Tryptophan metabolism, its relation to inflammation and stress markers and association with psychological and cognitive functioning: Tasmanian Chronic Kidney Disease pilot study

Raw Data in five data sheets including Patients relevant metadata, quantified metabolites (given at Οg/L as well as Οmol/L), psychology measures, common medication and comorbidities. (XLS 58 kb

Heritability of Urinary Amines, Organic Acids, and Steroid Hormones in Children

Variation in metabolite levels reflects individual differences in genetic and environmental factors. Here, we investigated the role of these factors in urinary metabolomics data in children. We examined the effects of sex and age on 86 metabolites, as measured on three metabolomics platforms that target amines, organic acids, and steroid hormones. Next, we estimated their heritability in a twin cohort of 1300 twins (age range: 5.7-12.9 years). We observed associations between age and 50 metabolites and between sex and 21 metabolites. The monozygotic (MZ) and dizygotic (DZ) correlations for the urinary metabolites indicated a role for non-additive genetic factors for 50 amines, 13 organic acids, and 6 steroids. The average broad-sense heritability for these amines, organic acids, and steroids was 0.49 (range: 0.25-0.64), 0.50 (range: 0.33-0.62), and 0.64 (range: 0.43-0.81), respectively. For 6 amines, 7 organic acids, and 4 steroids the twin correlations indicated a role for shared environmental factors and the average narrow-sense heritability was 0.50 (range: 0.37-0.68), 0.50 (range; 0.23-0.61), and 0.47 (range: 0.32-0.70) for these amines, organic acids, and steroids. We conclude that urinary metabolites in children have substantial heritability, with similar estimates for amines and organic acids, and higher estimates for steroid hormones

Plasma Oxylipins and Their Precursors Are Strongly Associated with COVID-19 Severity and with Immune Response Markers

COVID-19 is characterised by a dysregulated immune response, that involves signalling lipids acting as mediators of the inflammatory process along the innate and adaptive phases. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyse over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). The second publication in a series reports the results of quantitative LC-MS/MS profiling of 63 small lipids including oxylipins, free fatty acids, and endocannabinoids. Compared to samples taken from ward patients, intensive care unit (ICU) patients had 2–4-fold lower levels of arachidonic acid (AA) and its cyclooxygenase-derived prostanoids, as well as lipoxygenase derivatives, exhibiting negative correlations with inflammation markers. The same derivatives showed 2–5-fold increases in recovering ward patients, in paired comparison to early hospitalisation. In contrast, ICU patients showed elevated levels of oxylipins derived from poly-unsaturated fatty acids (PUFA) by non-enzymatic peroxidation or activity of soluble epoxide hydrolase (sEH), and these oxylipins positively correlated with markers of macrophage activation. The deficiency in AA enzymatic products and the lack of elevated intermediates of pro-resolving mediating lipids may result from the preference of alternative metabolic conversions rather than diminished stores of PUFA precursors. Supporting this, ICU patients showed 2-to-11-fold higher levels of linoleic acid (LA) and the corresponding fatty acyl glycerols of AA and LA, all strongly correlated with multiple markers of excessive immune response. Our results suggest that the altered oxylipin metabolism disrupts the expected shift from innate immune response to resolution of inflammation

Severe COVID-19 is characterised by perturbations in plasma amines correlated with immune response markers, and linked to inflammation and oxidative stress

The COVID-19 pandemic raised a need to characterise the biochemical response to SARS-CoV-2 infection and find biological markers to identify therapeutic targets. In support of these aims, we applied a range of LC-MS platforms to analyse over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). The first publication in a series reports the results of quantitative LC-MS/MS profiling of 56 amino acids and derivatives. A comparison between samples taken from ICU and ward patients revealed a notable increase in ten post-translationally modified amino acids that correlated with markers indicative of an excessive immune response: TNF-alpha, neutrophils, markers for macrophage, and leukocyte activation. Severe patients also had increased kynurenine, positively correlated with CRP and cytokines that induce its production. ICU and ward patients with high IL-6 showed decreased levels of 22 immune-supporting and anti-oxidative amino acids and derivatives (e.g., glutathione, GABA). These negatively correlated with CRP and IL-6 and positively correlated with markers indicative of adaptive immune activation. Including corresponding alterations in convalescing ward patients, the overall metabolic picture of severe COVID-19 reflected enhanced metabolic demands to maintain cell proliferation and redox balance, alongside increased inflammation and oxidative stress.Analytical BioScience

