Background/Purpose: Axial spondyloarthritis (AxSpA) is immune-mediated inflammatory arthritis, which affects the sacroiliac and spinal joints, and is associated with gut inflammation. Disease pathogenesis is associated with host genetics (HLA-B27), environmental factors, and gut microbial dysbiosis. Previous studies have shown HLA-B27-associated microbial dysbiosis in ankylosing spondylitis patients as well in experimental models of spondyloarthritis. However, not all microbial changes might drive the chronic inflammatory response or elicit host IgA responses. Here, we report the presence of specific IgA-coated microbes that may be disease contributors in AxSpA patients.

Methods: Microbial community structure and IgA coating from feces and saliva samples from AxSpA patients (n=17) and healthy controls (n=12-14) were determined by 16S rRNA sequencing (16S sequencing) and IgA sequencing (IgA-SEQ) respectively. IgA-SEQ involves sorting IgA-coated microbes using flow cytometry and performing 16S sequencing on the IgA positive and negative fractions. Correlation analyses were performed to determine the disease association between IgA-coated microbes in AxSpA patients and the disease activity score. Furthermore, metagenomic contribution of IgA positive and negative microbes was estimated by using the bioinformatic tool PICRUSt2

Results: 16S sequencing of oral and fecal microbiota showed distinct microbial community composition in AxSpA patients as compared with the healthy controls. AxSpA patients showed a significant decrease in oral microbial diversity, whereas the decrease in fecal microbial diversity was not significant. However, the lack of microbial differences in diversity in fecal samples did not suggest a lack of immunological impact of the gut microbes. AxSpA patients had many microbes at a genus level with increased IgA coating (e.g., Akkermansia, Klebsiella, Ruminococcus, Lachnospira, Pseudomonas) in comparison with the healthy controls. Despite significant changes in microbial diversity in the saliva of AxSpA patients, only a few microbes such as Prevotellaceae, NK3831 group, and Alloprevotella were enriched in IgA coating. We also found a positive correlation between IgA-coated Clostridium Family XIII and the disease activity. Predictive metagenomic analysis of IgA coated microbes showed perturbation of pathways belonging to propanoate and glutathione metabolism, biosynthesis of secondary metabolites, and bacterial secretion system in AxSpA patients. Analysis of individual genes showed the alterations of the genes belonging to the tryptophan and butanoate pathways, further emphasizing the importance of IgA coating in targeting immune responsive bacteria.

Conclusion: We show that the immune response to oral and fecal microbes is altered in AxSpA patients, with IgA coated Clostridium positively correlating with disease activity. Predictive metagenome analysis revealed perturbations of metabolic and oxidative stress-related pathways in AxSpA patients. Taken together, our results suggest that HLA-B27-associated increase in IgA coated microbes may indicate an aberrant immune response to gut commensal microbes, which may contribute to the development of AxSpA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-b27-is-associated-with-altered-mucosal-iga-response-to-oral-and-fecal-microbiota-in-patients-with-axial-spondyloarthritis/