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

Abstract

ABSTRACTDiverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). To further investigate this we performed metagenomic analysis of a case-control cohort of 250 Han-Chinese subjects. Previous reports of gut dysbiosis in AS were re-confirmed and several notable bacterial species and functional categories were differentially abundant. TNF-inhibitor (TNFi) therapy at least partially restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of AS patients, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy of AS patients was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients. An AS-associated SNP in RUNX3 significantly influenced the microbiome in two independent cohorts, highlighting a host genotype (other than HLA-B27) potentially influencing AS via the microbiome. These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS.