scholarly journals P003 Metabolomics for improved patient stratification in inflammatory bowel disease: Characterisation of the ulcerative colitis metabolome

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S130-S131
Author(s):  
J Diab ◽  
T Hansen ◽  
R Goll ◽  
H Stenlund ◽  
E Jensen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ulcerative Colitis ◽  
Amino Acid ◽  
Metabolic Pathways ◽  
Personalised Medicine ◽  
Healthy Controls ◽  
Patient Stratification ◽  
Metabolomic Profile ◽  
Metabolic Signature ◽  
Treatment Naïve

Abstract Background The onset of ulcerative colitis (UC) is characterised by a dysregulated mucosal immune response triggered by several genetic and environmental factors in the context of host-microbe interaction. This complexity makes UC ideal for metabolomic studies to unravel the disease pathobiology and to improve the patient stratification strategies toward personalised medicine. This study aims to explore the mucosal metabolomic profile in treatment-naïve and deep remission UC patients, and to define the metabolic signature of UC. Methods Treatment-naive UC patients (n = 18), UC patients in deep remission (n = 10), and healthy volunteers (n = 14) were recruited. Mucosa biopsies were collected during colonoscopy. The UC activity and the state of deep remission were assessed by endoscopy, histology, and by measuring TNF gene expression. Metabolomic analysis was performed by combined gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS) and ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). In total, 177 metabolites from 50 metabolic pathways were identified. Results Multivariate data analysis revealed a distinct metabolomic profile in inflamed mucosa taken from treatment- naïve UC patients compared with non-inflamed mucosa taken from UC remission patients and healthy controls. The mucosal metabolome in UC remission patients differed to a lesser extent from the healthy controls. The most prominent metabolome changes among the study groups were in lysophosphatidylcholine, acylcarnitine, and amino acid profiles. Several metabolic pathways were perturbed, ranging from amino acid metabolism (such as tryptophan metabolism, and alanine, aspartate and glutamate metabolism) to antioxidant defence pathway (glutathione pathway). Furthermore, the pathway analysis revealed a disruption in the long-and short-chain fatty acid (LCFA and SCFA) metabolism, namely linoleic metabolism and butyrate metabolism. Conclusion The mucosal metabolomic profiling revealed a metabolic signature during the onset of UC, and reflected the homeostatic disturbance in the gut. The altered metabolic pathways highlight the importance of system biology approaches to identify key drivers of IBD pathogenesis which prerequisite personalised treatment.

scholarly journals Mucosal Metabolomic Profiling and Pathway Analysis Reveal the Metabolic Signature of Ulcerative Colitis

Metabolites ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 291 ◽  
Author(s):  
Joseph Diab ◽  
Terkel Hansen ◽  
Rasmus Goll ◽  
Hans Stenlund ◽  
Einar Jensen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ulcerative Colitis ◽  
Amino Acid ◽  
Pathway Analysis ◽  
High Performance ◽  
Acid Metabolism ◽  
Study Groups ◽  
Mucosal Immune Response ◽  
Metabolic Signature ◽  
Flight Mass Spectrometry

The onset of ulcerative colitis (UC) is characterized by a dysregulated mucosal immune response triggered by several genetic and environmental factors in the context of host–microbe interaction. This complexity makes UC ideal for metabolomic studies to unravel the disease pathobiology and to improve the patient stratification strategies. This study aims to explore the mucosal metabolomic profile in UC patients, and to define the UC metabolic signature. Treatment- naïve UC patients (n = 18), UC patients in deep remission (n = 10), and healthy volunteers (n = 14) were recruited. Mucosa biopsies were collected during colonoscopies. Metabolomic analysis was performed by combined gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS) and ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). In total, 177 metabolites from 50 metabolic pathways were identified. The most prominent metabolome changes among the study groups were in lysophosphatidylcholine, acyl carnitine, and amino acid profiles. Several pathways were found perturbed according to the integrated pathway analysis. These pathways ranged from amino acid metabolism (such as tryptophan metabolism) to fatty acid metabolism, namely linoleic and butyrate. These metabolic changes during UC reflect the homeostatic disturbance in the gut, and highlight the importance of system biology approaches to identify key drivers of pathogenesis which prerequisite personalized medicine.

