Gut microbiota-derived D-serine protects against acute kidney injury
Gut microbiota-derived D-serine protects against acute kidney injury
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肠道微生物衍生的D-丝氨酸保护急性肾损伤
DOI：
10.1172/jci.insight.97957
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发表时间：
2018-10-18
期刊：
影响因子：
8
通讯作者：
Wada, Takashi
中科院分区：
文献类型：
--
作者：
Nakade, Yusuke;Iwata, Yasunori;Wada, Takashi
肠道微生物衍生的代谢产物在健康和疾病中起着重要作用。D-氨基酸及其L-型是肠道微生物群的代谢产物，具有不同的功能。在这项研究中，我们显示了D-氨基酸与人类和小鼠急性肾损伤（阿基）肠道微生物群相关的病理生理作用。在小鼠肾脏缺血/再灌注模型中，肠道微生物群保护肾小管损伤。AKI诱导的肠道生态失调导致D-氨基酸代谢改变。在D-氨基酸中，只有D-丝氨酸在肾脏中可检测到。损伤肾D-氨基酸氧化酶活性降低。相反，丝氨酸消旋酶的活性增加。口服D-丝氨酸可减轻B6小鼠和D-丝氨酸缺失小鼠的肾脏损伤。D-丝氨酸抑制缺氧诱导的肾小管损伤并促进缺氧后肾小管细胞增殖。最后，循环中的D-丝氨酸水平与阿基患者的肾功能下降显著相关。这些结果证明了肠源性D-丝氨酸在阿基中的肾脏保护作用，揭示了健康和阿基中肠道微生物群与肾脏之间的相互作用，并强调D-丝氨酸作为阿基的潜在新治疗靶点和生物标志物。
Gut microbiota-derived metabolites play important roles in health and disease. D-amino acids and their L-forms are metabolites of gut microbiota with distinct functions. In this study, we show the pathophysiologic role of D-amino acids in association with gut microbiota in humans and mice with acute kidney injury (AKI). In a mouse kidney ischemia/reperfusion model, the gut microbiota protected against tubular injury. AKI-induced gut dysbiosis contributed to the altered metabolism of D-amino acids. Among the D-amino acids, only D-serine was detectable in the kidney. In injured kidneys, the activity of D-amino acid oxidase was decreased. Conversely, the activity of serine racemase was increased. The oral administration of D-serine mitigated the kidney injury in B6 mice and D-serine-depleted mice. D-serine suppressed hypoxia-induced tubular damage and promoted posthypoxic tubular cell proliferation. Finally, the D-serine levels in circulation were significantly correlated with the decrease in kidney function in AKI patients. These results demonstrate the renoprotective effects of gut-derived D-serine in AKI, shed light on the interactions between the gut microbiota and the kidney in both health and AKI, and highlight D-serine as a potential new therapeutic target and biomarker for AKI.