Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Adv. 2023 Jul 21;9(29):eadh5552. doi: 10.1126/sciadv.adh5552. Epub 2023 Jul 19.
damages the colonic mucosa through the action of two potent exotoxins. Factors shaping pathogenesis are incompletely understood but are likely due to the ecological factors in the gastrointestinal ecosystem, mucosal immune responses, and environmental factors. Little is known about the role of pharmaceutical drugs during infection (CDI), but recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI. The mechanism underlying this phenomenon remains unclear. Here, we show that NSAIDs exacerbate CDI by disrupting colonic epithelial cells (CECs) and sensitizing cells to toxin-mediated damage independent of their canonical role of inhibiting cyclooxygenase (COX) enzymes. Notably, we find that NSAIDs and toxins target the mitochondria of CECs and enhance toxin-mediated damage. Our results demonstrate that NSAIDs exacerbate CDI by synergizing with toxins to damage host cell mitochondria. Together, this work highlights a role for NSAIDs in exacerbating microbial infection in the colon.
通过两种强效外毒素的作用，破坏结肠黏膜。发病机制的影响因素尚不完全清楚，但可能与胃肠道生态系统中的生态因素、黏膜免疫反应和环境因素有关。在感染（CDI）期间，药物的作用知之甚少，但最近的研究表明，非甾体抗炎药（NSAIDs）会使 CDI 恶化。这种现象的机制尚不清楚。在这里，我们表明 NSAIDs 通过破坏结肠上皮细胞（CEC）并使细胞对毒素介导的损伤敏感，从而加重 CDI，而与它们抑制环氧化酶（COX）酶的典型作用无关。值得注意的是，我们发现 NSAIDs 和毒素靶向 CEC 的线粒体，并增强毒素介导的损伤。我们的结果表明，NSAIDs 通过与毒素协同作用破坏宿主细胞的线粒体来加重 CDI。总的来说，这项工作强调了 NSAIDs 在加重结肠中微生物感染中的作用。
