Background The composition of intestinal microbiota is perturbed in patients with new-onset rheumatoid arthritis (RA) and those with chronic RA. However, it is not known whether the changes in the intestinal microbiome precede the development of arthritis or are rather a consequence of the inflammatory processes. Furthermore, while both germ-free condition and administration of oral antibiotics prevent arthritis in mice, it is unclear whether modulation of the intestinal microbiota after the onset of arthritis may still suppress the disease.
Objectives We aimed to assess potential alterations of the intestinal microbiome in the preclinical phase of inflammatory arthritis, and to determine the efficacy of microbiota modulations in the treatment of established disease in mice.
Methods We sequenced fecal bacterial 16S rRNA to define the intestinal microbiome in mice before immunization with collagen and 21 days later before the booster injection for the induction of collagen-induced arthritis (CIA). To assess the efficacy of microbiota modulation during arthritis, mice with ongoing CIA were treated orally by a broad-spectrum antibiotic cocktail for one week to partially eliminate the intestinal microbiota. T cell differentiation and production of cytokines in intestinal lamina propria and joint-draining lymph nodes were assessed by flow cytometry and Luminex. Arthritis was assessed macroscopically and by histology. Serum-transfer arthritis induced by intraperitoneal injections of arthritogenic K/BxN mouse serum was used as a control, T cell-independent, model.
Results The preclinical phase of inflammatory arthritis in mice was characterized by marked changes in the intestinal microbiome, represented by a significant increase of the phylum Bacteroidetes and a decrease of Firmicutes and Proteobacteria. Among the most abundant bacterial families, S24–7 and Staphylococcaceae were expanded, whereas Lachnospiraceae were reduced during the immune priming phase of CIA. Several operational taxonomic units associated with S24–7 family increased, while those assigned to Lachnospiraceae and Ruminococcaceae decreased in the intestinal microbiota before the clinical onset of arthritis. The abundance of intestinal lamina propria Th17 cells significantly correlated with the severity of CIA; however, intestinal Th1 cells were not correlated with the disease. Elimination of intestinal microbiota in mice with ongoing CIA specifically suppressed intestinal Th17 cell differentiation without affecting Th1 and Treg cells. Importantly, elimination of intestinal microbiota suppressed Th17 cell differentiation and IL-17 production in joint-draining lymph nodes, and reduced the severity of established CIA. In contrast, the T cell-independent serum-transfer arthritis was not affected by this strategy.
Conclusions These observations suggest that perturbations of the intestinal microbiome may precede the development of inflammatory arthritis. Similar studies are warranted in human pre-RA or at-risk individuals to shed light on the functional role of the microbiome in the development of RA. Our studies also suggest that modulation of the intestinal microbiota after the onset arthritis may still provide opportunities to treat inflammatory arthritis.
Disclosure of Interest None declared