Chen Yihang, Chen Zhenzhen, Liang Lirong, Li Jifeng, Meng Liukun, Yuan Wen, Xie Boqia, Zhang Xun, Feng Lin, Jia Yanxiong, Fu Zhou, Su Pixiong, Tong Zhaohui, Zhong Jiuchang, Liu Xiaoyan
Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China; Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, 100029, China.
EBioMedicine. 2025 May;115:105686. doi: 10.1016/j.ebiom.2025.105686. Epub 2025 Apr 11.
Gut microbiota dysbiosis has been implicated in pulmonary arterial hypertension (PAH). However, the exact roles and underlying mechanisms of multi-kingdom gut microbiota, including bacteria, archaea, and fungi, in PAH remain largely unclear.
The shotgun metagenomics was used to analyse multi-kingdom gut microbial communities in patients with idiopathic PAH (IPAH) and healthy controls. Furthermore, fecal microbiota transplantation (FMT) was performed to transfer gut microbiota from IPAH patients or monocrotaline (MCT)-PAH rats to normal rats and from normal rats to MCT-PAH rats.
Gut microbiota analysis revealed substantial alterations in the bacterial, archaeal, and fungal communities in patients with IPAH compared with healthy controls. Notably, FMT from IPAH patients or MCT-PAH rats induced PAH phenotypes in recipient rats. More intriguingly, FMT from normal rats to MCT-PAH rats significantly ameliorated PAH symptoms; restored gut bacteria, archaea, and fungi composition; and shifted the plasma metabolite profiles of MCT-PAH rats toward those of normal rats. In parallel, RNA-sequencing analysis demonstrated the expression of genes involved in key signalling pathways related to PAH. A panel of multi-kingdom markers exhibited superior diagnostic accuracy compared with single-kingdom panels for IPAH.
Our findings established an association between multi-kingdom gut microbiota dysbiosis and PAH, thereby indicating the therapeutic potential of FMT in PAH. More importantly, apart from gut bacteria, gut archaea and fungi were also significantly associated with PAH pathogenesis, highlighting their indispensable role in PAH.
This work was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Projects No. 2024ZD0531200, No. 2024ZD0531201 (Research on Prevention and Treatment of Cancer, Cardiovascular and Cerebrovascular Diseases, Respiratory Diseases, and Metabolic Diseases), the National Natural Science Foundation of China of China (No. 82170302, 82370432), Financial Budgeting Project of Beijing Institute of Respiratory Medicine (Ysbz2025004, Ysbz2025007), National clinical key speciality construction project Cardiovascular Surgery, Reform and Development Program of Beijing Institute of Respiratory Medicine (Ggyfz202417, Ggyfz202501), Clinical Research Incubation Program of Beijing Chaoyang Hospital Affiliated to Capital Medical University (CYFH202209).
肠道微生物群失调与肺动脉高压（PAH）有关。然而，包括细菌、古菌和真菌在内的多界肠道微生物群在PAH中的确切作用和潜在机制仍不清楚。
采用鸟枪法宏基因组学分析特发性PAH（IPAH）患者和健康对照者的多界肠道微生物群落。此外，进行了粪便微生物群移植（FMT），将IPAH患者或野百合碱（MCT）-PAH大鼠的肠道微生物群移植到正常大鼠体内，以及将正常大鼠的肠道微生物群移植到MCT-PAH大鼠体内。
肠道微生物群分析显示，与健康对照者相比，IPAH患者的细菌、古菌和真菌群落有显著改变。值得注意的是，来自IPAH患者或MCT-PAH大鼠的FMT在受体大鼠中诱导出PAH表型。更有趣的是，从正常大鼠到MCT-PAH大鼠的FMT显著改善了PAH症状；恢复了肠道细菌、古菌和真菌的组成；并使MCT-PAH大鼠的血浆代谢物谱向正常大鼠的谱转变。同时，RNA测序分析显示了与PAH相关的关键信号通路中基因的表达。一组多界标志物对IPAH的诊断准确性优于单界标志物组。
我们的研究结果建立了多界肠道微生物群失调与PAH之间的关联，从而表明FMT在PAH中的治疗潜力。更重要的是，除了肠道细菌外，肠道古菌和真菌也与PAH发病机制显著相关，突出了它们在PAH中不可或缺的作用。
本研究得到了国家科技重大专项非传染性慢性病（项目编号：2024ZD0531200、2024ZD0531201，癌症、心脑血管疾病、呼吸系统疾病和代谢疾病防治研究）、国家自然科学基金（项目编号：82170302、82370432）、北京呼吸疾病研究所财政预算项目（项目编号：Ysbz2025004、Ysbz2025007）、国家临床重点专科建设项目心血管外科、北京呼吸疾病研究所改革发展项目（项目编号：Ggyfz202417、Ggyfz202501）、首都医科大学附属北京朝阳医院临床研究孵化项目（项目编号：CYFH202209）的支持。
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