There is increasing evidence that the shaping of the immunological tolerance that goes awry in autoimmune disease is heavily influenced by commensal microbiota. Although this relationship between the microbiome and autoimmunity has been studied for autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis, it has not been investigated for autoimmune uveitis, a potentially blinding inflammatory condition affecting the eyes. Studying the relationship of the microbiome with uveitis may reveal important insights into the pathogenesis of this disease, but more importantly, may result in potential intervention through the use of novel treatment strategies. The hypothesis of this study is that altering the gut flora will affect the clinical severity of uvitis.
The first aim to test this hypothesis involves administering broad-spectrum antibiotics to reduce gut flora and to determine how and why this affects uveitis disease severity. Two animal models of autoimmune uveitis, experimental autoimmune uveitis (EAU), and aggrecan-induced uveitis will be tested for this purpose. Disease severity, relative abundances of bowel microorganisms, and the contribution of regulatory T lymphocytes will be assessed. To evaluate the microbiota, a well-developed rapid but robust technique to quantitatively characterize the microbiome of complex biological environments, such as the gut, will be used (Biome representational in silico karyotyping or BRISK). In the second and third aims, the effects of probiotics (commensal microrganisms that can regulate self-tolerance) and prebiotics (diets that affect the innate microbiome in a specific way) will be investigated for their effects on clinical disease severity and the ability to alter gut flora in the disease models above.

Public Health Relevance

The goal of this project is to explore the potential effects of altering non disease-causing microorganisms present in the gut on a potentially blinding inflammatory eye condition, uveitis, through the use of antibiotics, probiotics, or specific diets. This is relevant to public health because uveitis causes up to 10% of all cases of blindness, and this proposal suggests well known, safe methods to potentially alter the course of this disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZEY1-VSN (06))
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Agarwal, Neeraj
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Oregon Health and Science University
Schools of Medicine
United States
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Nakamura, Yukiko K; Janowitz, Cathleen; Metea, Christina et al. (2017) Short chain fatty acids ameliorate immune-mediated uveitis partially by altering migration of lymphocytes from the intestine. Sci Rep 7:11745
Asquith, Mark; Davin, Sean; Stauffer, Patrick et al. (2017) Intestinal Metabolites Are Profoundly Altered in the Context of HLA-B27 Expression and Functionally Modulate Disease in a Rat Model of Spondyloarthritis. Arthritis Rheumatol 69:1984-1995
Nakamura, Yukiko K; Metea, Christina; Karstens, Lisa et al. (2016) Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis. Invest Ophthalmol Vis Sci 57:3747-58
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Kopplin, Laura J; Shifera, Amde S; Suhler, Eric B et al. (2015) Biological response modifiers in the treatment of noninfectious uveitis. Int Ophthalmol Clin 55:19-36
Lin, Phoebe (2015) Infectious Uveitis. Curr Ophthalmol Rep 3:170-183

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