Department of Nephrology and Laboratory Medicine.
Division of Infection Control.
JCI Insight. 2018 Oct 18;3(20):97957. doi: 10.1172/jci.insight.97957.
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.
肠道微生物衍生代谢物在健康和疾病中发挥着重要作用。D-氨基酸及其 L 型是具有不同功能的肠道微生物代谢物。在这项研究中，我们展示了 D-氨基酸与肠道微生物在人类和急性肾损伤（AKI）小鼠中的病理生理作用。在小鼠肾缺血/再灌注模型中，肠道微生物可保护肾小管免受损伤。AKI 引起的肠道菌群失调导致 D-氨基酸代谢的改变。在 D-氨基酸中，只有 D-丝氨酸可在肾脏中检测到。在受损的肾脏中，D-氨基酸氧化酶的活性降低。相反，丝氨酸消旋酶的活性增加。D-丝氨酸的口服给药可减轻 B6 小鼠和 D-丝氨酸耗竭小鼠的肾脏损伤。D-丝氨酸可抑制低氧诱导的肾小管损伤，并促进低氧后肾小管细胞的增殖。最后，循环中的 D-丝氨酸水平与 AKI 患者肾功能下降显著相关。这些结果表明，肠道来源的 D-丝氨酸对 AKI 具有肾脏保护作用，揭示了肠道微生物与健康和 AKI 中肾脏之间的相互作用，并强调 D-丝氨酸作为 AKI 的潜在新治疗靶点和生物标志物。
