The role of the gut and microbes in the pathogenesis of spondyloarthritis.

The intestinal microbiota is firmly implicated not only in the pathogenesis of inflammatory bowel disease (IBD) but increasingly also in the development of inflammation at extraintestinal tissue sites. Significant clinical, genetic, immunological, and microbiological overlap exists between IBD and spondyloarthritis (SpA), which indicates that pathophysiological mechanisms are shared between these diseases and may center on the intestinal microbiota. Recently, culture-independent techniques have enabled the microbiota in health and disease to be described in increasing detail. Moreover, functional studies have identified myriad host effector and regulatory pathways that shape or are shaped by this microbial community. We consider the complex relationship between SpA pathogenesis and gut microbes, with a discussion of how manipulation of the gut microbiota itself may be a promising future target for SpA therapy.

[1]  R. Weissleder,et al.  Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut , 2014, Proceedings of the National Academy of Sciences.

[2]  J. Faith,et al.  Mining the human gut microbiota for effector strains that shape the immune system. , 2014, Immunity.

[3]  A. Hamann,et al.  Transforming growth factor‐β1‐induced expression of the mucosa‐related integrin αE on lymphocytes is not associated with mucosa‐specific homing , 1995 .

[4]  S. Mazmanian,et al.  Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota , 2010, Proceedings of the National Academy of Sciences.

[5]  D. Polk,et al.  Probiotic Bacterium Prevents Cytokine-induced Apoptosis in Intestinal Epithelial Cells* , 2002, The Journal of Biological Chemistry.

[6]  J. Meijerink,et al.  Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. , 2006, Gastroenterology.

[7]  R. Colbert,et al.  HLA-B27 misfolding and ankylosing spondylitis. , 2014, Molecular immunology.

[8]  L. Bradbury,et al.  Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive γ/δ T cells in patients with active ankylosing spondylitis. , 2012, Arthritis and rheumatism.

[9]  Qiushui He,et al.  HLA-B27 Modulates Intracellular Growth of Salmonella Pathogenicity Island 2 Mutants and Production of Cytokines in Infected Monocytic U937 Cells , 2012, PloS one.

[10]  George Kollias,et al.  Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells , 2013, Annals of the rheumatic diseases.

[11]  H. Harmsen,et al.  Reduction of Colitis by Prebiotics in HLA‐B27 Transgenic Rats Is Associated with Microflora Changes and Immunomodulation , 2005, Inflammatory bowel diseases.

[12]  M. Vos,et al.  Intestinal mucosal permeability in inflammatory rheumatic diseases , 1992 .

[13]  M. De Vos,et al.  Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model , 2012, Annals of the rheumatic diseases.

[14]  J. Taurog Animal models of spondyloarthritis. , 2009, Advances in experimental medicine and biology.

[15]  A. Stringaro,et al.  Direct Binding of Human NK Cell Natural Cytotoxicity Receptor NKp44 to the Surfaces of Mycobacteria and Other Bacteria , 2008, Infection and Immunity.

[16]  F. Powrie,et al.  Innate lymphoid cells drive IL-23 dependent innate intestinal pathology , 2010, Nature.

[17]  J. Esdaile,et al.  Antibiotics for Treatment of Reactive Arthritis: A Systematic Review and Metaanalysis , 2013, The Journal of Rheumatology.

[18]  C. Huttenhower,et al.  Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis , 2013, eLife.

[19]  J. Harley,et al.  A hypothesis for the HLA-B27 immune dysregulation in spondyloarthropathy: contributions from enteric organisms, B27 structure, peptides bound by B27, and convergent evolution. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Breban,et al.  Reverse Interferon Signature Is Characteristic of Antigen‐Presenting Cells in Human and Rat Spondyloarthritis , 2014, Arthritis & rheumatology.

[21]  Jennifer J Pointon,et al.  Elucidating the Chromosome 9 Association with AS; CARD9 is a Candidate Gene , 2010, Genes and Immunity.

