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

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.

SUBMITTER: Stoll ML

PROVIDER: S-EPMC5133160 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Stoll M L ML Kumar R R Lefkowitz E J EJ Cron R Q RQ Morrow C D CD Barnes S S

Genes and immunity 20161027 7

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 identif ...[more]

PMID: 27786174

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Project description:Axial spondyloarthritis (axSpA) is an inflammatory arthritis involving the spine and the sacroiliac joint with extra-articular manifestations in the eye, gut, and skin. The intestinal microbiota has been implicated as a central environmental component in the pathogenesis of various types of spondyloarthritis including axSpA. Additionally, alterations in the oral microbiota have been shown in various rheumatological conditions, such as rheumatoid arthritis (RA). Therefore, the aim of this study was to investigate whether axSpA patients have an altered immunoglobulin A (IgA) response in the gut and oral microbial communities. We performed 16S rRNA gene (16S) sequencing on IgA positive (IgA+) and IgA negative (IgA-) fractions (IgA-SEQ) from feces (n=17 axSpA; n=14 healthy) and saliva (n=14 axSpA; n=12 healthy), as well as on IgA-unsorted fecal and salivary samples. PICRUSt2 was used to predict microbial metabolic potential in axSpA patients and healthy controls (HCs). IgA-SEQ analyses revealed enrichment of several microbes in the fecal (Akkermansia, Ruminococcaceae, Lachnospira) and salivary (Prevotellaceae, Actinobacillus) microbiome in axSpA patients as compared with HCs. Fecal microbiome from axSpA patients showed a tendency towards increased alpha diversity in IgA+ fraction and decreased diversity in IgA- fraction in comparison with HCs, while the salivary microbiome exhibits a significant decrease in alpha diversity in both IgA+ and IgA- fractions. Increased IgA coating of Clostridiales Family XIII in feces correlated with disease severity. Inferred metagenomic analysis suggests perturbation of metabolites and metabolic pathways for inflammation (oxidative stress, amino acid degradation) and metabolism (propanoate and butanoate) in axSpA patients. Analyses of fecal and salivary microbes from axSpA patients reveal distinct populations of immunoreactive microbes compared to HCs using the IgA-SEQ approach. These bacteria were not identified by comparing their relative abundance alone. Predictive metagenomic analysis revealed perturbation of metabolites/metabolic pathways in axSpA patients. Future studies on these immunoreactive microbes may lead to better understanding of the functional role of IgA in maintaining microbial structure and human health.

Project description:BACKGROUND: Autism spectrum disorders (ASDs) are relatively common neurodevelopmental conditions whose biological basis has been incompletely determined. Several biochemical markers have been associated with ASDs, but there is still no laboratory test for these conditions. METHODS: We analyzed the metabolic profile of lymphoblastoid cell lines from 137 patients with neurodevelopmental disorders with or without ASDs and 78 normal individuals, using Biolog Phenotype MicroArrays. RESULTS: Metabolic profiling of lymphoblastoid cells revealed that the 87 patients with ASD as a clinical feature, as compared to the 78 controls, exhibited on average reduced generation of NADH when tryptophan was the sole energy source. The results correlated with the behavioral traits associated with either syndromal or non-syndromal autism, independent of the genetic background of the individual. The low level of NADH generation in the presence of tryptophan was not observed in cell lines from non-ASD patients with intellectual disability, schizophrenia or conditions exhibiting several similarities with syndromal autism except for the behavioral traits. Analysis of a previous small gene expression study found abnormal levels for some genes involved in tryptophan metabolic pathways in 10 patients. CONCLUSIONS: Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD+, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs.

Dataset Information

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

Publications

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

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