Gut microbiota has long been thought to contribute to inflammatory diseases, and multiple reports in animal models and humans suggest that antibiotic treatment alters autoimmune disease manifestations. We have recently demonstrated in rodents that specific microbes induce the differentiation of Th17 cells in the intestinal lamina propria. There is strong genetic and therapy-based evidence that """"""""pro-inflammatory"""""""" Th17 and """"""""anti- inflammatory"""""""" regulatory T cells (Treg) have critical roles in autoimmune diseases, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and Crohn's disease. We propose to study the role of gut (intestinal and oral) microbiota in RA and other inflammatory arthritides. Our primary hypotheses are that: 1) characterization of Th17-inducing microbes in human intestine will provide insight into disease pathogenesis;and 2) directed manipulation of the gut microbiota will result in alteration of arthritis biomarkers, including Th17/Treg balance. Insights attained may elucidate how the T cell network responds to microbial interactions with host intestinal components and provide a rationale for the development of new therapeutic approaches for RA.
Three Specific Aims are proposed: 1) To create a multidisciplinary center to characterize human gut microbiome in patients with RA and related conditions. 2) To employ Th17-dependent mouse models of RA to study the role of microbiota/T cell interactions in development of disease, to directly assess whether specific bacteria in RA patients can be implicated in disease pathogenesis. Both direct bacterial cocktails and bacteria identified in RA patients will be inoculated into the mice. 3) To study the role of human gut microbiota in RA pathogenesis by: a) cross-sectional study to determine whether a specific taxon or bacterial family in the human gut is associated with RA or PsA;b) clinical and blood examinations to assess baseline disease activity, genetic predisposition and immune cellular function of arthritis patients vs controls;c) prospective, interventional proof of concept biomarker study to determine whether alteration of the gut microbiota normalizes cellular immune functions in patients with RA. We will compare 2 antibiotic regimens to assess whether therapy induces i) characteristic changes in the gut microbiome (including changes in abundance of specific target taxons), and ii) alterations in immune biomarkers, particularly Th17 and Treg cell levels and/or function. Carefully selected outcomes should permit us to correlate the presence of a specific microorganism or microbiome pattern with changes in cellular immune response, other specific biomarkers, and clinical activity. Relevance: This project is consistent with the goals of the Human Microbiome Project, a major NIH Roadmap initiative, and has the potential to be truly transformative by filling a fundamental knowledge gap regarding the cause of inflammatory arthritis. The results could transform our understanding of the relationships between microbes and humans, and lead to innovative diagnostic tests and future treatments.
The proposed project - to study whether microbes that live in the human mouth and intestinal tract play a role in causing rheumatoid arthritis - is consistent with the goals of the Human Microbiome Project, a major NIH Roadmap initiative. The research proposed has the potential to be truly transformative by filling a fundamental knowledge gap regarding the cause of inflammatory arthritis. The results could transform our understanding of the relationships between microbes and humans, and lead to innovative diagnostic tests and future treatments.
| Isaac, Sandrine; Scher, Jose U; Djukovic, Ana et al. (2017) Short- and long-term effects of oral vancomycin on the human intestinal microbiota. J Antimicrob Chemother 72:128-136 |
| Abdollahi-Roodsaz, Shahla; Abramson, Steven B; Scher, Jose U (2016) The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions. Nat Rev Rheumatol 12:446-55 |
| Scher, Jose U; Abramson, Steven B (2016) Reply. Arthritis Rheumatol 68:1569-70 |
| Scher, Jose U; Littman, Dan R; Abramson, Steven B (2016) Microbiome in Inflammatory Arthritis and Human Rheumatic Diseases. Arthritis Rheumatol 68:35-45 |
| Scher, Jose U; Ubeda, Carles; Artacho, Alejandro et al. (2015) Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 67:128-39 |
| Scher, Jose U; Reddy, Soumya; Ubeda, Carles et al. (2015) Reply: To PMID 25319745. Arthritis Rheumatol 67:2280-2 |
| Scher, Jose U; Sczesnak, Andrew; Longman, Randy S et al. (2013) Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 2:e01202 |
| Zanin-Zhorov, Alexandra; Lin, Jiqiang; Scher, Jose et al. (2012) Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function. Proc Natl Acad Sci U S A 109:1625-30 |
| Honda, Kenya; Littman, Dan R (2012) The microbiome in infectious disease and inflammation. Annu Rev Immunol 30:759-95 |
| Scher, Jose U; Ubeda, Carles; Equinda, Michele et al. (2012) Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum 64:3083-94 |
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