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.

Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy and the host’s genotype upon microbiome composition

“…Comparatively fewer species were associated with the RUNX3 SNP in comparison to the number of species associated with AS status and TNFi treatment. Consistent with recent publications which have investigated the effect of the host’s genotype upon the abundance of specific taxa 47,50 , these data provide supporting evidence that the underlying host’s genetics may have a generalised effect upon the microbiome, with a subtle effect on a higher number of taxa as opposed to a marked effect on a select few.…”

“…Similar to the strain-level results for AS status and TNFi therapy, no observable bias in the underlying strain population was observed, indicating that RUNX3 variants likely affect the relative abundance of species, not necessarily strain composition (Supplementary Figure 6 47,50 ). Comparatively fewer species were associated with the RUNX3 SNP in comparison to the number of species associated with AS status and TNFi treatment.…”

“…Furthermore, sPLSDA revealed that the degree alteration appears dependent on whether the host carried a heterozygous or homozygous genotype (Figure 3A), with the homozygous genotype resulting in a more substantial shift. As further confirmation, we analysed a recently published 16S metabarcoding dataset 47 of 107 healthy control subjects which were sampled from six different body sites. This analysis re-confirmed discrimination of the microbiomes based on genotype (PERMANOVA; P = 0.0001) (Figure 3B).…”

“…Very recently, it was demonstrated that HLA-B27 is associated with a significant shift in the microbiome in healthy individuals 47 . Furthermore, in mouse models, MHC polymorphisms were demonstrated to contribute to an individual’s microbial composition, thus influencing health 88 .…”

New developments in our understanding of ankylosing spondylitis pathogenesis

“…81,82 Lastly, the presence or absence of HLA-B27, in and of itself, has recently been reported to have an influence on the gut microbiome. 83,84 The gut and joint metabolic environment and AS Tying the genetic evidence together with new data showing alterations in gut microbiome is the concept that dysregulated immune responses may result from changes in the local immunometabolic environment. This likely occurs both in the joint and in the gut, with the latter potentially driven by gut dysbiosis.…”