Short chain fatty acids ameliorate immune-mediated uveitis partially by altering migration of lymphocytes from the intestine

Yukiko K Nakamura,Christina Metea,Mark Asquith,Cathleen Janowitz,Lisa Karstens,James T Rosenbaum,Phoebe Lin

doi:10.1038/s41598-017-12163-3

Yukiko K Nakamura, Christina Metea + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-12163-3

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Abstract

Short chain fatty acids (SCFA) are metabolites of intestinal bacteria resulting from fermentation of dietary fiber. SCFA are protective in various animal models of inflammatory disease. We investigated the effects of exogenous administration of SFCAs, particularly propionate, on uveitis using an inducible model of experimental autoimmune uveitis (EAU). Oral SCFA administration attenuated uveitis severity in a mouse strain-dependent manner through regulatory T cell induction among lymphocytes in the intestinal lamina propria (LPL) and cervical lymph nodes (CLN). SCFA also suppressed effector T cell induction in the CLN and mesenteric lymph nodes (MLN). Alterations in intestinal morphology and gene expression demonstrated in the EAU model prior to the onset of uveitis were blunted by oral SCFA administration. Using a Kaede transgenic mouse, we demonstrated enhanced leukocyte trafficking between the intestine and the eye in EAU. Propionate suppressed T effector cell migration between the intestine and the spleen in EAU Kaede mice. In conclusion, our findings support exogenous administration of SCFAs as a potential treatment strategy for uveitis through the stabilization of subclinical intestinal alterations that occur in inflammatory diseases including uveitis, as well as prevention of trafficking of leukocytes between the gastrointestinal tract and extra-intestinal tissues.

Highlights

Immune-mediated uveitis is a heterogeneous group of disorders causing inflammation within the eye, and accounting for about 10% of blindness[1]
To examine whether bacterial metabolite Short chain fatty acids (SCFA) affect the development of autoimmune uveitis, sodium propionate (Prop, 150 or 300 mM), sodium butyrate (Buty, 300 mM), or sodium acetate (Acet, 300 mM) was orally administered to C57Bl/6J or B10.RIII experimental autoimmune uveitis (EAU) mice in drinking water starting from day −21 prior to immunization until euthanasia
We discovered that exogenous administration of short chain fatty acids attenuated uveitis in a mouse strain-dependent manner through induction of regulatory T cells in various tissues, as well as its suppressive impact on effector T cells

Summary

Introduction

Immune-mediated uveitis is a heterogeneous group of disorders causing inflammation within the eye, and accounting for about 10% of blindness[1]. Recent studies have shown that anaerobic bacteria, such as Firmicutes, produce relatively high levels of short chain fatty acids (SCFAs) as a metabolite of fermentation of dietary fiber These SCFAs are protective in immune-mediated diseases, such as multiple sclerosis[9], colitis[10,11], atopic disease[12], and graft-versus-host disease[13] partially through the expansion of regulatory T cells in the intestine, as well as through protective effects on the integrity of the intestinal epithelial barrier[14]. Current therapeutic options for immune-mediated uveitis typically target inflammatory pathways and have immunosuppressant effects, rather than targeting immune regulation that contributes to immune homeostasis Immunosuppressants, such as systemic or local corticosteroids, are the most commonly used treatment for immune-mediated uveitis, but these agents can cause serious, life-threatening systemic or blinding ocular side effects. In an effort to investigate novel treatment strategies for immune-mediated uveitis that might target immune regulation, we investigated the effects of exogenous orally administered SCFAs on uveitis severity, testing the hypothesis that oral SCFAs might attenuate disease by altering T cell subsets and/or enhancing intestinal homeostasis

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