Harpagide alleviates sepsis-induced acute respiratory distress syndrome via gut microbiota modulation.

BACKGROUND

Sepsis-associated acute respiratory distress syndrome (ARDS) remains a leading cause of mortality in critically ill patients, with limited therapeutic options beyond supportive care. The gut-lung axis is critical in sepsis pathogenesis, yet effective targeting strategies remain scarce. Harpagide (HPG), an iridoid glycoside from Scrophularia ningpoensis, exhibits anti-inflammatory properties, but whether it protects against sepsis-induced ARDS through gut microbiota modulation remains unexplored.

METHODS

Sepsis-induced ARDS was established using the cecal ligation and puncture (CLP) model. Gut microbiota dependency was assessed via antibiotic depletion (ABX) and fecal microbiota transplantation (FMT). Ffar2-/- mice were used to verify receptor necessity. Microbial composition and SCFAs were analyzed by 16S rRNA sequencing and GC-MS. Lung signaling was assessed by RNA-seq, Western blot, and RT-qPCR. Plasma SCFAs were quantified in sepsis-induced ARDS patients (n = 12) and healthy controls (n = 12) by LC-MS/MS.

RESULTS

HPG significantly improved survival, attenuated lung injury, and suppressed cytokine storm in septic mice. These effects were abolished by ABX but transferable via FMT, confirming microbiota dependency. HPG enriched acetate-producing taxa, elevating fecal and plasma acetate. Transcriptomic analysis revealed simultaneous suppression of NF-κB signaling and excessive IFN-γ/STAT1 activation. HPG-mediated protection was completely abrogated in Ffar2-/- mice, and exogenous sodium acetate recapitulated these effects in a Ffar2-dependent manner. Clinically, plasma acetate was significantly depleted in ARDS patients and correlated with disease severity.

CONCLUSIONS

HPG alleviates sepsis-induced ARDS by reshaping gut microbiota to boost acetate production, which activates FFAR2 to orchestrate immune reprogramming via NF-κB and IFN-γ/STAT1 pathways, offering a novel microbial-metabolic therapeutic strategy.