[22]  M. Moeschberger,et al.  New Bacterial Species Associated with Chronic Periodontitis , 2003, Journal of dental research.

[23]  S. Jalkanen,et al.  Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms , 1995, The Journal of experimental medicine.

[24]  E. Zoetendal,et al.  Duodenal infusion of donor feces for recurrent Clostridium difficile. , 2013, The New England journal of medicine.

[25]  J. Edmonds,et al.  A factor(s) in Klebsiella culture filtrates specifically modifies an HLA-B27-associated cell-surface component , 1980, Nature.

[26]  A. Mira,et al.  Microbial Geography of the Oral Cavity , 2013, Journal of dental research.

[27]  D. Laukens,et al.  CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn’s disease , 2004, Annals of the rheumatic diseases.

[28]  L. Klareskog,et al.  CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease , 2004, Arthritis research & therapy.

[29]  D. Breuillé,et al.  The Chronic Colitis Developed by HLA-B27 Transgenic Rats Is Associated with Altered In Vivo Mucin Synthesis , 2004, Digestive Diseases and Sciences.

[30]  B. Stockinger,et al.  IL-22 Mediates Goblet Cell Hyperplasia and Worm Expulsion in Intestinal Helminth Infection , 2013, PLoS pathogens.

[31]  R. Sumpter,et al.  Intestinal epithelial autophagy is essential for host defense against invasive bacteria. , 2013, Cell host & microbe.

[32]  R. Hammer,et al.  Defective dendritic cell (DC) function in a HLA-B27 transgenic rat model of spondyloarthropathy (SpA). , 1995, Advances in experimental medicine and biology.

[33]  A. Ebringer,et al.  The Link between Ankylosing Spondylitis, Crohn's Disease, Klebsiella, and Starch Consumption , 2013, Clinical & developmental immunology.

[34]  M. Lenarz,et al.  RORγt⁺ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. , 2013, Immunity.

[35]  S. Raimondo,et al.  Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation , 2013, Annals of the rheumatic diseases.

[36]  P. Revell,et al.  Histopathology of the synovial membrane of peripheral joints in ankylosing spondylitis. , 1982, Annals of the rheumatic diseases.

[37]  F. Bushman,et al.  Innate Lymphoid Cells Promote Anatomical Containment of Lymphoid-Resident Commensal Bacteria , 2012, Science.

[38]  E. Veys,et al.  Serum IgG, IgM, and IgA levels in ankylosing spondylitis. , 1973, Annals of the rheumatic diseases.

[39]  I. Ivanov,et al.  Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. , 2014, Immunity.

[40]  E. Zoetendal,et al.  Reduction of colonic inflammation in HLA-B27 transgenic rats by feeding Marie Ménard apples, rich in polyphenols† , 2009, British Journal of Nutrition.

[41]  H. Zanen,et al.  Identification of HLA-B27M1 and -M2 cross-reactive antigens in Klebsiella, Shigella and Yersinia. , 1984, Immunology.

[42]  Bihui Huang,et al.  Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals , 2013, Science.

[43]  Z. Filipovic,et al.  Repeated measurement of intestinal permeability as an assessment of colitis severity in HLA-B27 transgenic rats. , 1999, The Journal of pharmacology and experimental therapeutics.

[44]  B. Fleischer,et al.  Salmonella-reactive synovial fluid T-cell clones in a patient with post-infectious Salmonella arthritis. , 1990, Scandinavian journal of rheumatology.

[45]  J. Doré,et al.  Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis. , 2002, Rheumatology.

[46]  S. Nedospasov,et al.  Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. , 2011, Cell host & microbe.

[47]  F. Bushman,et al.  Innate lymphoid cells regulate CD4+ T cell responses to intestinal commensal bacteria , 2013, Nature.

[48]  Peer Bork,et al.  Enterotypes of the human gut microbiome , 2011, Nature.

[49]  C. De Simone,et al.  Probiotic bacteria enhance murine and human intestinal epithelial barrier function. , 2001, Gastroenterology.

