Bacterial catabolism of tryptophan to indole is required to induce collagen induced arthritis via the IL23/Th17 axis

Abstract

Abstract While intestinal dysbiosis is linked to the pathophysiology of inflammatory arthritides like rheumatoid arthritis (RA) and spondyloarthritis (SpA), the mechanisms by which this occurs are unknown. Therefore, we used the collagen-induced arthritis (CIA) model to connect the microbiome with bacteria-produced metabolites in the development of disease. After initially correlating CIA severity with bacteria-dependent alterations in dietary tryptophan metabolism, and specifically indole, we demonstrate that both bacteria and dietary tryptophan are required for disease, and that indole supplementation fulfills these requirements. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1β and Th17 cells. These findings were associated with increased anti-CII IgG2b, decreased anti-CII antibody sialyation, and increased complement fixation, suggesting that indole-mediated Th17 immunity may enhance autoantibody pathogenicity. Finally, exposure of human colon lymphocytes to indole increased expression of genes involved in the IL-17 signaling pathway in B and T cells. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of Th17 immunity. Blockade of indole generation may present a novel therapeutic pathway for RA and SpA. Supported by grants from NIH: NIAMS R01AR075933 (KAK), NIAMS T32AR007534 (WKJ, BT, AJB), NIAID T32AI007405 (BJS), NIAID F30AI174817 (BJS); and the Rheumatology Research Foundation: Future Physician Scientist Award (BJS) and Scientist Development Award (AJB).