Microbial Mechanisms of Rheumatoid Arthritis Pathogenesis.

PURPOSE OF REVIEW: Host-microbiome interactions have been implicated in the pathophysiology of rheumatoid arthritis (RA), but the data linking specific microbes to RA is largely associative. Here, we review recent studies that have interrogated specific mechanistic links between microbes and host in the setting of RA. RECENT FINDINGS: Several candidate bacterial species and antigens that may trigger the conversion of an anti-bacterial to an autoimmune response have been recently identified. Additional studies have identified microbial metabolic pathways that are altered in RA. Some of these microbial species and metabolic pathways have been validated in mouse models to induce RA-like immune responses, providing initial evidence of specific mechanisms by which the microbiota contributes to the development of RA. Several microbial species, antigens, and metabolites have been identified as potential contributors to RA pathophysiology. Further interrogation and validation of these pathways may identify novel biomarkers of or therapeutic avenues for RA.

Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice.

Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model, we identified alterations in tryptophan metabolism, and specifically indole, that correlated with disease. We demonstrated that both bacteria and dietary tryptophan were required for disease and that indole supplementation was sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1ß; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colonic lymphocytes to indole increased the expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a unique therapeutic pathway for RA and SpA.

3,3-dimethyl-1-butanol and its metabolite 3,3-dimethylbutyrate ameliorate collagen-induced arthritis independent of choline trimethylamine lyase activity.

Previous studies have identified significant alterations in intestinal carnitine metabolism in mice with collagen-induced arthritis (CIA), potentially linking bacterial dysbiosis with autoimmunity. Bacterial trimethylamine (TMA) lyases metabolize dietary carnitine to TMA, which is oxidized in the liver to trimethylamine-N-oxide (TMAO). TMAO is associated with inflammatory diseases, such as atherosclerosis, whose immunologic processes mirror that of rheumatoid arthritis (RA). Therefore, we investigated the possibility of ameliorating CIA by inhibiting TMA lyase activity using 3,3-dimethyl-1-butanol (DMB) or fluoromethylcholine (FMC). During CIA, mice were treated with 1% vol/vol DMB, 100mg/kg FMC, or vehicle. DMB-treated mice demonstrated significant (>50%) reduction in arthritis severity compared to FMC and vehicle-treated mice. However, in contrast to FMC, DMB treatment did not reduce cecal TMA nor circulating TMAO concentrations. Using gas chromatography, we confirmed the effect of DMB is independent of TMA lyase inhibition. Further, we identified a novel host-derived metabolite of DMB, 3,3-dimethyl-1-butyric acid (DMBut), which also significantly reduced disease and proinflammatory cytokines in CIA mice. Altogether, our study suggests that DMB the immunomodulatory activity of DMB and/or its metabolites are protective in CIA. Elucidating its target and mechanism of action may provide new directions for RA therapeutic development.