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Spanish National Center for Cardiovascular Research (CNIC)
Metabolomics, gut microbiota, biochemistry, analytical chemistry, biostatitistics, obesity, cardiovascul disease, lipidomics, diabetes, insulin resistance
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María Martínez-López, Salvador Iborra, Ruth Conde-Garrosa, Annalaura Mastrangelo, Camille Danne, Elizabeth R. Mann, Delyth M. Reid, Valérie Gaboriau-Routhiau, Maria Chaparro, María P. Lorenzo, Lara Minnerup, Paula Saz-Leal, Emma Slack, Benjamin Kemp, Javier P. Gisbert, Andrzej Dzionek, Matthew J. Robinson, Francisco J. Rupérez, Nadine Cerf-Bensussan, Gordon D. Brown, David Bernardo, Salomé LeibundGut-Landmann, and David Sancho
Immunity, ISSN: 10747613, eISSN: 10974180, Pages: 446-461.e9, Published: 19 February 2019 Elsevier BV
&NA; Production of interleukin‐17 (IL‐17) and IL‐22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk‐kinase‐coupled signaling pathway in dendritic cells (DCs) was critical for commensal‐dependent production of IL‐17 and IL‐22 by CD4+ T cells. The Syk‐coupled C‐type lectin receptor Mincle detected mucosal‐resident commensals in the Peyer's patches (PPs), triggered IL‐6 and IL‐23p19 expression, and thereby regulated function of intestinal Th17‐ and IL‐17‐secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c+ cells had impaired production of intestinal RegIII&ggr; and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c+ cells reinforces intestinal immune barrier and promotes host‐microbiota mutualism, preventing systemic inflammation. Graphical Abstract Figure. No caption available. HighlightsMincle detects mucosal commensals and triggers IL‐6 and IL‐23p19 in PPsLysoDC and CD11b+ DC from PPs prime a microbiota‐ and Mincle‐Syk‐dependent IL‐17Gut Th17 and ILCs producing IL‐17 and IL‐22 require Mincle and Syk in CD11c+ cellsMincle promotes the gut barrier, limiting microbial translocation and liver inflammation &NA; Martínez‐López et al. explore host signaling pathways linking recognition of commensal microbes and Th17 differentiation. They find that the Mincle‐Syk axis in Peyer's patch DCs detects mucosal‐resident bacteria, inducing IL‐6 and IL‐23p19 and stimulating IL‐17 and IL‐22 production by intestinal T cells and ILCs, which control the intestinal immune barrier function.
Annalaura Mastrangelo, Gabriel Á. Martos-Moreno, Francisco J. Rupérez, Julie A. Chowen, Coral Barbas, and Jesús Argente
Growth Hormone and IGF Research, ISSN: 10966374, eISSN: 15322238, Volume: 42-43, Pages: 28-31, Published: October - December 2018 Elsevier BV
OBJECTIVE Mutations in the pregnancy-associated plasma protein A2 (PAPP-A2) gene have recently been shown to cause postnatal growth failure in two prepubertal patients from a non-consanguineous Spanish family due to the resulting decrease in IGF1 bioavailability. Although a specific pharmacological treatment of this entity is yet to be established, both children received progressive subcutaneous doses (40 to 120 μg/kg) of rhIGF1 twice daily for 2 years. The improvements in growth, hyperinsulinemia and bone mineral density have been previously reported. The objective of this study was to analyze the changes in metabolism associated with these responses to rhIGF1 treatment. DESIGN Herein we present a detailed characterization of the acute and long-term changes in the metabolic profiles of these two siblings with PAPP-A2 deficiency after the initial injections of rhIGF1 and after two years of treatment. RESULTS By using a GC-MS-based untargeted metabolomics approach, metabolic fingerprinting yielded the identification of 70 serum metabolites including amino acids (46%), organic acids (21%) carbohydrates (16%), fatty acids (14%), and purine bases (3%). Free fatty acids (FFAs) and amino acids showed the largest changes in the compared metabolic profiles, suggesting that rhIGF1 treatment has the greatest effects on lipid and protein metabolic pathways in the PAPP-A2 deficient subjects. CONCLUSIONS The administration of rhIGF1 resulted in changes related to crucial metabolic pathways, including lipid and protein metabolism, and this could be associated with the previously reported treatment-induced improvement in the mild basal hyperinsulinemia.
