Genetics, Prevotella, and the pathogenesis of rheumatoid arthritis

Abstract

In 1909, Bailey1Bailey CF. The treatment of chronic rheumatic and rheumatoid arthritis by radiant heat and cataphoresis. BMJ 190; 1: 13–15.Google Scholar posited that rheumatoid arthritis is mediated by toxins produced by microorganisms residing in the gut. The first suggestion that Prevotella copri might be a causative intestinal organism came approximately 100 years later in a study2Scher JU Sczesnak A Longman RS et al.Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis.Elife. 2013; 2e01202Crossref PubMed Google Scholar of treatment-naive patients with new-onset rheumatoid arthritis. A putative role for P copri in the pathogenesis of rheumatoid arthritis was subsequently validated in another sequencing study3Maeda Y Kurakawa T Umemoto E et al.Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine.Arthritis Rheumatol. 2016; 68: 2646-2661Crossref PubMed Scopus (268) Google Scholar and further suggested by work4Pianta A Arvikar S Strle K et al.Evidence for immune relevance of Prevotella copri, a gut microbe, in patients with rheumatoid arthritis.Arthritis Rheumatol. 2017; 69: 964-975Crossref PubMed Scopus (160) Google Scholar showing increased immunological reactivity to P copri among patients with rheumatoid arthritis. A limitation of these studies is that the direction of causality cannot be established. Could inflammatory changes in patients with rheumatoid arthritis result in the outgrowth of P copri, rather than the other way around? Or could individuals with arthritis change their diet or lifestyle in a manner so as to alter the faecal microbiota environment? Certainly. Observations that administration of P copri to germ-free mice resulted in worsened arthritis certainly support the hypothesis of a causal association,3Maeda Y Kurakawa T Umemoto E et al.Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine.Arthritis Rheumatol. 2016; 68: 2646-2661Crossref PubMed Scopus (268) Google Scholar but this study was done in a contrived model and is not necessarily applicable to humans. If rheumatoid arthritis-associated genes can be shown to not only affect the microbiota, but to do so in a manner that is consistent with known associations between rheumatoid arthritis and the microbiota, then the effect of the genes on disease development might be mediated at least in part through these microbiota alterations. A study5Asquith M Sternes PR Costello ME HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome.Arthritis Rheumatol. 2019; 71: 1642-1650Crossref PubMed Scopus (50) Google Scholar in healthy volunteers showed that the HLA-DR4 serotype was associated with an altered microbiota, but this study was limited to this single rheumatoid arthritis-associated gene; no association with P copri was reported. In The Lancet Rheumatology, Philippa Wells and colleagues6Wells PM Adebayo AS Bowyer RCE Associations between gut microbiota and genetic risk for rheumatoid arthritis in the absence of disease: a cross-sectional study.Lancet Rheumatol. 2020; 2: e418-e427Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar studied a cohort of 1650 healthy volunteers from the TwinsUK cohort, examining the association between a polygenic risk score (PRS) that they developed for rheumatoid arthritis and the gut microbiota. The authors reported a strong association between the PRS and the abundance of a particular amplicon sequence variant (ASV), which they called Prevotella_7. In a validation study of 133 first-degree relatives of patients with rheumatoid arthritis from the SCREEN-rheumatoid arthritis cohort, Prevotella_7 was associated with the shared epitope HLA-DRBI risk allele. Interestingly, a different ASV that also fell within the Prevotella genus, which the authors called Prevotella_9, was associated with preclinical rheumatoid arthritis in the SCREEN-RA cohort and specifically matched to P copri. To some extent, this study might be perceived as difficult to reconcile with previous work in the field. Specifically, the authors showed that among the asymptomatic first-degree relatives of patients with rheumatoid arthritis, P copri was associated with the presence of the shared epitope, whereas Scher and colleagues2Scher JU Sczesnak A Longman RS et al.Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis.Elife. 2013; 2e01202Crossref PubMed Google Scholar showed precisely the opposite. In that study, in patients with newly diagnosed rheumatoid arthritis, the abundance of P copri was lower in patients with the shared epitope, compared with those without. Given the strong association between the shared epitope, antibodies to cyclic citrullinated proteins (CCPs) and rheumatoid arthritis,7Scherer HU Häupl T Burmester GR The etiology of rheumatoid arthritis.J Autoimmun. 2020; (published online Jan 21.)DOI:10.1016/j.jaut.2019.102400Crossref PubMed Scopus (54) Google Scholar Scher and colleagues’ findings might simply reflect the fact that in patients without the shared epitope, some other substantial environmental risk factor—such as high abundance of P copri—is required to develop the disease. Because Wells and colleagues assessed asymptomatic participants who were largely negative for anti-CCPs, the two findings are not directly comparable. Another observation that lacks obvious explanation is that among 18 discordant twin pairs for rheumatoid arthritis, the abundance of P copri (Prevotella_9) was numerically, if not statistically significantly, lower in the siblings with versus those without the disease. Importantly, abundance of Prevotella_7, the ASV associated with the PRS, was higher in patients with rheumatoid arthritis compared with the discordant twins. In summary, three studies (one in Japan3Maeda Y Kurakawa T Umemoto E et al.Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine.Arthritis Rheumatol. 2016; 68: 2646-2661Crossref PubMed Scopus (268) Google Scholar, one in the USA,2Scher JU Sczesnak A Longman RS et al.Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis.Elife. 2013; 2e01202Crossref PubMed Google Scholar and now one in the UK6Wells PM Adebayo AS Bowyer RCE Associations between gut microbiota and genetic risk for rheumatoid arthritis in the absence of disease: a cross-sectional study.Lancet Rheumatol. 2020; 2: e418-e427Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar) all show evidence of an association between the Prevotella genus and rheumatoid arthritis, with the study by Wells and colleagues furthermore showing that genes that predispose one to rheumatoid arthritis are also associated with an increased abundance of the same Prevotella ASV that was increased in the UK patients with rheumatoid arthritis. Together, these findings suggest that Prevotella is pathogenic in rheumatoid arthritis, even if geographical features might affect this association at the species or strain level. The next logical steps are to explore the mechanism by which Prevotella species are associated with rheumatoid arthritis and perhaps to explore the potential benefit of altering the balance of Prevotella among high-risk individuals. An Italian study8De Filippis F Pasolli E Tett A et al.Distinct genetic and functional traits of human intestinal Prevotella copri strains are associated with different habitual diets.Cell Host Microbe. 2019; 25 (53.e3): 444Summary Full Text Full Text PDF PubMed Scopus (125) Google Scholar suggested that diet affected P copri at the strain level. Whether certain strains are more arthritogenic than others, and whether diet could alter this risk, is but one potential direction that could ensue from this research. I declare no competing interests. Associations between gut microbiota and genetic risk for rheumatoid arthritis in the absence of disease: a cross-sectional studyPrevotella spp in the gut microbiota are associated with the rheumatoid arthritis genotype in the absence of rheumatoid arthritis, including in individuals at high risk of developing rheumatoid arthritis. Our findings suggest that host genotype is associated with microbiota profile before disease onset. Full-Text PDF Open Access

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