Indole production by the gut microbiome stimulates the development of collagen-induced arthritis.

Altered tryptophan catabolism has been identified in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (SpA). Using the collagen-induced arthritis (CIA) model, changes in tryptophan metabolism, specifically indole, were identified that were associated with the disease.

It was revealed that both bacteria and dietary tryptophan were required for the disease and that indole supplementation was sufficient to cause disease in their absence. When CIA mice on a low-tryptophan diet were supplemented with indole, significant increases in serum IL-6, TNF, and IL-1β, collagen-stimulated RORγt + CD4 + T cells, IL-17 production, anti-collagen antibody and glycosylation 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.

Taken together, intestinal dysbiosis during inflammatory arthritis leads to altered tryptophan catabolism, leading to indole stimulation and arthritis development.

Blockade of indole formation presents a unique therapeutic pathway for RA and SpA.

SOURCE: J .Clin Invest. 2024