Chac1 deficiency confers sepsis resistance by enriching gut microbiota-derived indole-3-carboxylic acid to drive macrophage metabolic shifts

INTRODUCTION: Sepsis is a life-threatening dysregulated host response to infection, lacks effective therapies. ChaC glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) is elevated in sepsis and correlates with severity, but its functional role in the pathogenesis of sepsis-induced organ damage is unclear. OBJECTIVES: We aimed to define the contribution of CHAC1 to sepsis-induced organ injury and elucidate the underlying mechanisms involving gut microbiota-derived metabolites and host immunity. METHODS: mice were subjected to LPS-induced endotoxemia to evaluate organ injury. The gut microbiota's role was defined by 16S rRNA gene sequencing, microbiota depletion and fecal microbiota transplantation (FMT). The effect of microbiota-derived metabolite indole-3-carboxylic acid (ICA) was assessed in vivo. Underlying mechanisms were investigated via macrophage depletion, AHR pharmacological/genetic inhibition, and in vitro studies with RAW264.7 cells and bone marrow-derived macrophages. RESULTS: mice exhibited a remodeled gut microbiota, with enrichment of Akkermansia muciniphila and increased levels of the tryptophan metabolite ICA. Exogenous ICA or A. muciniphila supplementation recapitulated the protective phenotype. ICA treatment improved survival, attenuated inflammation, and reduced organ injury by activating the aryl hydrocarbon receptor (AHR) in macrophages. This was evidenced by AHR nuclear translocation, and siRNA-mediated AHR knockdown abolished ICA's effects. ICA reprogrammed macrophage metabolism, inhibiting glycolysis (reduced lactate) and enhancing oxidative phosphorylation (increased ATP, oxygen consumption rate), leading to suppressed pro-inflammatory responses. CONCLUSION: Chac1 deficiency confers sepsis resistance by enriching protective gut microbiota and elevating ICA, which acts as a major downstream effector. ICA activates the AHR in macrophages, driving a metabolic shift from glycolysis to oxidative phosphorylation that dampens inflammation and organ injury. This CHAC1-microbiota-ICA-AHR-macrophage axis identifies ICA as a promising therapeutic candidate and CHAC1 as a potential prognostic biomarker for sepsis.