CFM-ID 3.0: Significantly Improved ESI-MS/MS Prediction and Compound Identification

Metabolite identification for untargeted metabolomics is often hampered by the lack of experimentally collected reference spectra from tandem mass spectrometry (MS/MS). To circumvent this problem, Competitive Fragmentation Modeling-ID (CFM-ID) was developed to accurately predict electrospray ionization-MS/MS (ESI-MS/MS) spectra from chemical structures and to aid in compound identification via MS/MS spectral matching. While earlier versions of CFM-ID performed very well, CFM-ID’s performance for predicting the MS/MS spectra of certain classes of compounds, including many lipids, was quite poor. Furthermore, CFM-ID’s compound identification capabilities were limited because it did not use experimentally available MS/MS spectra nor did it exploit metadata in its spectral matching algorithm. Here, we describe significant improvements to CFM-ID’s performance and speed. These include (1) the implementation of a rule-based fragmentation approach for lipid MS/MS spectral prediction, which greatly improves the speed and accuracy of CFM-ID; (2) the inclusion of experimental MS/MS spectra and other metadata to enhance CFM-ID’s compound identification abilities; (3) the development of new scoring functions that improves CFM-ID’s accuracy by 21.1%; and (4) the implementation of a chemical classification algorithm that correctly classifies unknown chemicals (based on their MS/MS spectra) in >80% of the cases. This improved version called CFM-ID 3.0 is freely available as a web server. Its source code is also accessible online

Differential metabolic host response to pathogens associated with community-acquired pneumonia

Background: Metabolic changes induced by the host immune response to pathogens found in patients with community-acquired pneumonia (CAP) may provide insight into its pathogenesis. In this study, we characterized differences in the host metabolic response to common CAP-associated pathogens. Method: Targeted metabolomic profiling was performed on serum samples obtained from hospitalized CAP patients (n = 119) at admission. We quantified 347 unique metabolites across multiple biochemical classes, including amines, acylcarnitines, and signaling lipids. We evaluated if unique associations between metabolite levels and specific CAP-associated pathogens could be identified. Results: Several acylcarnitines were found to be elevated in C. burnetii and herpes simplex virus and lowered in M. pneumoniae as compared to other pathogens. Phenylalanine and kynurenine were found elevated in L. pneumophila as compared to other pathogens. S-methylcysteine was elevated in patients with M. pneumoniae, and these patients also showed lowered cortisol levels in comparison to almost all other pathogens. For the herpes simplex virus, we observed a unique elevation of eicosanoids and several amines. Many lysophosphatidylcholines showed an altered profile in C. burnetii versus S. pneumoniae, L. pneumophila, and respiratory syncytial virus. Finally, phosphatidylcholines were negatively affected by the influenza virus in comparison to S. pneumoniae. Conclusions: In this exploratory analysis, metabolites from different biochemical classes were found to be altered in serum samples from patients with different CAP-associated pathogens, which may be used for hypothesis generation in studies on differences in pathogen host response and pathogenesis of CAP

Additional file 4: of Tryptophan metabolism, its relation to inflammation and stress markers and association with psychological and cognitive functioning: Tasmanian Chronic Kidney Disease pilot study

Raw Data in five data sheets including Patients relevant metadata, quantified metabolites (given at Οg/L as well as Οmol/L), psychology measures, common medication and comorbidities. (XLS 58 kb

