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

https://doi.org/10.1016/j.berh.2014.10.018Get rights and content

Abstract

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.

Introduction

The potential of the human microbiota to redefine our understanding of spondyloarthritic diseases or spondyloarthritides (SpAs) is discussed within this review. We begin with an overview of the microbiota, moving to potential relationships between the intestinal microbiota and SpA pathogenesis as this has been a major and ongoing focus of research efforts. This discussion includes consideration of different inflammatory pathways that may intersect with an altered gut microbiota, a phenomenon termed “dysbiosis”. We further consider how extraintestinal translocation of intestinal microbes or microbial products may contribute to SpA-related disease, in addition to microbiota-related immune pathways that may link gut and joint pathology. Finally, we review therapeutic manipulation of the microbiota and future research directions for both clinicians and basic scientists. The authors acknowledge the valuable contributions of many to this field, especially those that could not be cited in this review due to space constraints.

Section snippets

The human microbiome

The past decade has seen the advent of high-throughput sequencing approaches to characterize the human microbiota in increasing detail. The human body provides a plethora of habitats for the colonization of trillions of microbes. This is manifest in the high degree of inter-site variation in the community structure of microbiota. For instance, anaerobic Firmicutes/Bacteroidetes spp. dominate the intestine, whereas Actinobacteria and Proteobacteria spp. are found in high abundance on the skin [1]

Links between SpA and bowel disease

SpA refers to a group of clinically and genetically related disorders, whose entities include ankylosing spondylitis (AS), psoriatic arthritis (PsA), juvenile SpA, reactive arthritis (ReA), and inflammatory bowel disease (IBD)-related arthritis. Dependent on the predominant symptoms, SpA can be classified as axial SpA, including both AS and non-radiographical axial SpA (nr-axSpA), or as peripheral SpA. The typical clinical features include inflammatory back pain, sacroiliitis, oligoarticular

Links between bacteria and SpA

Beyond the links between IBD and SpA, multiple sets of observations implicate bacteria as being causally related to SpA pathogenesis.

Dysbiosis in IBD and SpA

A convincing body of data ports the concept that the gut microbiota is altered in IBD patients, although the identification of dysbiotic changes in SpA patients remains in its infancy. Nonetheless, given the significant disease overlap between these diseases, it is reasonable to hypothesize that they may share common changes to the intestinal microbiota. The most reproducible findings in CD patients are the outgrowth of enterobacteria and a reduction in anaerobes (reviewed by Ref. [24]). The

Pathways of dysbiosis and inflammation

The main hypothesis in CD pathogenesis is an aberrant immune response to intestinal commensal bacteria due to environmental and genetic factors. Very convincing evidence for the importance of microbial–mucosal interactions in IBD was the discovery of nucleotide-binding oligomerization domain-containing protein 2 (NOD2)/caspase-associated recruitment domain 15 (CARD15) polymorphisms that predispose to CD. NOD2 is a pattern recognition receptor (PRR) that recognizes bacterial peptidoglycans and,

Disrupted first defenses

The epithelial monolayer of the intestine is a dynamic frontier between gut-resident microbes and the underlying stromal and immune cells of the intestinal lamina propria. Beyond the physical barrier afforded by the intestinal epithelium, many mediators are secreted into the intestinal lumen including mucus, antimicrobial peptides (AMPs), and secretory immunoglobulin A (IgA). Studies of both SpA and CD intestinal tissue indicate that these first defenses may be disturbed relative to healthy

Microbial sensing and barrier function

Constitutive sensing of local microbial products plays an intrinsic role in epithelial integrity and the maintenance of barrier function. Microbes stimulate signaling pathways such as NFκB, mitogen-activated protein (MAP) kinase, and inflammasome/caspase signaling, which modulate several aspects of IEC biology and the activation of local immune cells. These include epithelial proliferation and differentiation, expression of adhesion molecules/tight junction proteins, and secretion of chemokines

Bacterial handling – autophagy and ER stress

In addition to defects in microbial sensing, diminished bacterial handling by host immune and nonimmune cells may also lead to an altered intestinal microbiota and/or the propagation of inflammatory responses to intestinal microbes.

Autophagy promotes cellular immunity by the degradation of intracellular pathogens and homeostasis by the degradation and recycling of cellular organelles. Autophagy inhibits reactive oxygen species generation, which may directly cause tissue damage itself or trigger

Chronic immune activation and migration to joint

A dysfunctional interaction between gut bacteria and the mucosal immune system could also play an important role in the initiation and/or perpetuation of SpA. Following this hypothesis, an aberrant reaction to luminal antigens and/or bacteria in the gut leads to mucosal inflammation. This would then ultimately lead to joint disease through a process that is only partially understood. Suggested mechanisms based on histological and immunological studies involve uncontrolled immune activation

The IL-23/Th17 axis

IL-23 and Th17 signature cytokines, IL17 and IL-22, also provide another link between mucosal and joint immunity. IL-23 and IL-17 expression has been reported to be upregulated in the gut, peripheral blood, and synovium of SpA patients, although with significant variations that may reflect disease activity or duration and the tissue or cell types examined (reviewed by Ref. [66]). Nonetheless, these cytokines drive a number of processes that may be relevant to pathogenesis in the joint,

Probiotics

While there is a large, mostly unregulated market for probiotics, rigorous scientific study of the putative benefits of these agents and the mechanism of action is sparse. However, studies have shown that even a single bacterial species in the gut can bias the homeostatic balance of the immune system in either direction. Bacteroides fragilis, a common culturable commensal microorganism, promotes anti-inflammatory responses by activating IL-10-producing Tregs through its polysaccharide A

Summary and future directions

Our knowledge of the microbiota in SpA pathogenesis will undoubtedly benefit from increased resolution of the intestinal microbiota. Community-wide analysis of the microbiota by 16s sequencing will be facilitated by rapidly increased sequencing speeds, reduced sequencing cost, and ability to multiplex hundreds of samples in the same sequencing run. Whereas 16s sequencing largely provides sequencing data at the genus level, whole bacterial genome sequencing or metagenomics allows resolution of

Conflict of interest

The authors declare no conflict of interest.

