Microbial metabolite oxindole curbs acute lung injury by suppressing CXCL13
Abstract
The gut–lung axis is involved in acute lung injury (ALI) and its fatal sequela, acute respiratory distress syndrome (ARDS), yet the molecular mechanisms governing this crosstalk remain poorly defined. Untargeted metabolomics of plasma revealed significant dysregulation of tryptophan metabolism in ARDS patients compared to healthy controls. Murine dietary interventions demonstrated that high tryptophan intake alleviated ALI severity, whereas deficiency exacerbated injury, with protection being gut microbiota dependent. 16S ribosomal RNA (16S rRNA) gene sequencing revealed marked depletion of a functionally central bacterium Lactobacillus johnsonii ( L. johnsonii ) during ALI. Supplementation with L. johnsonii or its encapsulated form attenuated ALI, but this required dietary tryptophan sufficiency. Mechanistically, L. johnsonii converts tryptophan into oxindole, which enters pulmonary macrophages, promotes the aryl hydrocarbon receptor-RelA binding, and thereby suppresses RelA-mediated transcriptional activation of C-X-C motif chemokine 13 (CXCL13). Both genetic ablation and pharmacological inhibition of CXCL13 ameliorated ALI symptoms. Importantly, oxindole and CXCL13 levels correlated with ARDS severity in patients, suggesting their clinical relevance. Collectively, these findings define a protective microbiota-dependent gut–lung axis in ALI/ARDS that is mediated by dietary tryptophan-derived oxindole, which acts at least partially through CXCL13 suppression to underscore targetable diet–microbe–metabolite therapeutic paradigms.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Shixin Tang
Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University
Jun Zhang
Zhenghai He
Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University
Gang Liu
Shenyou Nie
Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Department of Urology of the Second Affiliated Hospital, College of Pharmacy, Chongqing Medical University
Xingyang Shi
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University
Kun Zhang
Dandan Pi
Department of Intensive Care Unit, Children’s Hospital of Chongqing Medical University
Xiao Gui
Department of Emergency, The University-Town Hospital of Chongqing Medical University
Yi He
College of Chemistry and Chemical Engineering
Shuang Zhao
Ministry of Education Key Laboratory of Cluster Science, Beijing Key Laboratory of Photoelectronic/Electrophotonic Conversion Materials, Frontiers Science Center for High Energy Materials, School of Chemistry and Chemical Engineering, Advanced Technology Research Institute (Jinan), Advanced Research Institute of Multidisciplinary Science
Zhihui Liu
Lejiao Mao
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University
Yu Jiang
Mingjun Wu
Innovation Centre of Chongqing Medical University
Ju Cao
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University
Jingfu Qiu
Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University
Chengzhi Chen
Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University
Zhen Zou
State Key Laboratory of Animal Biodiversity Conservation and Integrated Pest Management, Institute of Zoology, Chinese Academy of Sciences