A Multi-omics Data Analysis Workflow Packaged as a FAIR Digital Object

In current biomedical and complex trait research, increasing numbers of large molecular profiling (omics) data sets are being generated. At the same time, many studies fail to be reproduced (Baker 2016, Kim 2018). In order to improve study reproducibility and data reuse, including integration of data sets of different types and origins, it is imperative to work with omics data that is findable, accessible, interoperable, and reusable (FAIR, Wilkinson 2016) at the source. The data analysis, integration and stewardship pillar of the Netherlands X-omics Initiative aims to facilitate multi-omics research by providing tools to create, analyze and integrate FAIR omics data. We here report a joint activity of X-omics and the Netherlands Twin Register demonstrating the FAIRification of a multi-omics data set and the development of a FAIR multi-omics data analysis workflow.The implementation of FAIR principles (Wilkinson 2016) can improve scientific transparency and facilitate data reuse. However, Kim (2018) showed in a case study that the availability of data and code are required but not sufficient to reproduce data analyses. They highlighted the importance of interoperable and open formats, and structured metadata. In order to increase research reproducibility on the data analysis level, additional practices such as version-control, code licensing, and documentation have been proposed. These include recommendations for FAIR software by the Netherlands eScience Center and the Dutch Data Archiving and Networked Services (DANS), and FAIR principles for research software proposed by the Research Data Alliance (Chue Hong 2022). Data analysis in biomedical research usually comprises multiple steps often resulting in complex data analysis workflows and requiring additional practices, such as containerization, to ensure transparency and reproducibility (Goble 2020, Stoudt 2021).We apply these practices to a multi-omics data set that comprises genome-wide DNA methylation profiles, targeted metabolomics, and behavioral data of two cohorts that participated in the ACTION Biomarker Study (ACTION, Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies, see consortium members in Suppl. material 1) (Boomsma 2015, Bartels 2018, Hagenbeek 2020, van Dongen 2021, Hagenbeek 2022). The ACTION-NTR cohort consists of twins that are either longitudinally concordant or discordant for childhood aggression. The ACTION-Curium-LUMC cohort consists of children referred to the Dutch LUMC Curium academic center for child and youth psychiatry. With the joint analysis of multi-omics data and behavioral data, we aim to identify substructures in the ACTION-NTR cohort and link them to aggressive behavior. First, the individuals are clustered using Similarity Network Fusion (SNF, Wang 2014), and latent feature dimensions are uncovered using different unsupervised methods including Multi-Omics Factor Analysis (MOFA) (Argelaguet 2018) and Multiple Correspondence Analysis (MCA, Lê 2008, Husson 2017). In a second step, we determine correlations between -omics and phenotype dimensions, and use them to explain the subgroups of individuals from the ACTION-NTR cohort. In order to validate the results, we project data of the ACTION-Curium-LUMC cohort onto the latent dimensions and determine if correlations between omics and phenotype data can be reproduced.Integration of data across cohorts and across data types, requires interoperability. We applied different practices to make the data FAIR, including conversion of files to community-standard formats, and capturing experimental metadata using the ISA (Investigation, Study, Assay) metadata framework (Johnson 2021) and ontology-based annotations. All data analysis steps including pre-processing of different omics data types were implemented in either R or Python and combined in a modular Nextflow (Di Tommaso 2017) workflow, where the environment for each step is provided as a Singularity (Kurtzer 2017) container. The analysis workflow is packaged in a Research Object Crate (RO-Crate) (Soiland-Reyes 2022). The RO-Crate is a FAIR digital object that contains the Nextflow workflow including ontology-based annotations of each analysis step. Since omics data is considered to be potentially personally identifiable, the packaged workflow contains a minimal synthetic data set resembling the original data structure. Finally, the code is made available on GitHub and the workflow is registered at Workflowhub (Goble 2021). Since our Nextflow workflow is set up in a modular manner, the individual analysis steps can be reused in other workflows. We demonstrate this replicability by applying different sub-workflows to data from two different cohorts