Immunomodulatory effects of dietary non-digestible oligosaccharides in T cell-mediated autoimmune arthritis

Background/Purpose: Accumulating evidence indicates the relevance of intestinal microbiota in shaping the immune response and supports its contribution to the development of autoimmune diseases. Prebiotic nondigestible oligosaccharides are known to selectively support growth of commensal Bifidobacteria and Lactobacilli and adjust the microbiota composition. The aim of this study was to assess the efficacy of microbiota modulation using non-digestible oligosaccharides as a therapeutic approach for T cell-dependent autoimmune arthritis. Methods: IL-1 receptor antagonist (IL-1Ra) deficient mice spontaneously developing an autoimmune T cell- and interleukin (IL)-17- dependent arthritis were used for this study. We previously showed that spontaneous arthritis in IL-1Ra-/- mice depends on the presence of commensal microbiota, since germ-free mice develop less severe disease. To examine the feasibility of microbiota modulation as a therapeutic approach during established disease, IL-1Ra-/-mice which had already developed arthritis under conventional microbial status were orally fed a prebiotic diet containing 2.5% or 5% short-chain galacto- and long-chain fructooligosaccharides (scGos:lcFos, 9:1). Disease progression was monitored and intestinal and systemic T cell differentiation was studied. Results: Oral treatment of arthritic IL-1Ra-/-mice with scGoslcFos significantly suppressed the progression of arthritis. Furthermore, dual-energy X-ray absorptiometry scanning revealed that a prebiotic diet containing scGoslcFos significantly improved bone mineral density and tended to increase bone mineral content in arthritic IL-1Ra-/-mice. Gene expression of T-bet and RORγt, the Th1 and Th17-related transcription factors, in lymph nodes draining the arthritic joints was significantly reduced in the group receiving the scGoslcFos diet. Flow cytometry analysis of the lymph nodes showed no effect on the percentages of Th1, Th17 and regulatory T cells (Tregs). However, the percentage of CD3+CD4+IL-4 producing cells tended to be increased in the scGoslcFos treated group. Interestingly, small intestine lamina propria of mice receiving scGoslcFos diet contained increased percentages of CD3+CD4+FoxP3+regulatory T cells. In addition, intestinal gene expression of the Treg-related transcription factor FoxP3 as well as anti-inflammatory cytokine IL-10 were increased with scGoslcFos. Accordingly, small intestine lamina propria lymphocytes of mice receiving the 5% scGoslcFos diet produced significant higher levels of IL-10 upon ex vivo stimulation with PMA and ionomycin. Production of IL-4 and IFNγ also tended to be increased, while production of TNFα, IL-6 and IL-17 was not affected by the prebiotic diet. Conclusion: Our data suggest that scGoslcFos suppresses arthritis progression, potentially through induction of anti-inflammatory cytokines such as IL-10 and IL-4. Suppression of disease progression using dietary intervention with prebiotic scGoslcFos may be applicable as a therapeutic approach to suppress autoimmune arthritis.