AS- and RA-Related HLA Alleles Affect the Gut Microbiome

Investigators analyzed the outcome of HLA-B27 ankylosing spondylitis and HLA-DRB1 rheumatoid arthritis risk alleles on the composition of the intestinal microbiome in healthy individuals.

The alleles for human leukocyte antigens (HLAs; B27 and DRB1) associated with ankylosing spondylitis (AS) and rheumatoid arthritis (RA), respectively, were found to affect the gut microbiome in healthy individuals, supporting the possibility that intestinal microbiome changes in carriers may cause these diseases, or at least increase the risk for AS and RA, according to report results published in Arthritis & Rheumatology.

Although HLA genotypes are known to elevate susceptibility to many diseases, including AS and RA, the mechanisms behind such associations remain largely unknown, and although there are often related intestinal mucosal and fecal microbiome changes in patients with AS and RA, it is unclear whether they are a consequence or cause of the disease states. Investigators sought to determine the nature of these connections by examining how carriage of HLA-B27 and HLA-DRB1 affects gut microbiome composition in otherwise healthy people.

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Two different cohorts were considered for this study. The first comprised 107 healthy participants (age range, 40-75 years; 57% female; 90% white) seen for colorectal cancer screening, from whom stool samples and 568 mucosal biopsies at 6 intestinal sites were taken. The second consisted of 696 twin pairs (n = 1392) who provided stool samples only.

The microbiomes of all participants were profiled via 16S rRNA bacterial marker amplification and sequencing, using the Illumina CoreExome SNP microarray, with HLA genotypes derived from the resulting data.

After adjustment for sex and body mass index, significant associations were found between intestinal microbial composition and the HLA-B27 and HLA-DRB1 alleles, in both the first (P =.0002 and P =.00001, respectively) and second (P =.023 and P =.033) cohorts. Regarding potentially relevant covariates, there were significant differences between mucosal and stool samples (P <.0001) and significant differences among mucosal biopsy sites when stool samples were excluded (P <.0001).

Microbiome composition was also significantly associated with body mass index category (P =.0022), and there was a significant difference in microbial composition between men and women (P =.0004), despite substantial overlap. In terms of microbiome species carriage, there were alterations (increases and decreases) at multiple sampling sites in both HLA-B27-positive and HLA-DRB1-positive participants.

This was the first time that research had demonstrated the definitive influence of the 2 disease-associated HLA alleles on the gut microbiome of healthy individuals without AS or RA. The investigators recommended that future studies control for sex and body mass index, consider using whole-genome sequencing metagenomics, and explore the possibility of gut microbiome manipulation as a means of treating or even preventing disease.

“Our studies suggest that HLA molecules could be important factors that contribute to the heterogeneity of the microbiome and operate at least partially through this mechanism in the pathogenesis of many different diseases, not just AS and RA,” noted the authors.


Asquith M, Sternes PR, Costello ME, et al. HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome [published online April 30, 2019]. Arthritis Rheumatol. doi:10.1002/art.40917