Is Rheumatoid Arthritis Driven by the Gut Microbiome?
There is some evidence for the gut microbiome to play an important role in a range of comparatively poorly understood conditions involving pain, inflammation, and at least the suspicion of autoimmunity, from the better researched rheumatoid arthritis to the dark forest of overlapping symptoms containing fibromyalgia, myofascial pain syndrome, idiopathic peripheral neuropathies, and more. If many of these conditions do derive from microbial activities, however indirectly, this may go some way towards explaining the lack of progress towards finding definitive mechanisms and causes - until comparatively recently, no-one was looking at the gut microbiome.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder. The hallmark of RA is progressive joint disease, with potential for systemic involvement. Understanding the RA disease spectrum with recognition of at risk individuals has propelled RA research into prevention strategies. The generation of IgA class anticitrullinated protein antibodies (ACPAs) in individuals at risk of RA, combined with epidemiological links with smoking and periodontal disease, points to a mucosal origin of inflammation. The mucosal origin hypothesis proposes that localised inflammation at mucosal sites can initiate a broader immune response, via T cell activation and a subsequent inflammatory cytokine cascade, leading to B cell antibody production. Supporting this, an immunoglobulin class switch from IgA ACPAs to IgG ACPAs indicates potential triggering of systemic autoimmunity by diverse antigenic stimuli at mucosal sites. This shift, accompanied with broadening of antibody targets, suggests that mucosal barrier deterioration and the ensuing spread of an IgG ACPA response might be more significant in the initial stages of RA than the loss of tolerance to self-antigens.
Profiling of the gut microbiome in individuals at risk of RA and people diagnosed with RA consistently demonstrates a dysbiotic microbiome when compared with healthy controls. However, there remains little consensus on the bacterial constituent members of an RA-related dysbiosis. Subsequently, a variety of gut bacteria have been implicated as a potential impetus in the development of RA, none more so than Prevotella copri. Prevotella species have been demonstrated to be overabundant in new-onset rheumatoid arthritis (NORA), in at risk individuals and especially those with genetic risk. Their abundance decreases after disease-modifying antirheumatic drug (DMARD) therapy, with reversion to a eubiotic state on treatment. Furthermore, mouse models support a role for Prevotellaceae strains derived from patients with RA in RA development. However, Prevotellaceae overabundance does not appear to be an ubiquitous finding across all RA gut microbiome studies.
This work aimed to resolve the conflicting reports on Prevotellaceae abundance in the development of rheumatoid arthritis (RA) and to observe structural, functional and temporal changes in the gut microbiome in RA progressors versus non-progressors. Our data suggest conflicting reports on Prevotellaceae overabundance are likely due to sampling within a heterogeneous population along a dynamic disease spectrum, with certain Prevotellaceae strains/clades possibly contributing to the establishment and/or progression of RA. Gut microbiome changes in RA may appear at the transition to clinical arthritis as a late manifestation, and it remains unclear whether they represent a primary or secondary phenomenon.