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Phoebe Lin, Christina Metea, Cathleen Moscibrocki, Mark Asquith, James T Rosenbaum, Yukiko Nakamura; Bacterial metabolites of fermentable dietary fibers ameliorate experimental autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 2016;57(12):No Pagination Specified.
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© ARVO (1962-2015); The Authors (2016-present)
Short chain fatty acids (SCFAs) are fermentation products of certain commensal gut bacteria that can induce regulatory T cells in the colon. We tested the hypothesis that orally administered SCFAs can induce regulatory T cells resulting in attenuation of experimental autoimmune uveitis (EAU).
EAU was induced using interphotoreceptor binding protein peptides 161-180 or 1-20 in B10.RIII or C57Bl/6 mice, respectively. Mice were treated orally (PO) with 3 SCFAs: sodium propionate, butyrate, or acetate vs. sodium chloride (NaCl) starting 3 weeks prior to immunization. Eyes, spleen, cervical/mesenteric lymph nodes (CLN/MLN), and lamina propia lymphocytes (LPL) from the cecum and colon were collected on day 21 or 28. We performed clinical grading of eyes, flow cytometry analysis to quantify regulatory T lymphocytes (Treg), Th1, and Th17 cells, and immunohistochemistry staining with Image J cell counting on retinal whole mounts to quantitate Treg prevalence in the eye. Mann-Whitney U test was used for statistical comparison.
PO administration of 150 mM sodium propionate significantly reduced EAU clinical score in C57Bl/6 mice compared to NaCl control (mean clinical score 0.25 vs. 1.0, p=0.008). While 300 mM butyrate reduced mean clinical score in B10.RIII mice (0.4 vs. 1.8, p=0.1), propionate (2.8 vs. 1.8, p=0.2) and acetate (3.3 vs. 3.0, p=0.7) did not. Tregs (CD4+, FoxP3+) were increased in the cecal LPLs (mean 8.9% vs 7.5%, p=0.03), CLN (6.7% vs. 4.7%, p=0.02), and retinas (34.4% vs 22.8%, p=0.02) of C57Bl/6 propionate-treated mice, but Tregs were not affected in the MLN, spleen, or colonic LPLs. Th1 cells (IFNγ+, CD4+) were reduced in MLN (2.5% vs 7.3%, p=0.02)and spleen (18.1% vs 26.1%, p=0.02), whereas Th17 cells (IL-17+, CD4+) were reduced in CLN (0.7% vs. 1.7%, p=0.03), MLN (1.1% vs. 2.9%, p=0.008), and spleen (3.8% vs. 5.4%, p=0.008), of propionate-treated C57Bl/6 EAU mice.
The bacterial metabolite SCFAs, propionate and butyrate, reduced the severity of uveitis through induction of Tregs in the gut and cervical lymph node, and suppression of Th1 and Th17 cells in multiple extraintestinal lymphoid tissues. Oral administration of certain SCFAs are potential adjunctive treatments for autoimmune uveitis, and demonstrate the importance of gut microbiota metabolites on immune homeostasis.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
Propionate attenuates uveitis. A-B: NaCl control; C-D: Propionate; E: Time course
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