[50]  M. Breban,et al.  Increased Production of Interleukin‐17 Over Interleukin‐10 by Treg Cells Implicates Inducible Costimulator Molecule in Experimental Spondyloarthritis , 2014, Arthritis & rheumatology.

[51]  W. Xin,et al.  Tregs are Dysfunctional in Vivo in a Spontaneous Murine Model of Crohn’s Disease , 2012, Mucosal Immunology.

[52]  G. Kollias,et al.  Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. , 1999, Immunity.

[53]  M. Mareel,et al.  Subclinical gut inflammation in spondyloarthropathy patients is associated with upregulation of the E-cadherin/catenin complex , 2000, Annals of the rheumatic diseases.

[54]  S. Raimondo,et al.  Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjögren's syndrome , 2011, Annals of the rheumatic diseases.

[55]  M. De Vos,et al.  Intestinal mucosal permeability in inflammatory rheumatic diseases. II. Role of disease. , 1991, Journal of Rheumatology.

[56]  K. Honda,et al.  Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species , 2011, Science.

[57]  H. Leonhardt,et al.  Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production , 2014, Nature Immunology.

[58]  Y. Belkaid,et al.  Microbiota-Dependent Crosstalk Between Macrophages and ILC3 Promotes Intestinal Homeostasis , 2014, Science.

[59]  J. Gordon,et al.  Inflammatory Bowel Disease and Adenomas in Mice Expressing a Dominant Negative N-Cadherin , 1995, Science.

[60]  A. Herr,et al.  IgA and IgA-specific receptors in human disease: structural and functional insights into pathogenesis and therapeutic potential , 2006, Springer Seminars in Immunopathology.

[61]  M. Brown,et al.  Interleukin‐23 Mediates the Intestinal Response to Microbial β‐1,3‐Glucan and the Development of Spondyloarthritis Pathology in SKG Mice , 2014, Arthritis & rheumatology.

[62]  R. Xavier,et al.  Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. , 2013, Gastroenterology.

[63]  S. Brophy,et al.  Internet-based randomised controlled trials for the evaluation of complementary and alternative medicines: probiotics in spondyloarthropathy , 2008, BMC musculoskeletal disorders.

[64]  G. Ridgway,et al.  Role of Chlamydia trachomatis and HLA-B27 in sexually acquired reactive arthritis. , 1978, British medical journal.

[65]  C. Huttenhower,et al.  Inflammatory bowel disease as a model for translating the microbiome. , 2014, Immunity.

[66]  A. Ebringer,et al.  Ankylosing spondylitis is linked to Klebsiella—the evidence , 2007, Clinical Rheumatology.

[67]  D. Elewaut,et al.  Joint expedition: linking gut inflammation to arthritis , 2008, Mucosal Immunology.

[68]  Christophe Benoist,et al.  Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. , 2010, Immunity.

[69]  B. Becher,et al.  Innate lymphoid cells regulate intestinal epithelial cell glycosylation , 2014, Science.

[70]  H. Hammad,et al.  Invariant natural killer T cells are natural regulators of murine spondylarthritis. , 2010, Arthritis and rheumatism.

[71]  M. De Vos,et al.  Histopathology of intestinal inflammation related to reactive arthritis. , 1987, Gut.

[72]  Macrophages expressing the scavenger receptor CD163: a link between immune alterations of the gut and synovial inflammation in spondyloarthropathy , 2001, The Journal of pathology.

[73]  M. De Vos,et al.  Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort , 2013, Annals of the rheumatic diseases.

[74]  T. Mcclanahan,et al.  IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells , 2012, Nature Medicine.

[75]  M. N. Giacomodonato,et al.  Consumption of Lactobacillus casei Fermented Milk Prevents Salmonella Reactive Arthritis by Modulating IL-23/IL-17 Expression , 2013, PloS one.

[76]  G. Tannock,et al.  PCR/DGGE and 16S rRNA gene library analysis of the colonic microbiota of HLA‐B27/β2‐microglobulin transgenic rats , 2006, Letters in applied microbiology.

