Results from a recent research study published in the Annals of the Rheumatic Diseases emphasize the key role of the gut microbiome in the pathogenesis of ankylosing spondylitis (AS) and the efficacy of tumor necrosis factor inhibitor (TNFi) therapy on the microbiome.
Using shotgun metagenomic sequencing, researchers sought to define the key microbial characteristics that drive AS and to examine the effects of TNFi therapy on the microbiome in this patient population. Stool samples were collected from a case-control cohort and sequenced, and patient data were genotyped using the Illumina CoreExome SNP microarray.
The total study cohort included 127 Han Chinese patients with AS who met the 1984 modified New York criteria for AS and 123 healthy controls from Shanghai, China. Before the analysis, both cohorts were divided into discovery and validation cohorts: the discovery cohort included 97 patients with AS and 93 healthy controls; the validation cohort included 30 patients with AS and 30 healthy controls. No significant baseline differences were observed among any of the groups.
In both the discovery and validation cohorts, 7 bacterial species were identified as differentially abundant among patients with AS and healthy controls. In the AS group, Clostridiales bacterium 1 7 47FAA, Clostridium bolteae, and Clostridium hatheway were enriched, and Bifidobacterium adolescentis, Coprococcus comes, Lachnospiraceae bacterium 5 1 63FAA, and Roseburia inulinivorans were depleted. Six other differentially abundant KEGG orthogroups were noted in both cohorts, but no differentially abundant MetaCyc metabolic pathways were noted. Strain-level profiling of dysbiotic microbes did not result in any differences in strain composition between [the patient group] and the control group, which suggests that gut dysbiosis may primarily be a result of “differential abundance at the species level,” noted the researchers.
To examine the effect of TNFi therapy on the gut microbiome, investigators combined the discovery and validation cohorts and created the following categories: healthy controls (n=123), patients with AS who received TNFi therapy (n=67), and patients with AS who did not receive TNFi therapy (n=60). A multivariate comparison of patients who received and did not receive TNFi therapy indicated an effect of TNFi treatment on overall microbiome composition; untreated cases were significantly different compared with healthy controls (P =.0002), whereas treated cases were not significantly different than healthy controls (P =.069).
In 6 of the 8 species that exhibited signs of significant depletion in untreated AS, TNFi treatment was correlated with restoration “to levels indistinguishable from healthy controls.”
Finally, researchers assessed the bacterial peptides homologous to HLA-B27 epitopes in order to examine the potential effects of HLA-B27 on shaping the gut microbiome. Among patients with AS, significant enrichment of these peptide sequences was noted, with 24 sequences across the discovery and validation cohorts. The overall abundance and diversity of HLA-B27 epitopes were significantly different between TNFi treatment categories, and patients with untreated AS demonstrated an increased abundance and diversity of peptides.
Study limitations included a lack of generalizability due to known heterogeneity within the gut microbiome in different geographical locations and the small study sample size.
“These findings are consistent with disease models in which AS pathogenesis is driven by interactions between a genetically primed host immune system, and the gut microbiome and point to potential therapeutic and/or preventative approaches for the disease,” the researchers concluded.
Yin J, Sternes PR, Wang M, et al. 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. Ann Rheum Dis. 2020;79(1):132-140.