Heightened Sulfur Amino Acid Oxidation in Plasma and Erythrocytes in β-Thalassemia Major.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4065-4065
Author(s):  
Anurag K. Agrawal ◽  
Jung H. Suh ◽  
Bruce N. Ames ◽  
Elliott P. Vichinsky ◽  
Ashutosh Lal
Keyword(s):  
Oxidative Stress ◽  
Amino Acid ◽  
Iron Overload ◽  
Metabolic Pathways ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Healthy Controls ◽  
Liver Iron ◽  
Redox States ◽  
Plasma Compartment

Abstract Abstract 4065 Poster Board III-1000 Background Oxidative stress in β-thalassemia major is a well documented problem thought in part to be due to transfusional iron overload. Sulfur amino acid (SAA)-derived metabolites, chiefly glutathione (GSH), are critical components of cellular antioxidant defense. Inability to adequately regulate endogenous antioxidant status may lead to further exacerbation of oxidative stress. To characterize whether alteration in SAA metabolism contributes to heightened oxidative stress in thalassemia, we utilized a novel liquid chromatography linked electrospray positive tandem mass spectrometric (LC-MS/MS) technique to simultaneously quantify the redox states of cysteine (Cys) and GSH as well as the concentrations of major amino acid-derived metabolites in plasma and erythrocytes. Methods After institutional review board approval, adult and pediatric subjects with β-thalassemia major were recruited for fasting blood samples drawn immediately prior to the next scheduled blood transfusion. Plasma and red blood cell samples were analyzed using the LC-MS/MS technique (J Chromatogr B 2009;in press) and compared with healthy controls. Results Twelve subjects with β-thalassemia major were recruited. The median age of the group was 26.5 years (range 11-41). The median liver iron concentration (LIC) determined by ferritometer was 11.9 mg/g dry-wt (range 1.0-34.8). The median ferritin level for the group was 1980 ng/mL (379-4730). Evidence of myocardial iron overload (T2* <20 msec) was present in 5 of 11 subjects. Plasma SAA redox analysis in these subjects showed significant oxidation of Cys and GSH. Total Cys redox status (Cysteine/2*Cystine ratios) decreased from 0.1 ± 0.01 in healthy controls to 0.08 ± 0.02 in thalassemia (p=0.02). Similarly, the plasma GSH redox state (GSH/2*GSSG ratio) decreased from 38.9 ± 13.7 in healthy controls to 6.7 ± 5.3 in thalassemia subjects (p=0.005). The total GSH and total Cys pools in the plasma did not differ between the two groups. Mirroring the patterns observed in the plasma compartment, the proportion of erythrocyte GSSG was also significantly elevated in thalassemia (0.65% vs. 0.04%, p=0.009), without a concomitant decline in total erythrocyte GSH pool. A significant 3-fold elevation in plasma cystathionine and S-adenosylmethionine levels suggests that key SAA metabolic pathways to augment synthesis of GSH may be up-regulated in thalassemia. In addition to alterations in SAA metabolite profiles, the thalassemia group was >3-fold deficient in plasma valine, spermine and citrulline compared with controls. We found that within this small group, the level of iron overload measured by serum ferritin, liver iron concentration and cardiac MRI T2* showed no correlation with the amount of oxidative stress measured by glutathione redox. Discussion Assessment of SAA redox states and metabolic pathways has the potential to be a novel important marker in β-thalassemia major. The alterations in both Cys and GSH redox states without concomitant decline in their total concentration suggests either a significant increased rate of SAA oxidation and/or a decline in the capacity for NADPH-dependent reduction of oxidized disulfides. The latter may be supported by the evidence of profound hypocitrullinemia in thalassemia, which has been noted in subjects with inherited mitochondrial disorders (Proc Nat Acad Sci U S A 2009;106:3941-5). Finally, we show that the oxidative environment in the plasma affects the transfused erythrocytes which acquire characteristics of abnormal thiol metabolites observed in the plasma compartment. The demonstration of significant oxidative stress even in subjects with low body iron burden suggests that currently acceptable LIC levels may not be optimal, or that other contributors to the pro-oxidant state should be sought in thalassemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Elevated colonic microbiota-associated paucimannosidic and truncated N-glycans in pediatric ulcerative colitis

