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      Oral–Gut Microbiota and Arthritis: Is There an Evidence-Based Axis?

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          Abstract

          The gut microbiome appears to be a significant contributor to musculoskeletal health and disease. Recently, it has been found that oral microbiota are involved in arthritis pathogenesis. Microbiome composition and its functional implications have been associated with the prevention of bone loss and/or reducing fracture risk. The link between gut–oral microbiota and joint inflammation in animal models of arthritis has been established, and it is now receiving increasing attention in human studies. Recent papers have demonstrated substantial alterations in the gut and oral microbiota in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). These alterations resemble those established in systemic inflammatory conditions (inflammatory bowel disease, spondyloarthritides, and psoriasis), which include decreased microbial diversity and a disturbance of immunoregulatory properties. An association between abundance of oral Porphyromonas gingivalis and intestinal Prevotella copri in RA patients compared to healthy controls has been clearly demonstrated. These new findings open important future horizons both for understanding disease pathophysiology and for developing novel biomarkers and treatment strategies. The changes and decreased diversity of oral and gut microbiota seem to play an important role in the etiopathogenesis of RA and OA. However, specific microbial clusters and biomarkers belonging to oral and gut microbiota need to be further investigated to highlight the mechanisms related to alterations in bones and joints inflammatory pathway.

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          Most cited references46

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          Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.

          Commensal microbes can have a substantial impact on autoimmune disorders, but the underlying molecular and cellular mechanisms remain largely unexplored. We report that autoimmune arthritis was strongly attenuated in the K/BxN mouse model under germ-free (GF) conditions, accompanied by reductions in serum autoantibody titers, splenic autoantibody-secreting cells, germinal centers, and the splenic T helper 17 (Th17) cell population. Neutralization of interleukin-17 prevented arthritis development in specific-pathogen-free K/BxN mice resulting from a direct effect of this cytokine on B cells to inhibit germinal center formation. The systemic deficiencies of the GF animals reflected a loss of Th17 cells from the small intestinal lamina propria. Introduction of a single gut-residing species, segmented filamentous bacteria, into GF animals reinstated the lamina propria Th17 cell compartment and production of autoantibodies, and arthritis rapidly ensued. Thus, a single commensal microbe, via its ability to promote a specific Th cell subset, can drive an autoimmune disease. Copyright 2010 Elsevier Inc. All rights reserved.
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            Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine.

            Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.
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              Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

              Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                22 October 2019
                October 2019
                : 8
                : 10
                : 0
                Affiliations
                [1 ]Laboratory of Clinical Microbiology, Department of Biomedical Sciences for Health & Microbiome, Culturomics and Biofilm related infections (MCB) Unit, “Invernizzi” Pediatric Clinical Research Center, University of Milan, 20133 Milan, Italy
                [2 ]Department of Pediatrics, V. Buzzi Childrens’ Hospital & “Invernizzi” Pediatric Clinical Research Center University of Milan, 20141 Milan, Italy; gianvincenzo.zuccotti@ 123456unimi.it
                [3 ]Carlo Luca Romanò, Studio Medico Cecca-Romanò, Corso Venezia, 2, 20121 Milano, Italy; carlo.romano@ 123456unimi.it
                [4 ]Romano Institute, Rruga Ibrahim Rugova, 1, 00100 Tirane, Albania
                [5 ]Rothman Institute, Thomas Jefferson University, Philadelphia, PA 89814, USA; karan.goswami@ 123456mail.com (G.K.); javadparvizi@ 123456gmail.com (P.J.)
                [6 ]IRCCS Fondazione Don Carlo Gnocchi, 20141 Milan, Italy; mail@ 123456villafane.it
                [7 ]Department of Biomedical, Surgical and Dental Science, University of Milan, 20133 Milan, Italy; roberto.mattina@ 123456unimi.it
                Author notes
                Author information
                https://orcid.org/0000-0002-5206-540X
                https://orcid.org/0000-0002-2795-9874
                https://orcid.org/0000-0001-6726-0593
                Article
                jcm-08-01753
                10.3390/jcm8101753
                6832398
                31652577
                58dc100d-15a2-4299-a175-57c0943d5ce9
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 July 2019
                : 15 October 2019
                Categories
                Review

                microbiota axis,gut microbiota,oral microbiota arthritis,joint inflammation

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