The role of the intestinal microbiota in ocular surface health

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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.