Dietary tryptophan supplementation prevents sepsis by enhancing macrophage bacterial defense through GPR37 activation

BACKGROUND: Sepsis, a critical and life-threatening condition, is one of the most common causes of death among inpatients. Emerging evidence suggests that active metabolites derived from gut microbe-associated metabolism of dietary essential amino acid L-tryptophan (Trp) help the host in combating infectious diseases. This study aims to investigate the mechanisms through which these active metabolites regulate sepsis progression. METHODS: The effects of dietary Trp and indole-3-pyruvate (IPyA) on the mouse septic model were evaluated by 72-hour survival rate monitoring, organ pathological injury score, bacterial load, and inflammatory factor expression. The changes in gut microbiota composition caused by dietary Trp were detected by 16S rRNA gene sequencing. The changes in Trp bacterial metabolites were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The effects of IPyA on macrophage phagocytosis were evaluated by flow cytometry and plate colony formation assay. The interaction between IPyA and G protein-coupled receptor 37 (GPR37) was evaluated by Western blot and surface plasmon resonance. Gpr37 knockout mice, small interfering RNA transfection in macrophages, and macrophage adoptive transfer assay were used to explore the detailed mechanism of IPyA in protecting sepsis. RESULTS: It is revealed that dietary Trp supplementation alleviated septic organ injury by modulating the abundance of key commensal microbes and their metabolic function. Furthermore, we found that GPR37 activation in macrophages by a key microbial metabolite, IPyA, raised after dietary Trp supplementation, protected the host against sepsis. Mechanistically, IPyA bound directly to GPR37 in macrophages, causing activation of small GTPases Ras-related C3 botulinum toxin substrate 1/Cell division cycle 42 (RAC1/CDC42) and increased expression of actin-related protein (Arp) 2/3, ultimately enhancing bacterial phagocytosis in macrophages. In addition, IPyA exhibited the potential to promote bacterial phagocytosis in macrophages obtained from patients. CONCLUSION: Targeting GPR37 through dietary Trp supplementation may be a potential prophylactic strategy to optimize gut microbiota metabolic functioning and ameliorate septic bacterial infections.