The clinical overlap between axSpA and bowel inflammation has long suggested an interaction between the gut and joint in its pathogenesis ( 2), and the condition of reactive arthritis caused by intestinal pathogens indicates that intestinal bacteria may trigger some forms of disease. Given the emerging role of tryptophan and its metabolites in immune function, altogether these data indicate that tryptophan metabolism into I3Ald and then IAA is one mechanism by which the gut microbiome potentially influences the development of axSpA.Īnkylosing spondylitis is a form of axial spondyloarthritis (axSpA) resulting in inflammation of the axial spine, peripheral joints, and entheses ( 1). Such genetic changes were not observed in CD, again suggesting disease specificity for axSpA.
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Specifically, gene abundance of indolepyruvate decarboxylase, which generates IAA and I3Ald, was significantly elevated in individuals with axSpA while gene abundances in HC demonstrated a propensity towards tryptophan synthesis. In spite of no significant differences in alpha-diversity among the 4 groups, our results confirmed differences in gene abundances of numerous enzymes involved in tryptophan metabolism. We then performed shotgun metagenomics of fecal samples to characterize gut microbial dysbiosis across these disease states. Using LC-MS based metabolomics of 4 non-inflamed pinch biopsies of the distal colon from subjects, we identified significant alterations in tryptophan pathway metabolites, including an expansion of indole-3-acetate (IAA) in axSpA and CD-axSpA compared to HC and CD and indole-3-acetaldehyde (I3Ald) in axSpA and CD-axSpA but not CD compared to HC, suggesting possible specificity to the development of axSpA. To identify potential disease-relevant, microbiome-produced metabolites, we performed metabolomics screening and shotgun metagenomics on paired colon biopsies and fecal samples, respectively, from subjects with axial SpA (axSpA, N=21), Crohn’s disease (CD, N=27), and Crohn’s-axSpA overlap (CD-axSpA, N=12), as well as controls (HC, N=24). One potential hypothesis suggests that the dysbiotic gut microbiome as a whole produces metabolites that influence human immune cells. Intestinal microbial dysbiosis, intestinal inflammation, and Th17 immunity are all linked to the pathophysiology of spondyloarthritis (SpA) however, the mechanisms linking them remain unknown.
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1Division of Rheumatology, Department of Medicine, University of Colorado, Aurora, CO, United States.Regner 2†, Andrew Stahly 1, Ana Brar 3, Julie A.