3The role of the gut and microbes in the pathogenesis of spondyloarthritis
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.
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