The role of the intestinal microbiota in ocular surface health

肠道微生物群在眼表健康中的作用

• 批准号: 10532228
• 负责人: DANIELLE M. ROBERTSON
• 金额: $ 20.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532228
• 关键词: Affect; American; Animal Model; Anti-Inflammatory Agents; Antibiotics; Biochemical; Biological Assay; Caring; Cells; Cellular Metabolic Process; Chronic; Clinical; Clinical Management; Cornea; Crista ampullaris; Defect; Development; Disease; Distal; Drops; Dry Eye Syndromes; Economic Burden; Emotional; Epithelial Cells; Epithelium; Exhibits; Exposure to; Eye; Germ-Free; Glycolysis; Goals; Health; Homeostasis; Immune response; In Vitro; Inflammation; Inflammatory; Intestines; Laboratories; Lacrimal gland structure; Link; Liquid substance; Lung; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Morphology; Mus; Patients; Phenotype; Primary Cell Cultures; Production; Reactive Oxygen Species; Reporting; Respiration; Role; Stress; Time; Tissues; Treatment Efficacy; Work; aqueous; corneal epithelium; cytokine; dysbiosis; eye dryness; gut bacteria; gut microbiota; immune cell infiltrate; immune modulating agents; innovation; intestinal epithelium; microbiome; microbiota; mitochondrial dysfunction; new therapeutic target; novel therapeutic intervention; ocular surface; ocular surface disease; palliative; respiratory; wound healing

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.

项目概要 干眼病 (DED) 是一种慢性、普遍、使人衰弱的疾病。 DED 是最常见的原因之一 患者向眼科护理人员寻求建议。迄今为止，DED 尚无治愈方法。治疗方法是 姑息治疗，重点是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。 最近，肠道微生物群被认为是眼表健康的重要贡献者。 DED。肠道菌群失调的诱发与眼表炎症、肠道功能缺陷有关。 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与代谢之间存在独特的关系 体内平衡。此外，肠道菌群失调引发的线粒体功能障碍可能会增强免疫功能。 反应并降低组织对抗炎剂和免疫调节剂的反应性。 我们实验室最近的工作表明，角膜上皮细胞暴露于高渗压力， DED 的显着特征是代谢和线粒体稳态表现出明显的变化。目标是 这个 R21 提案是将我们在角膜代谢方面的强大背景与新兴领域相结合 肠道微生物群相关的 DED。目标 1 将确定肠道微生物群消耗的影响 角膜上皮代谢稳态的影响。目标 2 将确定微生物群是否 相关的代谢变化影响眼表面抗炎和抗炎药物的敏感性 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 细胞培养、实时代谢流分析以及成熟的分子和生化检测 在我们的实验室。 所提出的概念验证研究具有创新性且意义重大，因为它们是第一个研究 研究肠道微生物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相关代谢重编程的缓解 可能会增加眼表炎症对抗炎和免疫调节药物的反应 代理。这可能会改变我们临床治疗干眼的方式，并承诺 数百万美国人患有这种疾病。