2021 ◽  
Author(s):  
Henghui Li ◽  
Xu Zhang ◽  
Rui Chen ◽  
Kai Cheng ◽  
Zhibin Ning ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Gut Microbiota ◽  
Bowel Disease ◽  
Severe Disease ◽  
Distinct Type ◽  
Rapid Progression ◽  
Treatment Naïve ◽  
Inflammatory Bowel

Pediatric ulcerative colitis (UC) is a distinct type of inflammatory bowel disease with severe disease activity and rapid progression, which can lead to detrimental life-long consequences. The pathogenesis of pediatric UC remains unclear, although dysbiosis of the gut microbiota has been considered an important factor. In this study, we used mass spectrometry-based glycomic approaches to examine the N-glycans that were associated with the intestinal mucosal-luminal interface microbiota cells of treatment-naive pediatric UC or control patients. We observed abundant paucimannosidic and other truncated N-glycans that were associated with the microbiota and found that the pediatric UC microbiota samples contained significantly higher levels of these atypical N-glycans compared to those of controls. This study indicates that intestinal N-glycans may be used as novel UC biomarker candidates and the aberrant metabolism of glycans by gut microbiota may be involved in the pathogenesis of UC in children.

Metabolomic Profile in Patients with Paroxysmal Nocturnal Hemoglobinuria

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2229-2229
Author(s):  
Patricia Eiko Yamakawa ◽  
Ana Rita Da Fonseca ◽  
Matheus Vescovi ◽  
Iara Baldim Rabelo Gomes ◽  
Ismael Dale Cotrim Guerreiro da Silva ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Conflicts Of Interest ◽  
Signs And Symptoms ◽  
Control Group ◽  
Operational Characteristic ◽  
Healthy Controls ◽  
Metabolomic Profile ◽  
Before And After ◽  
Functional Measure

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant clonal disease of hematopoietic cells with a complex pathophysiology and variable clinical spectrum, characterized by signs and symptoms related to intravascular hemolysis, hypercoagulability, and cytopenias. Metaboloma is the end product of an organism's genetic configuration plus the influence of all factors to which it is exposed. Metabolomic profile is able to provide a more accurate functional measure of a phenotype formed by the result of genomic, transcriptomic and proteomic changes. Aims: To compare a metabolomic profile in the PNH hemolytic group with healthy controls, and to compare a metabolomic profile before and after the administration of eculizumab in PNH patients. Methods: To perform metabolomic profile, we used mass spectrometry in 23 patients with hemolytic PNH and in 166 healthy adults, as control group. Twelve PNH patients samples were also collected before and 24 hours after receiving eculizumab. Liquid chromatography with mass spectrometry was performed using the AbsoluteIDQ P180 Biocrates kit (Biocrates, Life Science AG, Innsbruck, Austria): 186 metabolites from 7 different classes were identified and quantified. The data were imported to the analytical site MetaboAnalyst 4.0 and ROCCET: ROC Curve Explorer & Tester for the generation of Univariate and Multivariate Operational Characteristic curves of the Receiver (ROC). Results: In the patients with hemolytic PNH, of the 186 metabolites analyzed, 92 of them showed significant differences between patients and controls, with positive or negative correlation. The major metabolites increased in the PNH group were long-chain acylcarnitines, while the major metabolites reduced in the PNH group were histidine, taurine, glutamate, glutamine, aspartate and phosphatidylcholines. The C14:1/C16:1 ratio lower than 1.4 was shown to be a reliable marker in patients with PNH, suggesting a disorder in lipid elongation. Besides, PNH patients had a significant increase in C6:1 levels and C14:1/C6 and C4/C6 ratios. After receiving eculizumab, patients reached levels comparable to those of normal subject. Conclusion: We observed differences in the metabolome of PNH patients as compared to healthy controls, suggesting a unique metabolomic profile of these patients, characterized by an altered acylcarnitine balance, reduction in aminoacids participating in the glycogenesis pathway and an impaired glutaminolysis. Acylcarnitines levels seem to significantly reduce with the use of eculizumab, demonstrating that the use of the antibody has action in reducing hemolysis and possibly in mitochondrial function of these patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Amino acid and fatty acid metabolomic profile during fasting and hyperinsulinemia in girls with polycystic ovarian syndrome

