DataSheet1_Proton pump inhibitor alters Th17/Treg balance and induces gut dysbiosis suppressing contact hypersensitivity reaction in mice.pdf

Proton pump inhibitors (PPIs), such as omeprazole, are the most commonly prescribed drugs. Treatment with PPIs alters gut microbiota composition and reduces the production of reactive oxygen (ROS) and proinflammatory IL-1β, IL-6, and TNF-α cytokines. Here, using the T cell-dependent contact hypersensitivity (CHS) response, an animal model of allergic contact dermatitis (ACD) that affects up to 30% of the population, we demonstrated that a two-week omeprazole treatment suppresses the development of CHS. Omeprazole treatment before CHS induction, reduced inflammatory response in ears measured by ear swelling, ear biopsy weight, MPO activity, and proinflammatory cytokine production. These changes were associated with reduced frequency of TCRαβ+ CD4+ IL-17A+ and TCRαβ+ CD8+ IL-17A+ T cells and increased frequency of TCRαβ+ CD4+ CD25+ FoxP3+ Treg, and TCRαβ+ CD4+ IL-10+ Tr1 cells in peripheral lymphoid organs. Omeprazole treatment decreased the production of ROS, TNF-α, and IL-6, which supported Th17 cell induction, and increased the frequency of Clostridium cluster XIVab and Lactobacillus, implicated in Treg cell induction. The fecal microbiota transplantation (FMT) experiment confirmed the role of omeprazole-induced changes in gut microbiota profile in CHS suppression. Our data suggests that omeprazole ameliorates inflammatory response mediated by T-cells.

质子泵抑制剂（Proton pump inhibitors, PPIs）如奥美拉唑，是临床最常用的处方药物。PPI治疗可重塑肠道菌群组成，并降低活性氧（Reactive Oxygen Species, ROS）以及促炎细胞因子白细胞介素1β（Interleukin 1β, IL-1β）、白细胞介素6（Interleukin 6, IL-6）和肿瘤坏死因子α（Tumor Necrosis Factor α, TNF-α）的产生。本研究采用T细胞依赖性接触性超敏反应（T cell-dependent contact hypersensitivity, CHS）模型开展实验，该模型模拟的变应性接触性皮炎（allergic contact dermatitis, ACD）可影响多达30%的人群。本研究证实，为期两周的奥美拉唑干预可抑制CHS的发生发展。在CHS诱导前施以奥美拉唑治疗，可减轻耳部炎症反应，该炎症反应可通过耳肿胀程度、耳活检组织重量、髓过氧化物酶（Myeloperoxidase, MPO）活性及促炎细胞因子产生水平进行评估。上述变化与外周淋巴器官中T细胞受体αβ阳性CD4阳性白细胞介素17A阳性（TCRαβ+ CD4+ IL-17A+）、T细胞受体αβ阳性CD8阳性白细胞介素17A阳性（TCRαβ+ CD8+ IL-17A+）T细胞的频率降低，以及T细胞受体αβ阳性CD4阳性CD25阳性叉头框P3阳性（TCRαβ+ CD4+ CD25+ FoxP3+）调节性T细胞（regulatory T cell, Treg）、T细胞受体αβ阳性CD4阳性白细胞介素10阳性（TCRαβ+ CD4+ IL-10+）1型调节性T细胞（type 1 regulatory T cell, Tr1）的频率升高密切相关。奥美拉唑治疗可降低活性氧、TNF-α以及IL-6的产生——上述物质可促进Th17细胞的诱导——同时升高与调节性T细胞诱导相关的梭菌属XIVab簇（Clostridium cluster XIVab）和乳杆菌属（Lactobacillus）的相对丰度。粪便菌群移植（fecal microbiota transplantation, FMT）实验证实，奥美拉唑诱导的肠道菌群谱改变在CHS抑制过程中发挥了关键作用。本研究数据表明，奥美拉唑可改善T细胞介导的炎症反应。