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.
Yusuke Nakade, Yasunori Iwata, Kengo Furuichi, Masashi Mita, Kenji Hamase, Ryuichi Konno, Taito Miyake, Norihiko Sakai, Shinji Kitajima, Tadashi Toyama, Yasuyuki Shinozaki, Akihiro Sagara, Taro Miyagawa, Akinori Hara, Miho Shimizu, Yasutaka Kamikawa, Kouichi Sato, Megumi Oshima, Shiori Yoneda-Nakagawa, Yuta Yamamura, Shuichi Kaneko, Tetsuya Miyamoto, Masumi Katane, Hiroshi Homma, Hidetoshi Morita, Wataru Suda, Masahira Hattori, Takashi Wada