Microbiota-dependent indole production is required for the development of collagen-induced arthritis.

Autor:	Seymour BJ; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Trent B; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Allen B; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Berlinberg AJ; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Tangchittsumran J; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Jubair WK; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Chriswell ME; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Liu S; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Ornelas A; Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Stahly A; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Alexeev EE; Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Dowdell AS; Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Sneed SL; Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Fechtner S; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Kofonow JM; Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Robertson CE; Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Dillon SM; Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Wilson CC; Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Anthony RM; Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Frank DN; Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Colgan SP; Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Kuhn KA; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 13. Date of Electronic Publication: 2023 Oct 13.
DOI:	10.1101/2023.10.13.561693
Abstrakt:	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 identify alterations in tryptophan metabolism, and specifically indole, that correlate with disease. We demonstrate that both bacteria and dietary tryptophan are required for disease, and indole supplementation is 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-1β; 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 colon lymphocytes to indole increased 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 novel therapeutic pathway for RA and SpA. Competing Interests: Conflict-of-interest statement: the authors have declared that no conflict of interest exists.
Databáze:	MEDLINE
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