。微生物群衍生的短链脂肪酸和有效的氨基酸利用可能具有肾脏保护作用，而这些因素的丧失可能会加重无菌肾功能衰竭小鼠的肾脏损伤。因此，微生物群在产生有害尿毒症溶质方面起着重要作用，但相反，没有微生物群的生长对 CKD 进展有不利影响。
