Zhan Minghua, Li Ziyao, Chen Jianing, Zhao Yanling, Bai Zhou, Lu Binghuai, Chen Hongbin, Liu Yudong
National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/ National Center of Gerontology, China; Department of Clinical Laboratory, First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China.
Peking Union Medical College, Chinese Academy of Medical Sciences; Changping Laboratory; Laboratory of Clinical Microbiology and Infectious Diseases, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.
Clin Immunol. 2025 Mar;272:110430. doi: 10.1016/j.clim.2025.110430. Epub 2025 Jan 26.
Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have a high risk of serious infection, in particular severe pneumonia. This study aimed to investigate the transcriptional landscape, lower respiratory tract (LRT) microbiome and metabolomic profiles in the lung of RA-ILD patients with pneumonia.
A total of 10 RA-ILD with pneumonia were enrolled in this study. In addition, 11 patients with COVID-19-associated pneumonia and 6 patients with non-autoimmune and non-COVID-19-related ILD with pneumonia were included as controls. Bronchoalveolar lavage fluid (BALF) was collected and prepared for metagenomic next-generation sequencing (mNGS), non-targeted metabolomics and bulk RNA-seq.
Neutrophil-related genes were shared in the BALF cells of RA-ILD patients with pneumonia and patients with COVID-19-associated pneumonia. Carnobacterium, Wujia, Intestinimonas, Apibacter, Anaerotignum and Parvimonas were enriched in the LRT microbiome of RA-ILD, while Wujia, Apibacter, Pseudocitrobacter, and Thermobacillus were enriched in the LRT microbiome of COVID-19. Metabolomics analysis of BALF revealed significant elevation of indoxyl sulfate (IS) in the BALF of RA-ILD patients in comparison to COVID-19. Mechanistically, IS exerts an pro-inflammatory effect on macrophages and bronchial epithelial cells for pro-inflammatory cytokine production and potentiated neutrophils for neutrophil extracellular traps (NETs) formation.
Our results demonstrated a significant differences in the LRT microbiome and BALF metabolites between RA-ILD and COVID-19 patients with pneumonia, although they displayed similar local immune responses against lung infection. Alterations of LRT microbiome and related metabolites may be implicated in the pathogenesis of pneumonia in RA-ILD.
类风湿关节炎相关间质性肺疾病（RA-ILD）患者发生严重感染尤其是重症肺炎的风险很高。本研究旨在调查肺炎RA-ILD患者肺部的转录图谱、下呼吸道（LRT）微生物组和代谢组学特征。
本研究共纳入10例肺炎RA-ILD患者。此外，纳入11例COVID-19相关肺炎患者和6例非自身免疫且非COVID-19相关的ILD合并肺炎患者作为对照。收集支气管肺泡灌洗液（BALF）并准备用于宏基因组下一代测序（mNGS）、非靶向代谢组学和大量RNA测序。
肺炎RA-ILD患者和COVID-19相关肺炎患者的BALF细胞中存在与中性粒细胞相关的基因。肉杆菌属、伍氏菌属、肠道单胞菌属、阿皮杆菌属、厌氧嗜热栖菌属和小杆菌属在RA-ILD的LRT微生物组中富集，而伍氏菌属、阿皮杆菌属、假柠檬酸杆菌属和嗜热芽孢杆菌属在COVID-（此处原文有误，推测为COVID-19）的LRT微生物组中富集。BALF的代谢组学分析显示，与COVID-19相比，RA-ILD患者BALF中的硫酸吲哚酚（IS）显著升高。从机制上讲，IS对巨噬细胞和支气管上皮细胞产生促炎作用，促进促炎细胞因子的产生，并增强中性粒细胞以促进中性粒细胞胞外陷阱（NETs）的形成。
我们的结果表明，尽管肺炎RA-ILD患者和COVID-19患者对肺部感染表现出相似的局部免疫反应，但两者在LRT微生物组和BALF代谢物方面存在显著差异。LRT微生物组和相关代谢物的改变可能与RA-ILD肺炎的发病机制有关。