Paulina Samczuk, Magdalena Luba, Joanna Godzien, Annalaura Mastrangelo, Hady Razak Hady, Jacek Dadan, Coral Barbas, Maria Gorska, Adam Kretowski, and Michal Ciborowski
Journal of Pharmaceutical and Biomedical Analysis, ISSN: 07317085, eISSN: 1873264X, Volume: 151, Pages: 219-226, Published: 20 March 2018 Elsevier BV
Graphical abstract Figure. No caption available. HighlightsChanges in metabolism after bariatric surgeries (LSG, LRYGB) were evaluated.Metabolic fingerprinting of serum samples with LC–MS and GC–MS was performed.LSG and RYGB evoked partially different changes in serum metabolome.Modulations of gut microbiota related metabolites were observed.Gear mechanism showing molecular changes evoked by bariatric procedures was proposed. ABSTRACT Mechanisms responsible for metabolic gains after bariatric surgery are not entirely clear. The purpose of this study was evaluation of metabolic changes after laparoscopic Roux‐en‐Y gastric bypass or laparoscopic sleeve gastrectomy in semi‐annual follow up. The study participants were selected from obese patients with T2DM who underwent one of the mentioned bariatric procedures. Serum metabolic fingerprinting by use of liquid and gas chromatography with mass spectrometry detection was performed on samples obtained from studied patients before, one, and six months post‐surgery. Performed analyses resulted in 49 significant and identified metabolites. Comparison of the two described procedures has allowed to detect metabolites linked with numerous pathways, processes and diseases. Based on the metabolites detected and pathways affected, we propose a “gear mechanism” showing molecular changes evoked by both bariatric procedures. Critical evaluation of clinical data and obtained metabolomics results enables us to conclude that both procedures are very similar in terms of general clinical outcome, but they strongly differ from each other in molecular mechanisms leading to the final effect. For the first time general metabolic effect of bariatric procedures is described. New hypotheses concerning molecular mechanisms induced by bariatric surgeries and new gut microbiota modulations are presented.
G Á Martos-Moreno, A Mastrangelo, V Barrios, A García, J A Chowen, F J Rupérez, C Barbas, and J Argente
International Journal of Obesity, ISSN: 03070565, eISSN: 14765497, Pages: 1473-1480, Published: 1 October 2017 Springer Science and Business Media LLC
Background/Objectives:Insulin resistance (IR) is the cornerstone of the obesity-associated metabolic derangements observed in obese children. Targeted metabolomics was employed to explore the pathophysiological relevance of hyperinsulinemia in childhood obesity in order to identify biomarkers of IR with potential clinical application.Subjects/Methods:One hundred prepubertal obese children (50 girls/50 boys, 50% IR and 50% non-IR in each group), underwent an oral glucose tolerance test for usual carbohydrate and lipid metabolism determinations. Fasting serum leptin, total and high molecular weight-adiponectin and high-sensitivity C-reactive protein (CRP) levels were measured and the metabolites showing significant differences between IR and non-IR groups in a previous metabolomics study were quantified. Enrichment of metabolic pathways (quantitative enrichment analysis) and the correlations between lipid and carbohydrate metabolism parameters, adipokines and serum metabolites were investigated, with their discriminatory capacity being evaluated by receiver operating characteristic (ROC) analysis.Results:Twenty-three metabolite sets were enriched in the serum metabolome of IR obese children (P<0.05, false discovery rate (FDR)<5%). The urea cycle, alanine metabolism and glucose-alanine cycle were the most significantly enriched pathways (PFDR<0.00005). The high correlation between metabolites related to fatty acid oxidation and amino acids (mainly branched chain and aromatic amino acids) pointed to the possible contribution of mitochondrial dysfunction in IR. The degree of body mass index-standard deviation score (BMI-SDS) excess did not correlate with any of the metabolomic components studied. In the ROC analysis, the combination of leptin and alanine showed a high IR discrimination value in the whole cohort (area under curve, AUCALL=0.87), as well as in boys (AUCM=0.84) and girls (AUCF=0.91) when considered separately. However, the specific metabolite/adipokine combinations with highest sensitivity were different between the sexes.Conclusions:Combined sets of metabolic, adipokine and metabolomic parameters can identify pathophysiological relevant IR in a single fasting sample, suggesting a potential application of metabolomic analysis in clinical practice to better identify children at risk without using invasive protocols.
