Harpagide通过调节肠道微生物群缓解败血症引起的急性呼吸窘迫综合征
Harpagide alleviates sepsis-induced acute respiratory distress syndrome via gut microbiota modulation.
摘要(中文译文)
脓毒症相关急性呼吸窘迫综合征（ARDS）仍是危重症患者死亡的主要原因，除支持治疗外治疗选择有限。肠-肺轴在脓毒症发病机制中至关重要，但有效的靶向策略仍然匮乏。哈帕苷（Harpagide，HPG）是一种来源于玄参的环烯醚萜苷，具有抗炎特性，但其是否通过调节肠道菌群对脓毒症诱导的ARDS发挥保护作用尚不清楚。采用盲肠结扎穿刺（CLP）模型建立脓毒症诱导的ARDS。通过抗生素清除（ABX）和粪菌移植（FMT）评估肠道菌群依赖性。使用Ffar2基因敲除小鼠验证受体的必要性。通过16S rRNA测序和GC-MS分析微生物组成及短链脂肪酸（SCFAs）。通过RNA-seq、Western blot和RT-qPCR评估肺部信号通路。采用LC-MS/MS对脓毒症诱导的ARDS患者（n = 12）和健康对照者（n = 12）进行血浆SCFAs定量检测。HPG显著提高了脓毒症小鼠的生存率，减轻了肺损伤，并抑制了细胞因子风暴。这些效应被ABX消除，但可通过FMT转移，证实了其菌群依赖性。HPG富集了产乙酸菌群，提高了粪便和血浆乙酸水平。转录组分析揭示NF-κB信号通路和过度激活的IFN-γ/STAT1信号通路同时受到抑制。HPG介导的保护作用在Ffar2基因敲除小鼠中被完全消除，外源性乙酸钠以Ffar2依赖的方式重现了这些效应。在临床上，ARDS患者血浆乙酸显著降低，且与疾病严重程度相关。HPG通过重塑肠道菌群促进乙酸生成，乙酸激活FFAR2，通过NF-κB和IFN-γ/STAT1通路协调免疫重编程，从而缓解脓毒症诱导的ARDS，提供了一种新型的微生物-代谢治疗策略。
Abstract
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. 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. 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. 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.
如何引用
AMA
Yuting Sun, Di Xie, Huimin Fu, Meilin He, Jiaqi Li, Chaomin Wu, et al. Harpagide alleviates sepsis-induced acute respiratory distress syndrome via gut microbiota modulation.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158329.
APA
Yuting Sun, Di Xie, Huimin Fu, Meilin He, Jiaqi Li, Chaomin Wu, 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
GB/T 7714
Yuting Sun, Di Xie, Huimin Fu, Meilin He, Jiaqi Li, Chaomin Wu, et al. Harpagide alleviates sepsis-induced acute respiratory distress syndrome via gut microbiota modulation.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158329.
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