The role of the intestinal microbiota in ocular surface health

项目总结 干眼病(DED)是一种慢性的、流行的、令人衰弱的疾病。死亡是最常见的原因之一。 患者向眼科护理从业者寻求建议。到目前为止，DED还没有治愈的方法。治疗是 姑息性，专注于稳定泪液和减少眼表炎症。尽管 广泛使用外用抗炎和免疫调节剂治疗DED，疗效观察 仍然很低。 肠道微生物区系最近被认为是眼表健康的重要因素 戴德。肠道生态失调的诱导与眼表炎症有关， 角膜上皮屏障功能，以及角膜发育和伤口愈合的变化。新兴 有证据表明，肠道微生物区系和新陈代谢之间存在着独特的关系。 动态平衡。此外，由肠道生物失调引发的线粒体功能障碍可能会放大免疫。 反应和降低组织对抗炎和免疫调节剂的反应性。 我们实验室最近的工作表明，暴露在高渗透压应激下的角膜上皮细胞 DED的显著特征是代谢和线粒体动态平衡发生明显变化。的目标是 R21的建议是将我们在角膜代谢方面的强大背景与新兴的 肠道微生物区系相关的DED。目标1将确定肠道微生物区系枯竭的影响 关于角膜上皮的代谢动态平衡。目标2将决定微生物区系是否- 相关的代谢变化影响眼表对抗炎和 免疫调节剂。为了实现这些目标，我们将使用补充动物模型，主要是 细胞培养、实时代谢流量分析以及成熟的分子和生化分析 在我们的实验室里。 拟议的概念验证研究具有创新性和重要意义，因为它们是第一个 大鼠角膜上皮细胞代谢与肠道微生物区系的关系 戴德。DED患者线粒体功能障碍的缓解及微生物区系相关的代谢重编程 可能增加眼表炎症对抗炎和免疫调节的反应性 探员们。这可能会改变我们临床治疗干眼症的方式，并提供 数以百万计的美国人患有这种疾病。

PROJECT SUMMARY Dry eye disease (DED) is a chronic, prevalent, debilitating condition. DED is one of the most common reasons that patients seek advice from eye care practitioners. To date, there are no cures for DED. Treatment is palliative, focused on stabilization of the tear fluid and a reduction in ocular surface inflammation. Despite the widespread use of topical anti-inflammatory and immunomodulatory agents for DED, treatment efficacy remains low. The intestinal microbiota has recently been identified as an important contributor to ocular surface health in DED. The induction of intestinal dysbiosis has been associated with ocular surface inflammation, defects in corneal epithelial barrier function, and alterations in corneal development and wound healing. Emerging evidence suggests that a unique relationship exists between the intestinal microbiota and metabolic homeostasis. Further, mitochondrial dysfunction triggered by intestinal dysbiosis may amplify the immune response and decrease tissue responsiveness to anti-inflammatory and immunomodulatory agents. Recent work in our laboratory has shown that corneal epithelial cells exposed to hyperosmolar stress, a distinguishing feature of DED, exhibit distinct changes in metabolic and mitochondrial homeostasis. The goal of this R21 proposal is to incorporate our strong background in corneal metabolism with the burgeoning field of intestinal microbiota-linked DED. Aim 1 will determine the effects of depletion of the intestinal microbiota on metabolic homeostasis in the corneal epithelium. Aim 2 will determine whether microbiota- associated metabolic changes impact the sensitivity of the ocular surface to anti-inflammatory and immunomodulatory agents. To accomplish these aims, we will use complementary animal models, primary cell cultures, real time metabolic flux analysis, and molecular and biochemical assays that are well established in our laboratory. The proposed proof of concept studies are innovative and significant because they are the first studies to investigate the relationship between the intestinal microbiota and corneal epithelial metabolism in DED. The alleviation of mitochondrial dysfunction and microbiota-associated metabolic reprogramming in DED may increase the responsiveness of ocular surface inflammation to anti-inflammatory and immunomodulatory agents. This could be a game changer in how we clinically manage dry eye and offer promise to millions of Americans that suffer from this disease.