Background/Purpose: Children with enthesitis-related arthritis (ERA) and adults with spondyloarthritis are at risk for intestinal inflammation. We have previously shown altered microbiota in children with ERA similar to inflammatory bowel disease. However, the mechanisms by which an altered microbiota might predispose to arthritis and intestinal inflammation remain unclear. Therefore, we explored expression profiles from fecal samples of children with ERA.

Methods: Fecal samples were obtained from patients with ERA and healthy controls. For metabolomics, samples were subjected to acid extraction and analyzed by nanoscale liquid chromatography coupled to tandem mass spectrometry (MS). Data analysis was performed with the mummichog for metabolomics program on the output of the positive and negative modes MS analyses, comparing metabolites identified by mass : charge ratio with at least a 1.5 fold difference between patients and controls, and a p-value of <0.05. This was repeated on a second cohort of largely newly diagnosed ERA patients and healthy controls. For metagenomics, fecal samples from a subset of the second cohort (10 with ERA & 8 controls) were subject to DNA purification and shotgun sequencing using MiSeq.

Results: The initial metabolomics run involved 12 ERA patients and 11 controls. Among the negative mode ions, pathway analysis revealed 5 pathways relatively under-represented in patients:  metabolism of biopterin, tryptophan, glycerophospholipid, urea cycle, and tyrosine. The repeat run was performed on 15 non-overlapping patients with largely newly diagnosed ERA and 11 controls. Tryptophan metabolism again emerged as under-represented in patients among the negative mode ions, as did the butanoate pathway. Additionally, both runs revealed far more ions over-represented in controls as compared to patients. Metagenomics analysis was generally consistent with the metabolomics: more genes and pathways were represented in the controls compared to patients. In addition, the patients had less taxonomic diversity.

Conclusion: Multi-omics analysis of children with ERA compared to healthy controls indicates lower functional metabolic potential and activity in ERA patients, decreased taxonomic diversity, and  possible differences in the fecal microbial metabolism of tryptophan. Thus, we have identified functional correlates to the diminished microbial diversity seen in many disease states. Also, tryptophan metabolism has been linked to the balance between Th17 and regulatory T cells; thus, it appears that the fecal microbiota may affect T cell development towards a pro- or anti-inflammatory phenotype. This may help to explain findings of intestinal inflammation and arthritis in children with ERA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multi-omics-studies-of-gut-microbiota-in-enthesitis-related-arthritis-identify-diminished-microbial-diversity-and-altered-typtophan-metabolism-as-potential-factors-in-disease-pathogenesis/