粪菌移植通过丁酸介导的HDAC3抑制和PI3K/Akt/eNOS信号调节减轻大鼠肝硬化门静脉高压
Fecal microbiota transplantation alleviates cirrhotic portal hypertension in rats via butyrate-mediated HDAC3 inhibition and PI3K/Akt/eNOS signaling regulation.
作者信息
Luo Ming, Du Yawei, Liu Xuanchen, Zhang Shuwen, Zhu Wenwen, Liu Kaipeng, Ren Xiubao, Zhang Ningning
机构信息
Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, 300060, Tianjin, PR China; Department of Gastroenterology, People's Hospital of Ningxia Hui Autonomous Region, Ningxia Medical University, 750000, Yinchuan, Ningxia Hui Autonomous Region, PR China.
Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, 300060, Tianjin, PR China.
出版信息
Eur J Pharmacol. 2025 Sep 5;1002:177781. doi: 10.1016/j.ejphar.2025.177781. Epub 2025 May 27.
BACKGROUND
Portal hypertension (PHT) is a severe complication of liver cirrhosis, with limited therapeutic options. Despite emerging evidence linking gut microbiota dysbiosis to PHT progression, the mechanisms by which microbial metabolites modulate liver sinusoidal endothelial cells (LSECs) dysfunction and the therapeutic efficacy of fecal microbiota transplantation (FMT) remain poorly understood. This study investigated the potential of FMT to alleviate PHT in cirrhotic rats, exploring the underlying mechanisms involving butyrate-mediated HDAC3 inhibition and PI3K/Akt/eNOS signaling regulation in LSECs.
METHODS
Cirrhosis with PHT was induced in Sprague-Dawley rats via intraperitoneal carbon tetrachloride injection, followed by FMT or butyrate supplementation via oral gavage. Analyses included portal hemodynamic measurements, gut microbiota sequencing, serum SCFA metabolomics profiling, HDAC3 activity assays, NO level quantification, and assessments of liver fibrosis, liver function, and LSEC ultrastructure. LSECs were isolated for PI3K/Akt/eNOS signaling analysis via qRT-PCR, Western blotting, and immunofluorescence staining.
RESULTS
A two-week FMT intervention in cirrhotic rats with PHT enriched butyrate-producing bacteria and increased serum butyrate levels, which were associated with reduced portal pressure and intrahepatic vascular resistance, without affecting liver fibrosis, function, or LSEC ultrastructure. FMT reduced HDAC3 activity by 2.17-fold and increased Akt and eNOS phosphorylation in primary LSECs by 1.69-fold and 1.25-fold, respectively, elevating plasma NO levels by 1.66-fold compared to untreated controls. In vitro experiments with primary LSECs confirmed these butyrate-mediated effects.
CONCLUSION
FMT alleviates cirrhotic PHT through butyrate-mediated HDAC3 inhibition and subsequent PI3K/Akt/eNOS signaling activation in LSECs, highlighting the therapeutic potential of targeting the gut-liver axis via microbial metabolites for PHT management.
背景
门静脉高压（PHT）是肝硬化的一种严重并发症，治疗选择有限。尽管越来越多的证据表明肠道微生物群失调与PHT进展有关，但微生物代谢产物调节肝窦内皮细胞（LSEC）功能障碍的机制以及粪便微生物群移植（FMT）的治疗效果仍知之甚少。本研究探讨了FMT缓解肝硬化大鼠PHT的潜力，探索了涉及丁酸盐介导的HDAC3抑制和LSEC中PI3K/Akt/eNOS信号调节的潜在机制。
方法
通过腹腔注射四氯化碳在Sprague-Dawley大鼠中诱导肝硬化伴PHT，然后通过口服灌胃进行FMT或补充丁酸盐。分析包括门静脉血流动力学测量、肠道微生物群测序、血清短链脂肪酸代谢组学分析、HDAC3活性测定、一氧化氮水平定量以及肝纤维化、肝功能和LSEC超微结构评估。分离LSEC，通过qRT-PCR、蛋白质印迹和免疫荧光染色进行PI3K/Akt/eNOS信号分析。
结果
对患有PHT的肝硬化大鼠进行为期两周的FMT干预，可使产生丁酸盐的细菌富集并提高血清丁酸盐水平，这与门静脉压力和肝内血管阻力降低相关，而不影响肝纤维化、功能或LSEC超微结构。FMT使原代LSEC中的HDAC3活性降低2.17倍，使Akt和eNOS磷酸化分别增加1.69倍和1.25倍，与未治疗的对照组相比，血浆一氧化氮水平升高1.66倍。原代LSEC的体外实验证实了这些丁酸盐介导的作用。
结论
FMT通过丁酸盐介导的HDAC3抑制以及随后LSEC中PI3K/Akt/eNOS信号激活来缓解肝硬化性PHT，突出了通过微生物代谢产物靶向肠-肝轴治疗PHT的潜力。
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