The role of the intestinal microbiota in ocular surface health

项目摘要 干眼症（DED）是一种慢性、流行、使人衰弱的疾病。DED是最常见的原因之一 患者应向眼科医生寻求建议。到目前为止，还没有治疗DED的方法。治疗是 姑息性，侧重于稳定泪液和减少眼表炎症。尽管 广泛使用局部抗炎和免疫调节剂治疗DED，治疗效果 仍然很低。 肠道微生物群最近已被确定为眼表健康的重要贡献者， DED。肠生态失调的诱导与眼表炎症、眼内分泌缺陷、 角膜上皮屏障功能以及角膜发育和伤口愈合的改变。新兴 有证据表明，肠道微生物群和代谢之间存在着独特的关系， 体内平衡此外，由肠道生态失调引发的线粒体功能障碍可能会放大免疫反应。 反应和降低组织对抗炎和免疫调节剂的反应。 我们实验室最近的工作表明，角膜上皮细胞暴露于高渗性应激， DED的显著特征表现出代谢和线粒体稳态的明显变化。的目标 这项R21的建议是将我们在角膜代谢方面的强大背景与新兴领域相结合， 肠道微生物相关的DED。目标1将确定肠道微生物群消耗的影响 对角膜上皮细胞代谢平衡的影响目标2将确定微生物群是否- 相关的代谢变化影响眼表面对抗炎和抗炎症的敏感性， 免疫调节剂。为了实现这些目标，我们将使用互补的动物模型，主要 细胞培养、真实的时间代谢通量分析以及已建立的分子和生物化学测定 在我们的实验室里。 提出的概念验证研究是创新的和重要的，因为它们是第一个研究， 研究肠道菌群与角膜上皮代谢之间的关系， DED。DED中线粒体功能障碍和微生物群相关代谢重编程的缓解 可以增加眼表炎症对抗炎和免疫调节的反应性 剂.这可能会改变我们在临床上如何管理干眼症的游戏规则，并提供承诺， 数百万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.