HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome

Abstract

Objective HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype–disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA–B27 and HLA–DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. Methods Five hundred sixty‐eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. Results Associations were observed between the overall microbial composition and both the HLA–B27 genotype and the HLA–DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). Conclusion This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA‐B27 and HLA–DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.

The Dynamic Interplay between the Gut Microbiota and Autoimmune Diseases

“…A data-driven study suggested that human gut microbial metabolites directly interact with 18.1% of all 166 RA-associated genes, participate in 71.4% of 311 RA-associated genetic pathways, and affect 51.3% ofRA-related phenotypes, including immune system pathways and phenotypes; this in turn demonstrated that the gut microbiota and its metabolites contribute to RA at genetic, functional, and phenotypic levels [55]. Another study reported that the HLA-B27 and HLA-DRB1 alleles affect susceptibility to RA, with effects on the gut microbiome that partially cause or increase the risk of RA [56]. In addition, changes in fecal bacteria may represent the RA condition or the outcome of RA progression.…”

A Metagenome-Wide Association Study of Gut Microbiome in Patients With Multiple Sclerosis Revealed Novel Disease Pathology

“…The studies focusing on the interaction between the metagenome and host genome in human complex diseases have become an interesting topic in the field of microbiome (Imhann et al, 2018;Asquith et al, 2019). Our study is the first to demonstrate the MWAS-GWAS interaction of the molecular pathways in the MS gut metagenome.…”

Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy

“…This in turn drives the Th1 response primarily by interferon gamma (IFNγ), and exacerbates gut inflammation ( 72 ). Another study focused on microbial dysbiosis associated with HLA alleles in healthy subjects with AS, and rheumatoid arthritis (RA), a chronic autoimmune disease defined by inflammation of the synovium and joint destruction ( 73 ). However, the authors did not observe HLA-B27-associated changes in Dialister in healthy subjects with either AS or RA associated alleles.…”