[77]  R. Blumberg,et al.  Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. , 2002, Immunity.

[78]  A. Rizzo,et al.  Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. , 2012, Arthritis and rheumatism.

[79]  A. Zinsmeister,et al.  Incidence of Spondyloarthropathy in Patients with Crohn’s Disease: A Population-based Study , 2012, The Journal of Rheumatology.

[80]  R. Ebringer,et al.  Klebsiella pneumoniae and acute anterior uveitis in ankylosing spondylitis. , 1979, British medical journal.

[81]  B. Fleischer,et al.  Multiclonal synovial T cell response to Yersinia enterocolitica in reactive arthritis: the Yersinia 61-kDa heat-shock protein is not the major target antigen. , 1993, The Journal of infectious diseases.

[82]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[83]  P. Schwimmbeck,et al.  Molecular mimicry between human leukocyte antigen B27 and Klebsiella. Consequences for spondyloarthropathies. , 1988, The American journal of medicine.

[84]  C. Tripodo,et al.  Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. , 2009, Arthritis and rheumatism.

[85]  D. Foell,et al.  Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage , 2009, Gut.

[86]  R. Sartor,et al.  Lactobacillus GG prevents recurrence of colitis in HLA-B27 transgenic rats after antibiotic treatment , 2000, Gut.

[87]  M. Leirisalo-Repo Prognosis, course of disease, and treatment of the spondyloarthropathies. , 1998, Rheumatic diseases clinics of North America.

[88]  R. Edwards,et al.  A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes , 2014, Nature Communications.

[89]  S. Jalkanen,et al.  Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis , 1990, The Lancet.

[90]  F. Mor,et al.  Lactobacillus GG bacteria ameliorate arthritis in Lewis rats. , 2004, The Journal of nutrition.

[91]  A. Hamann,et al.  Transforming growth factor-beta 1-induced expression of the mucosa-related integrin alpha E on lymphocytes is not associated with mucosa-specific homing. , 1995, European journal of immunology.

[92]  A. Kaser,et al.  Protective mucosal immunity mediated by epithelial CD1d and IL-10 , 2014, Nature.

[93]  R. Colbert,et al.  Review: The Interleukin‐23/Interleukin‐17 Axis in Spondyloarthritis Pathogenesis: Th17 and Beyond , 2014, Arthritis & rheumatology.

[94]  N. Pace,et al.  Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases , 2007, Proceedings of the National Academy of Sciences.

[95]  Richard A. Flavell,et al.  NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis , 2011, Cell.

[96]  W. Maksymowych,et al.  Bowel permeability and CD45RO expression on circulating CD20+ B cells in patients with ankylosing spondylitis and their relatives. , 1999, The Journal of rheumatology.

[97]  M. Schultz,et al.  Probiotic Therapy for the Treatment of Spondyloarthritis: A Randomized Controlled Trial , 2010, The Journal of Rheumatology.

[98]  A. Toivanen,et al.  Bacterial antigens in synovial biopsy specimens in yersinia triggered reactive arthritis. , 1991, Annals of the rheumatic diseases.

[99]  Omry Koren,et al.  AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition , 2013, Gut.

[100]  Lawrence A. David,et al.  Diet rapidly and reproducibly alters the human gut microbiome , 2013, Nature.

[101]  M. De Vos,et al.  The evolution of spondyloarthropathies in relation to gut histology. III. Relation between gut and joint. , 1995, The Journal of rheumatology.

[102]  H. Virgin,et al.  Kingdom-Agnostic Metagenomics and the Importance of Complete Characterization of Enteric Microbial Communities , 2014, Gastroenterology.

[103]  A. Kaser,et al.  The unfolded protein response and gastrointestinal disease , 2013, Seminars in Immunopathology.

[104]  Aaron Y. Lee,et al.  HLA-B27 and Human β2-Microglobulin Affect the Gut Microbiota of Transgenic Rats , 2014, PloS one.