The chronic infection with Helicobacter pylori (H. pylori), especially cytotoxin-associated gene A-positive (CagA+) strains, has been associated with various extragastric disorders. Evaluating the potential impacts of virulence factor CagA on intestine may provide a better understanding of H. pylori pathogenesis such as colitis. The intestinal mucosal barrier is essential for maintaining its integrity and functions. However, how persistent CagA+ H. pylori colonization influences barrier disruption and thereby affects chronic colitis is not fully understood. Chronic colitis models of CagA+ H. pylori-colonized mice treated with 2% Dextran sulphate sodium (DSS) were established to assess the disease activity and pertinent expression of tight junction proteins closely related to mucosal integrity. The aggravating effect of CagA+ H. pylori infection on DSS-induced chronic colitis was confirmed in mouse models. In addition, augmented Claudin-2 expression was detected in CagA+ H. pylori infection conditions and selected for mechanistic analysis. Next, GES-1 human gastric epithelial cells were cultured with CagA+ H. pylori or a recombinant CagA protein, and exosomes isolated from conditioned media were then identified. We assessed the Claudin-2 levels after exposure to CagA+ exosomes, CagA− exosomes, and IFN-γ incubation, revealing that CagA+ H. pylori compromised the colonic mucosal barrier and facilitated IFN-γ-induced intestinal epithelial destruction through CagA-containing exosome-mediated mechanisms. Specifically, CagA upregulated Claudin-2 expression at the transcriptional level via a CDX2-dependent mechanism to slow the restoration of wounded mucosa in colitis in vitro. These data suggest that exosomes containing CagA facilitate CDX2-dependent Claudin-2 maintenance. The exosome-dependent mechanisms of CagA+ H. pylori infection are indispensable for damaging the mucosal barrier integrity in chronic colitis, which may provide a new idea for inflammatory bowel disease (IBD) treatment.

中文翻译：

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来自幽门螺杆菌的外泌体 CagA 通过促进 Claudin-2 表达加重慢性结肠炎肠上皮屏障功能障碍

幽门螺杆菌 (H. pylori) 的慢性感染，尤其是细胞毒素相关基因 A 阳性 (CagA+) 菌株，与各种胃外疾病有关。评估毒力因子 CagA 对肠道的潜在影响可以更好地了解幽门螺杆菌的发病机制，例如结肠炎。肠粘膜屏障对于维持其完整性和功能至关重要。然而，持续的 CagA+ H. pylori 定植如何影响屏障破坏从而影响慢性结肠炎尚不完全清楚。建立了用 2% 葡聚糖硫酸钠 (DSS) 治疗的 CagA+ H. pylori 定植小鼠的慢性结肠炎模型，以评估与黏膜完整性密切相关的紧密连接蛋白的疾病活动和相关表达。CagA+ H 的加重作用。在小鼠模型中证实了 DSS 引起的慢性结肠炎的幽门螺杆菌感染。此外，在 CagA+ H. pylori 感染条件下检测到增强的 Claudin-2 表达，并选择用于机械分析。接下来，将 GES-1 人胃上皮细胞与 CagA+ H. pylori 或重组 CagA 蛋白一起培养，然后鉴定从条件培养基中分离的外泌体。我们评估了暴露于 CagA+ 外泌体、CagA- 外泌体和 IFN-γ 孵育后的 Claudin-2 水平，揭示了 CagA+ H. pylori 通过含有 CagA 的外泌体破坏了结肠粘膜屏障并促进了 IFN-γ 诱导的肠上皮破坏。介导的机制。具体而言，CagA 通过 CDX2 依赖性机制在转录水平上调 Claudin-2 的表达，以减缓体外结肠炎损伤粘膜的恢复。这些数据表明含有 CagA 的外泌体有助于 CDX2 依赖性 Claudin-2 的维持。CagA+ H. pylori 感染的外泌体依赖性机制对于破坏慢性结肠炎的黏膜屏障完整性是必不可少的，这可能为炎症性肠病 (IBD) 的治疗提供新思路。