Alessia Ferrarini, Laura Righetti, Ma Paz Martínez, Mariano Fernández-López, Annalaura Mastrangelo, Juan P. Horcajada, Antoni Betbesé, Andrés Esteban, Jordi Ordóñez, Joaquín Gea, Jesús Ruiz Cabello, Federica Pellati, José A. Lorente, Nicolás Nin, and Francisco J. Rupérez
Electrophoresis, ISSN: 01730835, eISSN: 15222683, Pages: 2341-2348, Published: September 2017 Wiley
Acute respiratory distress syndrome (ARDS) is a serious complication of influenza A (H1N1) virus infection. Its pathogenesis is unknown and biomarkers are lacking. Untargeted metabolomics allows the analysis of the whole metabolome in a biological compartment, identifying patterns associated with specific conditions. We hypothesized that LC-MS could help identify discriminant metabolites able to define the metabolic alterations occurring in patients with influenza A (H1N1) virus infection that developed ARDS. Serum samples from patients diagnosed with 2009 influenza A (H1N1) virus infection with (n = 25) or without (n = 32) ARDS were obtained on the day of hospital admission and analyzed by LC-MS/MS. Metabolite identification was determined by MS/MS analysis and analysis of standards. The specificity of the patterns identified was confirmed in patients without 2009 influenza A(H1N1) virus pneumonia (15 without and 17 with ARDS). Twenty-three candidate biomarkers were found to be significantly different between the two groups, including lysophospholipids and sphingolipids related to inflammation; bile acids, tryptophan metabolites, and thyroxine, related to the metabolism of the gut microflora. Confirmation results demonstrated the specificity of major alterations occurring in ARDS patients with influenza A (H1N1) virus infection.
Annalaura Mastrangelo and Coral Barbas
Advances in Experimental Medicine and Biology, ISSN: 00652598, eISSN: 22148019, Volume: 965, Pages: 235-263, Published: 1 January 2017 Springer International Publishing
Chronic diseases, also known as noncommunicable diseases (NCDs), are complex disorders that last for long periods of time and progress slowly. They currently account for the major cause of death worldwide with an alarming increase in rate both in developed and developing countries. In this chapter, the principal metabolomic-based investigations on chronic diseases (cardiovascular diseases, diabetes, and respiratory chronic diseases) and their major risk factors (particularly overweight/obesity) are described by focusing both on metabolites and metabolic pathways. Additional information on the contribution of metabolomics strategies in the ambit of the biomarker discovery for NCDs is also provided by exploring the major prospective studies of the last years (i.e., Framingham Heart Study, EPIC, MONICA, KORA, FINRIK, ECLIPSE). The metabolic signature of diseases, which arises from the metabolomic-based investigation, is therefore depicted in the chapter by pointing out the potential of metabolomics to explain the pathophysiological mechanisms underlying a disease, as well as to propose new therapeutic targets for alternative treatments.
A Mastrangelo, G Á Martos-Moreno, A García, V Barrios, F J Rupérez, J A Chowen, C Barbas, and J Argente
International Journal of Obesity, ISSN: 03070565, eISSN: 14765497, Pages: 1494-1502, Published: 1 October 2016 Springer Science and Business Media LLC
Background:Insulin resistance (IR) is usually the first metabolic alteration diagnosed in obese children and the key risk factor for development of comorbidities. The factors determining whether or not IR develops as a result of excess body mass index (BMI) are still not completely understood.Objectives:This study aimed to elucidate the mechanisms underpinning the predisposition toward hyperinsulinemia-related complications in obese children by using a metabolomic strategy that allows a profound interpretation of metabolic profiles potentially affected by IR.Methods:Serum from 60 prepubertal obese children (30 girls/30 boys, 50% IR and 50% non-IR in each group, but with similar BMIs) were analyzed by using liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry and capillary electrophoresis–mass spectrometry following an untargeted metabolomics approach. Validation was then performed on a group of 100 additional children with the same characteristics.Results:When obese children with and without IR were compared, 47 metabolites out of 818 compounds (P<0.05) obtained after data pre-processing were found to be significantly different. Bile acids exhibit the greatest changes (that is, approximately a 90% increase in IR). The majority of metabolites differing between groups were lysophospholipids (15) and amino acids (17), indicating inflammation and central carbon metabolism as the most altered processes in impaired insulin signaling. Multivariate analysis (OPLS-DA models) showed subtle differences between groups that were magnified when females were analyzed alone.Conclusions:Inflammation and central carbon metabolism, together with the contribution of the gut microbiota, are the most altered processes in obese children with impaired insulin signaling in a sex-specific fashion despite their prepubertal status.
Annalaura Mastrangelo, María I. Panadero, Laura M. Pérez, Beatriz G. Gálvez, Antonia García, Coral Barbas, and Francisco J. Rupérez
Biochemical Journal, ISSN: 02646021, eISSN: 14708728, Volume: 473, Pages: 2187-2203, Published: 2016 Portland Press Ltd.
