Background SLE is an archetypical systemic autoimmune disease, which has been attributed to interactions between genetic and environmental factors that are currently not well understood. Yet recent reports have begun to elucidate how intestinal bacteria influence the development of physiologic B-cell/T-cell responses, and can affect the pathogenesis of inflammatory and autoimmune conditions. Our studies are designed to shed light on the potential roles of the gut microbiome in SLE pathogenesis.
Methods We have assembled and characterised a cohort of 60 female SLE patients and 20 healthy controls. DNA from the unfractionated bacteria in faecal samples, and from the sorted endogenous IgA-coated and non-coated bacterial fractions, was then extracted. 16 S bacterial rRNA genes were then barcoded and amplified, and over 20,000 reads were determined per sample using illumina NGS technology. Faecal and serum total Ig and autoantibodies were measured by ELISA.
Results Our analysis showed less microbiome diversity in SLE than healthy controls (p = 0.002). This dysbiosis was treatment independent, with more severe intestinal dysbiosis and decreased bacterial diversity in patients with high disease activity, based on SLEDAI. In addition, SLE patients had increased representation of certain bacterial families, genus’s and species, based on 16 S rRNA assignments of operational taxonomic units (OTUs). Patients with active disease displayed contractions of bacterial taxa with reported protective properties and reciprocal expansions of taxa with putative pathobiont properties. We also assessed IgA, which is the most prevalent antibody isotype made by the human body, and found evidence of exuberant levels in both intestinal and blood samples of SLE patients. While only a minority of bacterial taxa are specifically coated by endogenous intestinal IgA, IgA-coated bacteria in SLE patients had differential representation with recurrent taxa-specific expansion in SLE patients. Strikingly, Prevotella copri, which has recently been linked to new-onset RA, was significantly over-represented among the IgA-coated taxa only in SLE patients with high disease activity, and was not detected in healthy controls.
Conclusion Our studies provide the first evidence that SLE is associated with gut microbiome dysbiosis with expansions of specific bacterial taxa that may contribute to immune dysregulation. This imbalance was more significant in patients with high disease activity Characterisation of in vivo IgA-coated bacteria demonstrated that certain microbes taxa/species are preferentially recognised by the adaptive immune system of SLE patients, and these differ significantly from healthy adults. We are now studying these candidate pathobionts in longitudinal studies to address whether the microbiome predicts and/or tracks flares.
Acknowledgements Supported in part by the Lupus Research Institute and the Judith and Stewart Colton Foundation
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