Introduction
Spondyloarthritis comprises of a group of inflammatory arthritic disorders affecting around 3 million people in the USA. These rheumatic disorders have common articular manifestations including enthesitis, axial skeletal inflammation, and abnormal bone formation. Gut inflammation frequently occurs as an extraarticular manifestation of spondyloarthritis.
A prototypic spondyloarthritis, ankylosing spondylitis, is genetically associated with the major histocompatibility complex (MHC) class I molecule, human leukocyte antigen (HLA)-B27.
Interestingly, germ-free HLA-B27 transgenic (Tg) rats do not develop arthritis or gut inflammation, and recolonization with commensal microbes is sufficient to drive disease development in these animals, thus suggesting the involvement of gut microbes in spondyloarthritis pathogenesis. While host genetics are a major influence in disease manifestation, the composition of gut microbes, and their modulation (via diet, environment, etc.), are implicated in disease development.
Therefore, it is essential to investigate the association of gut microbiota and host genetics with spondyloarthritis pathogenesis.
Gut microbiome in spondyloarthritis
Most gut microbes are highly resistant to laboratory culture conditions. Consequently, long after their role was discovered in spondyloarthritis, it has remained difficult to identify and characterize disease-associated microbes.
In a major advancement, development of culture-independent sequencing techniques (16s ribosomal RNA gene sequencing) has allowed for comparison between the gut microbial communities in healthy and diseased states. Multiple studies involving human subjects and animal models have established a strong association between HLA-B27 and gut microbial dysbiosis. Notably, spondyloarthritis patients often show evidence for perturbations or “dysbiosis” of the microbial community structure, with some studies associating specific microbes that occur together with the HLA-B27 allele as markers for disease. Another recent study showed that HLA risk alleles associated with ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome in healthy individuals.
Together, these studies suggest that the risk alleles may be exerting their effect via perturbation of the gut microbial balance. In an experimental model of spondyloarthritis, we have demonstrated that microbial dysbiosis in HLA-B27 Tg rats is highly dependent on the host genetic background, with probable contributions from the environment, while host immune dysregulation is almost identical.
These observations call for an ecological model of dysbiosis, where disease is associated with perturbations in microbial community structure rather than a single or few microbes.
Gut microbiome and the IL-23/IL-17 axis
The gut epithelial barrier is a first line of defense against harmful gut microbes. Disruption of the epithelial barrier may be sufficient to bring gut microbes in contact with host immune cells, thereby activating an aberrant inflammatory response. In fact, almost 60% of ankylosing spondylitis patients have microscopic gut lesions and some loss of epithelial barrier protection.
Activation of gut T helper 17 (Th17) cells by interleukin (IL)-23 promotes chronic tissue inflammation, and the IL-23/IL-17 cytokine axis presumably plays a key role in the chronic gut inflammation associated with spondyloarthritis. Despite its role in inflammation, IL-17 is also required for the maintenance of gut homeostasis. This may partly explain why IL-17 antagonists are associated with exacerbation of gut inflammation, and IL-23 antagonists are not effective in treatment of ankylosing spondylitis. On the other hand, certain gut microbes, such as segmented filamentous bacteria (SFB) can adhere to gut epithelial cells and induce the development and activation of Th17 cells, which in turn promotes inflammation.
Among other microbial differences, disease resistant HLA-B27 Tg rats lack SFB in their gut, implying microbial contribution in the pathogenesis of spondyloarthritis. In a recent study utilizing SKG mice that depend on the IL-23/IL-17 pathway for development of disease in the gut and joints, IL-23 favors outgrowth of spondyloarthritis-associated pathobionts and reduces gut microbial homeostasis.
Therefore, increased IL-23/IL-17-associated gut inflammation together with loss of epithelial barrier may result in an altered immune response to gut bacteria or their metabolites, leading to disease initiation and progression.
Host–microbe interaction in spondyloarthritis
Host–microbe interactions begin at birth of an organism; gut microbes help host immune development, and the host in turn shapes gut microbial composition. Modern approaches such as metagenome and metabolome analyses have allowed functional characterization of gut microbes and microbial metabolites. They represent a first step in understanding host–microbe interactions.
In spondyloarthritis, these analyses have provided unprecedented insights into HLA-B27-associated dysbiotic microbes and their metabolic functions. To highlight one such finding, metabolome analysis in HLA-B27 Tg rats indicates perturbation in levels of short-chain fatty acids (SCFA) such as butyrate during gut inflammation. Butyrate has anti-inflammatory effects and promotes the development of regulatory T cells. Another microbial metabolite, tryptophan, modulates the host–microbe interface, since gut microbes affect the host immune response through tryptophan metabolism.
Host–microbe interaction studies from our group have been focused on the relationship between the host immune response and the gut microbes. We discovered that dysbiotic microbes from various host genetic backgrounds associate with common host immune/inflammatory pathways (interferon gamma, tumor necrosis factor, and IL-23/IL-17). At the functional level, different inflammation-associated microbes on diverse host backgrounds exhibit common metabolic pathways (eg SCFA synthesis, steroid biosynthesis and bacterial motility). Insights into the microbial modulation of host immune response may allow for the identification of metabolites that can prevent or alleviate gut inflammation and arthritis.
Conclusion
While the gut microbiome is complex and the role of specific microbes is not yet fully understood, microbial dysbiosis and perturbed microbial metabolic function are potential contributors towards disease severity in spondyloarthritis, inflammatory bowel disease and other complex genetic disorders.
As our knowledge in the field of host–microbiome interaction and gut permeability, as well as microbial activation of the IL-23/IL-17 axis is increasing, we need to better elucidate the effects of this complex host–microbe interaction in the context of spondyloarthritis. Determination of host–microbe/metabolite interactions, as well as the effect of immune education and host genetics/environment, will uncover novel pathways that can be targeted for treatment of spondyloarthritis. The future has just begun!
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