Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma

Ried, Janina S.; Baurecht, Hansjörg; Stückler, Ferdinand; Krumsiek, Jan; Gieger, Christian; Heinrich, Joachim; Kabesch, Michael; Prehn, Cornelia; Peters, Annette; Rodríguez, Elke; Schulz, Holger; Strauch, K.; Suhre, Karsten; Wang-Sattler, Rui; Wichmann, H‐Erich; Theis, Fabian J.; Illig, Thomas; Adamski, Jerzy; Weidinger, Stephan

doi:10.1111/all.12110

Cited by 75 publications

(64 citation statements)

References 31 publications

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“…Previous metabolomics studies revealed metabolic alteration in the asthma exacerbated condition [32,[34][35][36]. Histidine, trimethylamine N-oxide, phenylacetylglycine, threonine, 4-aminohippurate and methylamine were decreased, whereas creatine, glucose, hippurate, alanine, glycolate, succinate, myo-inositol, dimethylamine, formate, homovanillate, acetylcarnitine, taurine, lactate, oxaloacetate, cis-aconitate, 2-methylglutarate, tyrosine, 1-methylhistamine, 2-hydroxyisobutyrate, acetone, carnitine, 3-methyladipate and 2-oxoglutarate were increased in asthmatic children during acute exacerbation.…”

Section: Discussionmentioning

confidence: 99%

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

Yang

Zhang

et al. 2017

Basic Clin Pharma Tox

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Inhaled budesonide and salbutamol represent the most important and frequently used drugs in asthmatic children during acute exacerbation. However, there is still no consensus about their resulting metabolic derangements; thus, this study was conducted to determine the distinct metabolic profiles of these two drugs. A total of 69 children with asthma during acute exacerbation were included, and their serum and urine were investigated using high-resolution nuclear magnetic resonance (NMR). A metabolomics analysis was performed using a principal component analysis and orthogonal signal correction-partial least squares using SIMCA-P. The different metabolites were identified, and the distinct metabolic profiles were analysed using MetPA. A high-resolution NMR-based serum and urine metabolomics approach was established to study the overall metabolic changes after inhaled budesonide and salbutamol in asthmatic children during acute exacerbation. The perturbed metabolites included 22 different metabolites in the serum and 21 metabolites in the urine. Based on an integrated analysis, the changed metabolites included the following: increased 4-hydroxybutyrate, lactate, cis-aconitate, 5-hydroxyindoleacetate, taurine, trans-4-hydroxy-l-proline, tiglylglycine, 3-hydroxybutyrate, 3-methylhistidine, glucose, cis-aconitate, 2-deoxyinosine and 2-aminoadipate; and decreased alanine, glycerol, arginine, glycylproline, 2-hydroxy-3-methylvalerate, creatine, citrulline, glutamate, asparagine, 2-hydroxyvalerate, citrate, homoserine, histamine, sn-glycero-3-phosphocholine, sarcosine, ornithine, creatinine, glycine, isoleucine and trimethylamine N-oxide. The MetPA analysis revealed seven involved metabolic pathways: arginine and proline metabolism; taurine and hypotaurine metabolism; glycine, serine and threonine metabolism; glyoxylate and dicarboxylate metabolism; methane metabolism; citrate cycle; and pyruvate metabolism. The perturbed metabolic profiles suggest potential metabolic reprogramming associated with a combination treatment of inhaled budesonide and salbutamol in asthmatic children.Glucocorticoids and beta2 agonists represent the most important and frequently used drugs for symptom control in asthmatic children during acute exacerbation [1,2]. Current guidelines recommend the combined use of glucocorticoids and beta2 agonists as the preferred therapy for asthmatic children during acute exacerbation [3,4]. The glucocorticoid and beta2 agonist therapies are effective at controlling airway inflammation, reducing asthma symptoms, decreasing airway hyper-responsiveness and reducing the frequency and severity of exacerbations as well as asthma mortality. Despite their undoubted effectiveness and safety, there is still no consensus about the resulting metabolic derangements, including the development of dyslipidaemia, insulin resistance, glucose intolerance, diabetes, central adiposity and skeletal muscle wasting [5][6][7].Both glucocorticoids and beta2 agonists have the potential to influence glucose, lipid and protein...

