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27-10-2016 | Microbiome | Article

Fecal metabolomics in pediatric spondyloarthritis implicate decreased metabolic diversity and altered tryptophan metabolism as pathogenic factors

Authors: M L Stoll, R Kumar, E J Lefkowitz, R Q Cron, C D Morrow, S Barnes

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Abstract

We have previously shown alterations in the composition of the gut microbiota in children with enthesitis-related arthritis (ERA). To explore the mechanisms by which an altered microbiota might predispose to arthritis, we performed metabolomic profiling of fecal samples of children with ERA. Fecal samples were collected from two cohorts of children with ERA and healthy control subjects. Nano-liquid chromatography—mass spectroscopy (LC-MS) was performed on the fecal water homogenates with identification based upon mass: charge ratios. Sequencing of the 16S ribosomal DNA (rDNA) on the same stool specimens was performed. In both sets of subjects, patients demonstrated lower diversity of ions and under-representation of multiple metabolic pathways, including the tryptophan metabolism pathway. For example, in the first cohort, out of 1500 negatively charged ions, 154 were lower in ERA patients, compared with only one that was higher. Imputed functional annotation of the 16S ribosomal DNA sequence data demonstrated significantly fewer microbial genes associated with metabolic processes in the patients compared with the controls (77 million versus 58 million, P=0.050). Diminished metabolic diversity and alterations in the tryptophan metabolism pathway may be a feature of ERA.

Genes Immun 2016;17:400–405. doi:10.1038/gene.2016.38

Interest in the composition of the gut microbiota in subjects with spondyloarthritis (SpA), like enthesitis-related arthritis (ERA)/juvenile idiopathic arthritis (JIA), has been accumulating.1 We and others have identified taxonomic differences in fecal bacteria between pediatric or adult SpA subjects and healthy controls.2, 3, 4 However, these studies have not provided a mechanism whereby dysbiosis can result in arthritis. One possible mechanism is through alterations in metabolic pathways. The metabolic capacity of bacteria is an under-appreciated aspect of the human microbiome. In total, bacteria contain over 3 million genes, 100 times the human host;5 they perform a variety of metabolic functions including metabolism of dietary components, drug detoxification and synthesis of vitamins and essential amino acids.5 Bacteria are not created equal in their capacity to perform these functions, and thus a particular microbiome may be more or less effective than another at carrying out certain activities. To evaluate the functional potential of the microbiome, fecal water metabolomics on children with ERA and controls was performed. The aim of metabolomics is to conduct a comprehensive analysis on the identities of the low molecular weight ions (in our facility, <1000 Da) present in a sample, so as to obtain insight into function.6Metabolomics of fecal water, the supernatant obtained following high-speed centrifugation of feces, can discriminate between inflammatory bowel disease (IBD) patients and healthy individuals, with some studies showing elevated levels of amino acids and decreased short chain fatty acids such as butyrate.7, 8 Our intent was to identify mechanisms by which the microbiota might predispose or contribute to arthritis in children with ERA.

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