Faculty Collaboration Database

Multi 'Omics Analysis of Intestinal Tissue in Ankylosing Spondylitis Identifies Alterations in the Tryptophan Metabolism Pathway. Front Immunol 2021;12:587119

Date

03/23/2021

Pubmed ID

33746944

Pubmed Central ID

PMC7966505

DOI

10.3389/fimmu.2021.587119

Scopus ID

2-s2.0-85102893020 (requires institutional sign-in at Scopus site)   49 Citations

Abstract

Intestinal microbial dysbiosis, intestinal inflammation, and Th17 immunity are all linked to the pathophysiology of spondyloarthritis (SpA); however, the mechanisms linking them remain unknown. One potential hypothesis suggests that the dysbiotic gut microbiome as a whole produces metabolites that influence human immune cells. 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). 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. We then performed shotgun metagenomics of fecal samples to characterize gut microbial dysbiosis across these disease states. 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. 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. Such genetic changes were not observed in CD, again suggesting disease specificity for axSpA. 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.

Author List

Berlinberg AJ, Regner EH, Stahly A, Brar A, Reisz JA, Gerich ME, Fennimore BP, Scott FI, Freeman AE, Kuhn KA

Author

Emilie Regner MD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Case-Control Studies
Computational Biology
Disease Susceptibility
Dysbiosis
Gastrointestinal Microbiome
Gene Expression Profiling
Gene Expression Regulation, Bacterial
Humans
Intestines
Metabolic Networks and Pathways
Metabolomics
Metagenomics
Spondylitis, Ankylosing
Tryptophan