Role of the Gut Microbiome in Modulating Arthritis Progression in Mice

Rheumatoid arthritis (RA) is a common autoimmune disease that results in cartilage degradation, progressive disability, systemic complications, early death, and high socioeconomic cost. Genome-wide association studies and other surveys have identified several genetic susceptibility loci1, of which HLA-DRB1 is the most predictive2. In addition, morbidity rates range from approximately 5% among dizygotic twins to 15–30% among monozygotic twins3. These observations indicate that the disease has a strong genetic component. Nevertheless, most cases of RA are of unknown cause, and environmental factors should be investigated. One such environmental factor is the microbiota, which numerous studies have demonstrated to be a key element in the initiation and progression of many diseases, including metabolic disorders such as obesity, diabetes, and RA4. Moreover, metabolic productsfrom gut microbiota are believed to elicit autoimmune diseases in genetically susceptible individuals5. In particular, molecular mimicry by the microbiome may trigger RA6. Probiotic supplementation may, on the other hand, also relieve inflammation and other symptoms in arthritic patients7,8. Thus, we hypothesised that the composition, structure, and functional capacity of the gut microbiota are directly associated with the onset and progression of RA. In DBA1 mice, arthritis can be stably induced in 80–100% of animals, using high-quality collagen9. This mouse model of arthritis shares immunological and pathological features with RA in humans and has been studied extensively to investigate pathogenesis and test candidate therapeutics. However, up to 20% of DBA1 mice do not develop arthritis symptoms after collagen-mediated induction. We speculated that microbial communities might also influence individual susceptibility or resistance to collagen-induced arthritis (CIA). To test this hypothesis, we analysed the microbiota in collagen-induced mice by surveying key bacterial phylotypes and other potential biomarkers before and after clinical onset of arthritis. Importantly, given that the gut microbiota shapes the development and activation of the mammalian immune system10, we showed that the transplantation of microbiota from CIA-susceptible mice into germ-free mice increased arthritis severity, the serum concentration of interleukin (IL)-17, and the proportions of CD8+ and IL-17-producing (Th17) T cells in the spleen.