Rheumatoid Arthritis Patients Harbour Aberrant Enteric Bacteriophages with Autoimmunity-Provoking Potential: a Paired Sibling Study

Objectives Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis.Methods Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The alpha and beta diversity of the virome and the virome-bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4+ T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied.Results The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4+ T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip.Conclusions This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.