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Abstract: FR-PO124

Elucidation of the Mechanism of Kidney-Gut Cross-Talk via the D-Serine Derived from Gut Microbiota

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Nakade, Yusuke, Kanazawa University Hospital, Kanazawa, Japan
  • Iwata, Yasunori, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Kitajima, Shinji, Kanazawa University Hospital, Kanazawa, Japan
  • Toyama, Tadashi, Kanazawa University Hospital, Kanazawa, Japan
  • Hara, Akinori, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Shimizu, Miho, Division of Nephrology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
  • Sakai, Norihiko, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Wada, Takashi, Kanazawa University, Kanazawa, ISHIKAWA, Japan
Background

While dysbiosis of the gut microbiota has been closely associated with kidney disease, the precise underlying mechanisms remain unclear. Recent advances have shed light on the chirality of amino acids. Free D-amino acids and their L-forms were quantified by 2D HPLC. Accumulating data revealed that D-amino acids were the primary microbial products, which showed physiologic roles in several organs. However, the involvement of D-amino acids in kidney diseases have yet to be revealed. Thus, we explored the pathophysiological role of D-amino acids in association with the gut microbiota in kidney disease.

Methods

Six-week-old male C57BL/6 (B6) mice and germ-free (Gf) B6 mice were subjects to sham or ischemia-reperfusion (I/R) operation, and evaluated 2, 5, 7 and 10 days after surgery.
D-serine was administered to mice via drinking water during I/R induced kidney injury.
We performed 16S rRNA gene sequencing analysis of the mouse gut microbiota and evaluated D- and L-amino acids in the mouse feces, plasma, kidney and urine using 2D HPLC system. We also obtained blood samples from patients with AKI to evaluate D- and L-amino acids.

Results

Specific gut bacteria were influenced by I/R. Further, I/R induced kidney injury was more severe in Gf B6 mice compared to B6 mice. Interestingly, fecal transplantation from normal mice attenuated the renal pathology in the Gf B6 mice. Next, we performed comprehensive analyses of chiral amino acids in I/R induced kidney injury. While various D-amino acids were detected in the feces, only D-serine was detected in the injured kidney. Furthermore, D-serine was not detected in the feces of Gf B6 mice, suggesting that gut microbiota produced D-serine in response to kidney disease. Further, the oral administration of D-serine attenuated I/R injury in normal mice. In addition, we assessed the association between D-serine and renal function in patients with AKI. The plasma levels of D-serine in patients with AKI was higher than in the plasma of healthy subjects, showing a high correlation with creatinine (r > 0.9).

Conclusion

These results demonstrate the renoprotective effects of gut-derived D-serine in AKI, shed light on the novel interactions between the gut microbiota and the kidney, and highlight D-serine as a potential new therapeutic target and biomarker for AKI.