The biological mechanisms involved in SARS-CoV-2 infection are only partially understood. Thus we explored the plasma metabolome of patients infected with SARS-CoV-2 to search for diagnostic and/or prognostic biomarkers and to improve the knowledge of metabolic disturbance in this infection. We analyzed the plasma metabolome of 55 patients infected with SARS-CoV-2 and 45 controls by LC-HRMS at the time of viral diagnosis (D0). We first evaluated the ability to predict the diagnosis from the metabotype at D0 in an independent population. Next, we assessed the feasibility of predicting the disease evolution at the 7th and 15th day. Plasma metabolome allowed us to generate a discriminant multivariate model to predict the diagnosis of SARS-CoV-2 in an independent population (accuracy > 74%, sensitivity, specificity > 75%). We identified the role of the cytosine and tryptophan-nicotinamide pathways in this discrimination. However, metabolomic exploration modestly explained the disease evolution. Here, we present the first metabolomic study in SARS-CoV-2 patients which showed a high reliable prediction of early diagnosis. We have highlighted the role of the tryptophan-nicotinamide pathway clearly linked to inflammatory signals and microbiota, and the involvement of cytosine, previously described as a coordinator of cell metabolism in SARS-CoV-2. These findings could open new therapeutic perspectives as indirect targets.

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ObjectiveThe extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway.DesignTargeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition.ResultsIn mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models.ConclusionOur study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4+T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT.

In this study, we validated a method for quantifying 20 tryptophan (Trp) catabolites by liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) in 4 different matrices (urine, serum, intestinal contents and liver). The detection limit for all metabolites ranged between 0.015 and 11.25 nmol/L and the dynamic range of the calibration curves were adjusted to allow quantification of metabolites at endogenous levels. Matrix effects were evaluated using isotope labeled internal standards. Reproducibility in the 4 matrices was characterized by CV = 6.2% with an accuracy of 6.6%. Our method has been applied to the determination and quantification of 20 metabolites concentrations in 5 different mouse compartments (plus cecal contents). Our results show that our approach allows for a global exploration of the Trp metabolism by quantifying a large number of Trp metabolites, at the individual level by multi-matrix approach.

BackgroundThe biological mechanisms involved in SARS-CoV-2 infection are only partially understood. Thus we explored the plasma metabolome of patients infected with SARS-CoV-2 to search for diagnostic and/or prognostic biomarkers and to improve the knowledge of metabolic disturbance in this infection.Materials and Methods We analyzed the plasma metabolome of 55 patients infected with SARS-CoV-2 and 45 controls by LC-HRMS at the time of diagnosis (D0). We first evaluated the ability to predict the diagnosis from the metabotype at D0 in an independent population. Next, we assessed the feasibility of predicting the disease evolution at the 7th and 15th day.ResultsPlasma metabolome allowed us to generate a discriminant multivariate model to predict the diagnosis of SARS-CoV-2 in an independent population (accuracy>74%, sensitivity, specificity>75%). We identified the role of the cytosine and tryptophan-nicotinamide pathways in this discrimination. However, metabolomic exploration modestly explained the disease evolution.DiscussionHere, we present the first metabolomic study in SARS-CoV-2 patients which showed a high reliable prediction of early diagnosis. We have highlighted the role of the tryptophan-nicotinamide pathway clearly linked to inflammatory signals and microbiota, and the involvement of cytosine, previously described as a coordinator of cell metabolism in SARS-CoV-2. These findings could open new therapeutic perspectives as indirect targets.

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Four new doubly bridged Cd(II)-azido complexes derived from sterically hindered NNN- and NN-donors were synthesized and structurally characterized. The tridentate amine ligands 2-methylquinolyl-2(ethyl-2-pyridyl)-methylamine (Meepmqa) and bis(2-methylypyridyl)methylamine (MeDPA) afforded the dinuclear complexes [Cd2(Meepmqa)2(μ1,3-N3)2(N3)2] (1) and [Cd2(MeDPA)2(μ1,1-N3)2(N3)2] (2) with di-EE- and di-EO-azido bridges, respectively. The N-substituted trialkyl ethylenediamine compounds N,N,N′-triethylethylenediamine (Et3en) and N,N,N′-trimethylethylenediamine (Me3en) resulted in the formation of 1D-polymeric chains {[Cd2(Et3en)2(μ1,1-N3)2(μ1,3-N3)2]} n (3) and {[Cd4(Me3en)4(μ1,1-N3)6(μ1,3-N3)2]} n (4) with alternative (di-EO/di-EE)- and di(EO/EO/EO/EE)-azido bonding modes. The IR asymmetric stretching vibration, νas(N3) of the azido ligands in these complexes and in related complexes, were analyzed in an attempt to predict the coordination bonding mode of the bridged azide. The fluorescence properties of the ligand Meepmqa and its complex 1 are reported. The Cd-complex 1 has increased fluorescence intensity compared to its free ligand. This was attributed to the strong Cd–N bond of the quinolyl group of Meepmqa and the nonflexibility of the corresponding five-membered chelate ring.

Currently, most clinical studies in metabolomics only consider a single type of sample such as urine, plasma, or feces and use a single analytical platform, either NMR or MS. Although some studies have already investigated metabolomics data from multiple fluids, the information is limited to a unique analytical platform. On the other hand, clinical studies investigating the human metabolome that combine multi-analytical platforms have focused on a single biofluid. Combining data from multiple sample types for one patient using a multimodal analytical approach (NMR and MS) should extend the metabolome coverage. Pre-analytical and analytical phases are time consuming. These steps need to be improved in order to move into clinical studies that deal with a large number of patient samples. Our study describes a standard operating procedure for biological specimens (urine, blood, saliva, and feces) using multiple platforms (1H-NMR, RP-UHPLC-MS, and HILIC-UHPLC-MS). Each sample type follows a unique sample preparation procedure for analysis on a multi-platform basis. Our method was evaluated for its robustness and was able to generate a representative metabolic map.