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

Abstract

ObjectivesDiverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome.MethodsThe stools from a case–control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray.ResultsPrevious reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration 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 patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely 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. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients.ConclusionThese findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.

New developments in our understanding of ankylosing spondylitis pathogenesis

“…Furthermore, patients with AS have recently been shown to have a different microbiome composition to controls, with evidence of dysbiosis. [78][79][80] It should be noted that different studies using different methodologies have found somewhat differing results, with no single species or genus of bacteria being consistently found enriched (or absent) in all studies. We would hypothesize that AS may be associated with broad change in the microbiota, perhaps leading to altered Type 17 immunogenicity or altered metabolic signalling (see below) or both.…”

Understanding the Pathogenesis of Spondyloarthritis

“…Taken together, there is substantial evidence supporting the notion that complex interactions between host genetics, environmental factors, and the gut microbiome drive the pathogenesis of SpA [ 146 ]. Pathogenic bacteria, and possibly viruses occurring in the gut of SpA patients, contribute to dysbiosis, and lead to immune dysfunction and modulation of the innate and adaptive immune responses ([ 126 ].…”

Molecular Mimicry Map (3M) of SARS-CoV-2: Prediction of potentially immunopathogenic SARS-CoV-2 epitopes via a novel immunoinformatic approach

“…Type IV hypersensitivity is mediated by CD4+ type 1 helper T cells (Th1) and CD8+ cytotoxic T cells, and it is classified as a delayed-type hypersensitivity since the response requires more than 12 hours after exposure to antigens. There have been increasing efforts for identifying cross-reactive T-cell epitopes of pathogens that can initiate type IV hypersensitivity reactions and contribute to the pathogenesis of autoimmune diseases via activation of autoreactive CD8+ cytotoxic T cells (Luo et al, 2018b; Venigalla et al, 2020; Whalley et al, 2020; Yin et al, 2020).…”