Background/Purpose: Evidence for a discrete intestinal microbiome signature in the terminal ileum (TI) of ankylosing spondylitis (AS) patients, compared to healthy controls, has recently been described. It has been hypothesised that HLA-B27 induces AS by effects on the intestinal microbiome, in turn driving spondyloarthritis by inducing immunological processes, particularly IL-23 production. Here we examine the effect of HLA-B27 on the composition of the intestinal microbiome in healthy individuals and twins, using culture independent 16S rRNA amplicon sequencing.

Methods: 135 samples from 6 intestinal sites were collected from otherwise healthy persons undergoing routine colorectal screening (age 40-75yrs). All patients were HLA-B typed and biopsies sequenced for the bacterial marker gene 16S rRNA and analysed. Further analysis was conducted using multivariate analysis package MixMC as implemented in R.The association between HLA-B27 status and intestinal microbiome was further examined in 1392 otherwise healthy twins with matched faecal 16S rRNA and genotype status from the TwinsUK registry. Linear mixed effects models were used to examine the association between the microbiome and genotype status. These models account for the correlation between twins within a family.

Results: Intestinal biopsy studies revealed that HLA-B27 genotype (n=10 B27+ and 85 B27- samples) influences overall microbial composition with increases in bacterial families Ruminococcaceae and Lachnospiraceae in the HLA-B27+ samples. Multivariate regression analysis of all samples demonstrated distinct clustering of HLA-B27+ from HLA-B27- samples (P=0.0063; PERMANOVA). The TI also showed clear and distinct clustering of HLA-B27+ from HLA-B27- samples driven by a decrease in Veillonellaceae (P<0.001) and the order Clostridiales (P<0.05), and increases in Bacteroidaceae (P<0.05) and Ruminococcaceae (P<0.05). The effect of genotype on the microbiome was further examined in the TwinsUK cohort (n=107 B27+ and 1285 B27- samples). HLA-B27 status was again associated with the bacterial families Ruminococcaceae, Lachnospiraceae and the order Clostridiales, in the same direction as seen in the intestinal biopsy data. This is consistent with the TI microbial signature previously described in AS cases and healthy HLA-B27+ patients.

Conclusion: This study shows that healthy HLA-B27+ individuals exhibit shared microbiota changes with AS, indicating an altered microbiota may be a primary event in AS pathogenesis rather than secondary to disease or its treatment. These findings support the hypothesis that HLA-B27 operates to cause AS through interaction with the intestinal microbiome, and suggests that therapies targeting the microbiome may be effective in AS prevention and/or treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-b27-and-ankylosing-spondylitis-have-shared-effects-on-the-gut-microbiome/