References (102)

  • P. Jacques et al.

    Joint expedition: linking gut inflammation to arthritis

    Mucosal Immunol

    (2008)
  • Y. Goto et al.

    Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal th17 cell differentiation

    Immunity

    (2014)
  • H.J. Wu et al.

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

    Immunity

    (2010)
  • A.V. Tumanov et al.

    Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge

    Cell Host Microbe

    (2011)
  • T. Glatzer et al.

    RORgammat(+) innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44

    Immunity

    (2013)
  • F. Heller et al.

    Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells

    Immunity

    (2002)
  • D. Ishikawa et al.

    Tregs are dysfunctional in vivo in a spontaneous murine model of Crohn's disease

    Mucosal Immunol

    (2013)
  • E. Baharav et al.

    Lactobacillus GG bacteria ameliorate arthritis in Lewis rats

    J Nutr

    (2004)
  • F. Yan et al.

    Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells

    J Biol Chem

    (2002)
  • K. Madsen et al.

    Probiotic bacteria enhance murine and human intestinal epithelial barrier function

    Gastroenterology

    (2001)
  • Human Microbiome Project C

    Structure, function and diversity of the healthy human microbiome

    Nature

    (2012)
  • A. Simon-Soro et al.

    Microbial geography of the oral cavity

    J Dent Res

    (2013)
  • L.A. David et al.

    Diet rapidly and reproducibly alters the human gut microbiome

    Nature

    (2014)
  • M. Arumugam et al.

    Enterotypes of the human gut microbiome

    Nature

    (2011)
  • L. Van Praet et al.

    Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model

    Ann Rheum Dis

    (2013)
  • R. Shivashankar et al.

    Incidence of spondyloarthropathy in patients with Crohn's disease: a population-based study

    J Rheumatol

    (2012)
  • H. Mielants et al.

    The evolution of spondyloarthropathies in relation to gut histology. III. Relation between gut and joint

    J Rheumatol

    (1995)
  • L. Van Praet 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

    Ann Rheum Dis

    (2014)
  • A.C. Keat et al.

    Role of Chlamydia trachomatis and HLA-B27 in sexually acquired reactive arthritis

    Br Med J

    (1978)
  • R. Merilahti-Palo et al.

    Bacterial antigens in synovial biopsy specimens in Yersinia triggered reactive arthritis

    Ann Rheum Dis

    (1991)
  • A.F. Geczy et al.

    A factor(s) in Klebsiella culture filtrates specifically modifies an HLA-B27 associated cell-surface component

    Nature

    (1980)
  • T. Rashid et al.

    Ankylosing spondylitis is linked to Klebsiella – the evidence

    Clin Rheumatol

    (2007)
  • R. Ebringer et al.

    Klebsiella pneumoniae and acute anterior uveitis in ankylosing spondylitis

    Br Med J

    (1979)
  • C.G. van Bohemen et al.

    Identification of HLA-B27M1 and -M2 cross-reactive antigens in Klebsiella, Shigella and Yersinia

    Immunology

    (1984)
  • R.H. Scofield 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

    Proc Natl Acad Sci U S A

    (1993)
  • S. Ge et al.

    HLA-B27 modulates intracellular growth of Salmonella pathogenicity island 2 mutants and production of cytokines in infected monocytic U937 cells

    PLoS One

    (2012)
  • A.J. Stagg et al.

    Defective dendritic cell (DC) function in a HLA-B27 transgenic rat model of spondyloarthropathy (SpA)

    Adv Exp Med Biol

    (1995)
  • J.D. Taurog

    Animal models of spondyloarthritis

    Adv Exp Med Biol

    (2009)
  • L.A. Dieleman et al.

    Lactobacillus GG prevents recurrence of colitis in HLA-B27 transgenic rats after antibiotic treatment

    Gut

    (2003)
  • P.S. Kumar et al.

    New bacterial species associated with chronic periodontitis

    J Dent Res

    (2003)
  • J.U. Scher et al.

    Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis

    eLife

    (2013)
  • S. Stebbings et al.

    Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis

    Rheumatology (Oxford)

    (2002)
  • W. McBurney et al.

    PCR/DGGE and 16S rRNA gene library analysis of the colonic microbiota of HLA-B27/beta2-microglobulin transgenic rats

    Lett Appl Microbiol

    (2006)
  • P. Lin et al.

    HLA-B27 and human beta2-microglobulin affect the gut microbiota of transgenic rats

    PLoS One

    (2014)
  • D.N. Frank et al.

    Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases

    Proc Natl Acad Sci U S A

    (2007)
  • F. Ciccia et al.

    Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis

    Arthritis Rheum

    (2012)
  • M. Faure et al.

    The chronic colitis developed by HLA-B27 transgenic rats is associated with altered in vivo mucin synthesis

    Dig Dis Sci

    (2004)
  • M. Shan et al.

    Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals

    Science

    (2013)
  • D. Laukens et al.

    CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease

    Ann Rheum Dis

    (2005)
  • I. Fert et al.

    Reverse interferon signature is characteristic of antigen-presenting cells in human and rat spondyloarthritis

    Arthritis Rheumatol

    (2014)
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