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Section: Discussionmentioning

confidence: 99%

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

Yang

Zhang

et al. 2017

Basic Clin Pharma Tox

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“…There appears to be a causal link between PC and lung surfactants levels, where reduction in PC level can lead to worsening in lung functions in asthma (Wright et al 2000;Ried et al 2013). BALF level of PC dipped, but its downstream metabolite choline level elevated in experimental asthma .…”

Section: Discussionmentioning

confidence: 99%

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

et al. 2014

Metabolomics

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The anti-malarial drug artesunate possesses anti-inflammatory and anti-oxidative actions in experimental asthma, comparable to corticosteroid. We hypothesized that artesunate may modulate disease-relevant metabolic alterations in allergic asthma. To explore metabolic profile changes induced by artesunate in allergic airway inflammation, we analysed bronchoalveolar lavage fluid (BALF) and serum from naïve and ovalbumininduced asthma mice treated with artesunate, using both gas and liquid chromatography-mass spectrometry metabolomics. Pharmacokinetics analyses of serum and lung tissues revealed that artesunate is rapidly converted into the active metabolite dihydroartemisinin. Artesunate effectively suppressed BALF total and differential counts, and repressed BALF Th2 cytokines, IL-17, IL-12(p40), MCP-1 and G-CSF levels. Artesunate had no effects on both BALF and serum metabolome in naïve mice. Artesunate promoted restoration of BALF sterols (cholesterol, cholic acid and cortol), phosphatidylcholines and carbohydrates (arabinose, mannose and galactose) and of serum 18-oxocortisol, galactose, glucose and glucouronic acid in asthma. Artesunate prevented OVA-induced increases in pro-inflammatory metabolites from arginine-proline metabolic pathway, particularly BALF levels of urea and alanine and serum levels of urea, proline, valine and homoserine. Multiple statistical correlation analyses revealed association between altered BALF and serum metabolites and inflammatory cytokines. Dexamethasone failed to reduce Wanxing Eugene Ho and Yong-Jiang Xu have contributed equally to this work.Electronic supplementary material The online version of this article (doi:10.1007/s11306-014-0699-x) contains supplementary material, which is available to authorized users. Metabolomics (2015) 11:380-390 DOI 10.1007 urea level and caused widespread changes in metabolites irrelevant to asthma development. Here we report the first metabolome profile of artesunate treatment in experimental asthma. Artesunate restored specific metabolic perturbations in airway inflammation, which correlated well with its anti-inflammatory actions. Our metabolomics findings further strengthen the therapeutic value of using artesunate to treat allergic asthma.

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“…From our study we can clearly see a trend of suppression of anti-inflammatory pathways by prednisone treatment and an increase in membrane phospholipid synthesis (Figure 5). Altered PC metabolism has been suggested in asthma with increase in level of PC and decrease in level of lyso-PC [39] and Crohn’s disease where phospholipids were increased [40]. Differences in free choline and PC level in serum have been associated with early markers of risk of having cardiovascular disease (CVD) [41].…”

Section: Discussionmentioning

confidence: 99%

Serum Metabolomic Response of Myasthenia Gravis Patients to Chronic Prednisone Treatment

et al. 2014

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Prednisone is often used for the treatment of autoimmune and inflammatory diseases but they suffer from variable therapeutic responses and significant adverse effects. Serum biological markers that are modulated by chronic corticosteroid use have not been identified. Myasthenia gravis is an autoimmune neuromuscular disorder caused by antibodies directed against proteins present at the post-synaptic surface of neuromuscular junction resulting in weakness. The patients with myasthenia gravis are primarily treated with prednisone. We analyzed the metabolomic profile of serum collected from patients prior to and after 12 weeks of prednisone treatment during a clinical trial. Our aim was to identify metabolites that may be treatment responsive and be evaluated in future studies as potential biomarkers of efficacy or adverse effects. Ultra-performance liquid chromatography coupled with electro-spray quadrupole time of flight mass spectrometry was used to obtain comparative metabolomic and lipidomic profile. Untargeted metabolic profiling of serum showed a clear distinction between pre- and post- treatment groups. Chronic prednisone treatment caused upregulation of membrane associated glycerophospholipids: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, 1, 2-diacyl-sn glycerol 3 phosphate and 1-Acyl-sn-glycero-3-phosphocholine. Arachidonic acid (AA) and AA derived pro-inflammatory eicosanoids such as 18-carboxy dinor leukotriene B4 and 15 hydroxyeicosatetraenoic acids were reduced. Perturbations in amino acid, carbohydrate, vitamin and lipid metabolism were observed. Chronic prednisone treatment caused increase in membrane associated glycerophospholipids, which may be associated with certain adverse effects. Decrease of AA and AA derived pro-inflammatory eicosanoids demonstrate that immunosuppression by corticosteroid is via suppression of pro-inflammatory pathways. The study identified metabolomic fingerprints that can now be validated as prednisone responsive biomarkers for the improvement in diagnostic accuracy and prediction of therapeutic outcome.

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Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma

Abstract: Our study demonstrated the potential of metabolomics to infer asthma-related biomarkers by the identification of potentially deregulated phospholipids that associate with asthma and asthma risk alleles.

Cited by 75 publications

References 31 publications

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

Serum Metabolomic Response of Myasthenia Gravis Patients to Chronic Prednisone Treatment

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