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Phoebe Lin, Christina Metea, Mark Asquith, Henry Gruner, James T Rosenbaum, Yukiko K Nakamura; The role of the gut microbiota in immune-mediated uveitis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):870.
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In both germ free and broad-spectrum oral antibiotic experiments, investigators have demonstrated an important role for the gut microbiota in extraintestinal immune-mediated diseases such as multiple sclerosis. We found that alteration of the gut microbiota using oral broad-spectrum antibiotics ameliorated experimental autoimmune uveitis (EAU). The objective of this study was to investigate the mechanism of this effect on regulatory and effector T cells.
Interphotoreceptor binding protein peptide 161-180 was used to induce uveitis in antibiotic-treated B10.RIII mice. Eyes, spleen, cervical, mesenteric lymph nodes (CLN, MLN), and lamina propia lymphocytes (LPL) were collected on days 7, 14, 21, and 28 after immunization. We performed flow cytometry for Foxp3, CD4, IL-17, and IFN-gamma staining to quantify regulatory T lymphocytes (Tregs), Th1, and Th17 cells.
A smaller proportion of antibiotic-fed animals had clinical EAU scores ≥ 3 compared with water-fed animals (7.7% vs 52%, p<0.001). There were higher proportions of Tregs (CD4+, FoxP3+) in the LPL of oral antibiotic-fed mice on day 7, 14, and 28, compared to water-fed mice (day 7: 41.66% vs. 25.05%, p<0.05; day 14: 45.76% vs. 31.61%, p<0.05; day 28: 32.73% vs. 14.03%, p<0.01; Figure 1A). Higher frequencies of Tregs were observed in MLN of antibiotic-fed mice on day 21 and day 28, compared to water-fed mice (day 21: 17.73% vs. 13.18%, p=0.05; day 28: 12.22% vs. 9.93 %, p<0.05, Figure 1B). Th1 and Th17 proportions were reduced early on, prior to onset of inflammation, in oral antibiotic-fed mice in both MLN and CLN (p<0.01 for both), but not spleen (p>0.05). We found a higher number of Tregs among infiltrating CD4+ T lymphocytes in the less-inflamed antibiotic-treated animal eyes at 2 weeks after immunization compared to water-fed EAU mice.
Alteration of the gut microbiota by oral antibiotic administration modulates changes in CD4+ effector and regulatory T cell populations in lymphoid organs and eyes, all tissues distant from the gut, which may explain the reduction in severity of EAU. These findings may lead to a better understanding of how uveitis can be treated or prevented by modulating the gut microbiota.
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