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.
Harpagide (HPG) significantly improved survival, attenuated lung injury, and suppressed cytokine storm in septic mice using the cecal ligation and puncture (CLP) model.
The protective effects of HPG against sepsis-induced ARDS were dependent on the gut microbiota, as demonstrated by antibiotic depletion and fecal microbiota transplantation experiments.
HPG enriched acetate-producing bacterial taxa, resulting in elevated fecal and plasma acetate levels.
HPG-mediated protection against sepsis-induced ARDS was completely abrogated in Ffar2-/- (free fatty acid receptor 2 knockout) mice, establishing receptor necessity.
Transcriptomic analysis revealed that HPG simultaneously suppressed NF-κB signaling and excessive IFN-γ/STAT1 activation in lung tissue.
Plasma acetate levels were significantly depleted in ARDS patients compared to healthy controls and correlated with disease severity.
This research suggests that a natural plant compound called harpagide (HPG), found in Scrophularia ningpoensis, can protect against the severe lung damage that occurs during sepsis (a life-threatening response to infection) by changing the bacterial community in the gut. Using a mouse model of sepsis-induced acute respiratory distress syndrome (ARDS), researchers found that HPG improved survival rates and reduced dangerous inflammation in the lungs. Critically, these benefits disappeared when the gut bacteria were wiped out with antibiotics, but could be transferred to other mice through fecal transplants, proving that the gut microbiome was essential to HPG's protective action. The study found that HPG works by promoting the growth of specific gut bacteria that produce a molecule called acetate (a type of short-chain fatty acid). This acetate travels through the body and binds to a receptor called FFAR2, which then helps regulate the immune system by dampening two major inflammatory pathways (NF-κB and IFN-γ/STAT1). When mice were genetically engineered to lack the FFAR2 receptor, HPG no longer provided protection, confirming that this receptor is essential to the mechanism. Giving mice supplemental sodium acetate produced similar protective effects, also requiring FFAR2, which further validated this pathway. Importantly, when the researchers measured acetate levels in the blood of actual human ARDS patients (12 patients versus 12 healthy controls), they found that acetate was significantly lower in patients with ARDS and that lower acetate levels corresponded to more severe disease. This research suggests that the gut-lung connection is a viable therapeutic target in ARDS, and that strategies aimed at boosting gut acetate production—whether through compounds like HPG, dietary interventions, or microbiome therapies—may represent a new direction for treating this life-threatening condition.
Sun Y, Xie D, Fu H, He M, Li J, Wu C, et al.. (2026). Harpagide alleviates sepsis-induced acute respiratory distress syndrome via gut microbiota modulation.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158329