Wang Chao, Yu Xin, Yu Xiao, Xiao Hui, Song Yuemeng, Wang Xinlei, Zheng Haoyu, Chen Kai, An Yiming, Zhou Zhengjie, Guo Xiaoping, Wang Fang
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.
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.
Redox Biol. 2025 May;82:103623. doi: 10.1016/j.redox.2025.103623. Epub 2025 Mar 28.
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.
过敏性气道炎症（AAI）是一种普遍存在的呼吸系统疾病，全球有大量个体受其影响。炎症、免疫反应和代谢过程之间存在复杂的相互作用，这在AAI的发病机制中至关重要。代谢失调和蛋白质翻译后修饰（PTM）是公认的疾病标志，在众多疾病的发生和发展中起关键作用。然而，迄今为止，肠道微生物群代谢产物在AAI发展中的作用以及它们在这种疾病背景下对PTM修饰的影响尚未得到充分探索和研究。在AAI患者中，琥珀酸被确定为关键代谢产物，与某些免疫参数和IgE水平呈正相关，具有良好的诊断价值。在AAI小鼠中，肠道细菌是高琥珀酸水平的主要来源。孟德尔随机化显示琥珀酸是哮喘的一个危险因素。外源性琥珀酸使小鼠的AAI恶化，增加气道阻力和炎症因子水平。AAI小鼠肺中的蛋白质琥珀酰化与正常小鼠有显著差异，代谢途径中的蛋白质上调。粪菌移植通过降低琥珀酸和蛋白质琥珀酰化水平缓解了AAI症状。在体外，琥珀酸促进了BEAS-2B细胞中的蛋白质琥珀酰化，超氧化物歧化酶2（SOD2）被确定为关键的琥珀酰化蛋白，K68位点对其修饰和酶活性调节至关重要。肠道菌群衍生的琥珀酸通过增加肺蛋白质琥珀酰化加重小鼠的AAI，而粪菌移植可以逆转这一过程。这些发现为AAI的机制和潜在治疗靶点提供了新的见解。