Obesity affects the functional capability of adipose-derived stem cells (ASCs) and their effective use in regenerative medicine through mechanisms that are still poorly understood. In the present study we used a multiplatform [LC/MS, GC/MS and capillary electrophoresis/MS (CE/MS)], metabolomics, untargeted approach to investigate the metabolic alteration underlying the inequalities observed in obesity-derived ASCs. The metabolic fingerprint (metabolites within the cells) and footprint (metabolites secreted in the culture medium), from obesity- and non-obesity-derived ASCs of humans or mice, were characterized to provide valuable information. Metabolites associated with glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and the polyol pathway were increased in the footprint of obesity-derived human ASCs, indicating alterations in carbohydrate metabolism, whereas, from the murine model, deep differences in lipid and amino acid catabolism were highlighted. Therefore, new insights on the ASCs’ metabolome were provided that enhance our understanding of the processes underlying ASCs’ stemness capacity and its relationship with obesity, in different cell models.
Laura M. Pérez, Aurora Bernal, Beatriz de Lucas, Nuria San Martin, Annalaura Mastrangelo, Antonia García, Coral Barbas, and Beatriz G. Gálvez
PLoS ONE, eISSN: 19326203, Published: 13 April 2015 Public Library of Science (PLoS)
Adipose stem cells (ASCs) are an appealing source of cells for therapeutic intervention; however, the environment from which ASCs are isolated may impact their usefulness. Using a range of functional assays, we have evaluated whether ASCs isolated from an obese environment are comparable to cells from non-obese adipose tissue. Results showed that ASCs isolated from obese tissue have a reduced proliferative ability and a loss of viability together with changes in telomerase activity and DNA telomere length, suggesting a decreased self-renewal capacity. Metabolic analysis demonstrated that mitochondrial content and function was impaired in obese-derived ASCs resulting in changes in favored oxidative substrates. These findings highlight the impact of obesity on adult stem properties. Hence, caution should be exercised when considering the source of ASCs for cellular therapies since their therapeutic potential may be impaired.
Annalaura Mastrangelo, Alessia Ferrarini, Fernanda Rey-Stolle, Antonia García, and Coral Barbas
Analytica Chimica Acta, ISSN: 00032670, eISSN: 18734324, Volume: 900, Pages: 21-35, Published: 2015 Elsevier BV
This tutorial provides a comprehensive description of the GC-MS-based untargeted metabolomics workflow including: ethical approval requirement, sample collection and storage, equipment maintenance and setup, sample treatment, monitoring of analytical variability, data pre-processing including deconvolution by free software such as AMDIS, data processing, statistical analysis and validation, detection of outliers and biological interpretation of the results. For each stage tricks will be suggested, pitfalls will be highlighted and advice will be provided on how to get the best from this methodology and technique. In addition, a step-by-step procedure and an example of our in-house library have been included in the supplementary material to lead the user through the concepts described herein. As a case study, an interesting example from one of our experiments at CEMBIO Research Centre is described, presenting an example of the use of this ready-to use protocol for identification of a metabolite that was not previously included in Fiehn commercial target library.
Alicia Navarrete, Emily G. Armitage, Monica Musteanu, Antonia García, Annalaura Mastrangelo, Renata Bujak, Pedro P. López-Casas, Manuel Hidalgo, and Coral Barbas
Pharmacology Research and Perspectives, eISSN: 20521707, Published: December 2014 Wiley
In a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was found to exhibit a biallelic inactivation of the PALB2 gene, involved in DNA repair in addition to another mutation in the TSC2 gene that induces susceptibility of the tumor to therapeutic targets of the PI3K-mTOR pathway. The aim of the study was to apply metabolomics to elucidate the modes of action of each therapy, suggesting why MMC was so successful in this patient and why it could be a more popular choice in future pancreatic cancer treatment. The effectiveness of MMC compared to rapamycin (RM), another relevant therapeutic agent has been evaluated through liquid- and gas-chromatography mass spectrometry-based metabolomic analyses of the xenograft tumors. The relative concentrations of many metabolites in the xenograft tumors were found to be increased by MMC relative to other treatments (RM and a combination of both), including a number that are involved in central carbon metabolism (CCM). Metabolic fingerprinting revealed statistically significantly altered pathways including, but not restricted to, the pentose phosphate pathway, glycolysis, TCA cycle, purine metabolism, fatty acid biosynthesis, in addition to many significant lipid and amino acid alterations. Given the genetic background of the patient, it was expected that the combined therapy would be most effective; however, the most effective was MMC alone. It is proposed that the effectiveness of MMC is owed to its direct effect on CCM, a vital region of tumor metabolism.
Current Topics in Medicinal Chemistry, ISSN: 15680266, eISSN: 18734294, Pages: 2627-2636, Published: 1 January 2014