Gut flora-derived succinate exacerbates Allergic Airway Inflammation by promoting protein succinylation
Chao Wang,
Xin Yu,
Xiao Yu,
Hui Xiao,
Yuemeng Song,
Xinlei Wang,
Haoyu Zheng,
Kai Chen,
Yiming An,
Zhengjie Zhou,
Xiaoping Guo,
Fang Wang
Affiliations
Chao Wang
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China; The Medical Basic Research Innovation Center of Airway Disease in North China, Ministry of Education of China, China
Xin Yu
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China; Department of Laboratory Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
Xiao Yu
Department of Histology & Embryology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
Hui Xiao
Department of Histology & Embryology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
Yuemeng Song
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
Xinlei Wang
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China; Jilin Provincial International Cooperation Key Laboratory of Pathogen Biology, China
Haoyu Zheng
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
Kai Chen
Department of Oral, Plastic and Aesthetic Surgery, Hospital of Stomatology, Jilin University, Changchun, 130021, China
Yiming An
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
Zhengjie Zhou
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China; Jilin Provincial International Cooperation Key Laboratory of Pathogen Biology, China
Xiaoping Guo
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China; Jilin Provincial International Cooperation Key Laboratory of Pathogen Biology, China
Fang Wang
Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China; The Medical Basic Research Innovation Center of Airway Disease in North China, Ministry of Education of China, China; JLU-USYD Joint Research Center for Respiratory Diseases, China; Jilin Provincial International Cooperation Key Laboratory of Pathogen Biology, China; Corresponding author. Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
Allergic airway inflammation (AAI) is a prevalent respiratory disorder that affects a vast number of individuals globally. There exists a complex interplay among inflammation, immune responses, and metabolic processes, which is of paramount importance in the pathogenesis of AAI. Metabolic dysregulation and protein translational modification (PTM) are well-recognized hallmarks of diseases, playing pivotal roles in the onset and progression of numerous ailments. However, the role of gut microbiota metabolites in the development of AAI, as well as their influence on PTM modifications within this disease context, have not been thoroughly explored and investigated thus far. In AAI patients, succinate was identified as a key metabolite, positively correlated with certain immune parameters and IgE levels, and having good diagnostic value. In AAI mice, gut bacteria were the main source of high succinate levels. Mendelian randomization showed succinate as a risk factor for asthma. Exogenous succinate worsened AAI in mice, increasing airway resistance and inflammatory factor levels. Protein succinylation in AAI mice lungs differed significantly from normal mice, with up-regulated proteins in metabolic pathways. FMT alleviated AAI symptoms by reducing succinate and protein succinylation levels. In vitro, succinate promoted protein succinylation in BEAS-2B cells, and SOD2 was identified as a key succinylated protein, with the K68 site crucial for its modification and enzyme activity regulation. Gut flora-derived succinate exacerbates AAI in mice by increasing lung protein succinylation, and FMT can reverse this. These findings offer new insights into AAI mechanisms and potential therapeutic targets.
