The tryptophan metabolite kynurenic acid ameliorates septic colonic injury through activation of the PPARγ signaling pathway

Sepsis is the leading cause of death among critically ill patients in clinical practice, making it urgent to reduce its incidence and mortality rates. In sepsis, macrophage dysfunction often worsens and complicates the condition. M1 and M2 macrophages, two distinct types, contribute to pro-inflammatory and anti-inflammatory effects, respectively. An imbalance between them is a major cause of sepsis. The aim of this study was to explore the potential of a differential metabolite between M1 and M2 macrophages in mitigating septic colonic injury via multiomics in combination with clinical data and animal experiments. Using nontargeted metabolomics analysis, we found that Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, was significantly upregulated in the supernatant of M2 macrophages. Furthermore, we discovered that the level of KYNA was significantly decreased in sepsis in both human and mouse serum and was negatively correlated with inflammatory factor levels. In vivo experiments demonstrated that KYNA can effectively alleviate septic colon injury and reduce inflammatory factor levels in mice, indicating that KYNA plays a very important protective role in sepsis. Mechanistically, KYNA promotes the transition of M1 macrophages to M2 macrophages by inhibiting the NF-κB signaling pathway and alleviates septic colonic injury through the PPARγ/NF-κB axis. This article reveals that KYNA, a differentially abundant metabolite between M1 and M2 macrophages, can become a new strategy for alleviating septic colon injury.

Kynurenic acid; M1 macrophages; M2 macrophages; Sepsis.