2019 ◽  
Vol 316 (5) ◽  
pp. E707-E718 ◽  
Author(s):  
Melanie Cree-Green ◽  
Anne-Marie Carreau ◽  
Haseeb Rahat ◽  
Yesenia Garcia-Reyes ◽  
Bryan C. Bergman ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Amino Acid ◽  
Polycystic Ovarian Syndrome ◽  
Metabolomic Profile ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Free Androgen Index ◽  
Metabolic Signature ◽  
Obesity And Diabetes ◽  
Ovarian Syndrome ◽  
Long Chain

Polycystic ovarian syndrome (PCOS) is associated with insulin resistance (IR) and altered muscle mitochondrial oxidative phosphorylation. IR in adults with obesity and diabetes is associated with changes in amino acid, free fatty acid (FFA), and mitochondrial acylcarnitine (AC) metabolism. We sought to determine whether these metabolites are associated with IR and/or androgens in youth-onset PCOS. We enrolled obese girls with PCOS [ n = 15, 14.5 yr (SD 1.6), %BMI 98.5 (SD 1.0)] and without PCOS [ n = 6, 13.2 yr (SD 1.2), %BMI 98.0 (SD 1.1)]. Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp. Untargeted metabolomics of plasma was performed while fasting and during hyperinsulinemia. Fasting arginine, glutamine, histidine, lysine, phenylalanine, and tyrosine were higher ( P < 0.04 for all but P < 0.001 for valine), as were glutamine and histidine during hyperinsulinemia ( P < 0.03). Higher valine during hyperinsulinemia was associated with IR ( r = 0.59, P = 0.006). Surprisingly, end-clamp AC C4 was lower in PCOS, and lower C4 was associated with IR ( r = −0.44, P = 0.04). End-clamp FFAs of C14:0, C16:1, and C18:1 were higher in PCOS girls, and C16:1 and C18:1 strongly associated with IR ( r = 0.73 and 0.53, P < 0.01). Free androgen index related negatively to short-, medium-, and long-chain AC ( r = −0.41 to −0.71, P < 0.01) but not FFA or amino acids. Obese girls with PCOS have a distinct metabolic signature during fasting and hyperinsulinemia. As in diabetes, IR related to valine and FFAs, with an unexpected relationship with AC C4, suggesting unique metabolism in obese girls with PCOS.

scholarly journals Lipidomics in Ulcerative Colitis Reveal Alteration in Mucosal Lipid Composition Associated With the Disease State

2019 ◽  
Vol 25 (11) ◽  
pp. 1780-1787 ◽  
Author(s):  
Joseph Diab ◽  
Terkel Hansen ◽  
Rasmus Goll ◽  
Hans Stenlund ◽  
Maria Ahnlund ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Lipid Metabolism ◽  
Lipid Composition ◽  
High Performance ◽  
Lipid Analysis ◽  
Relative Concentration ◽  
Study Groups ◽  
Disease State ◽  
Healthy Controls ◽  
Treatment Naïve

ABSTRACTBackgroundThe onset of ulcerative colitis (UC) is associated with alterations in lipid metabolism and a disruption of the balance between pro- and anti-inflammatory molecules. Only a few studies describe the mucosal lipid biosignatures during active UC. Moreover, the dynamics of lipid metabolism in the remission state is poorly defined. Therefore, this study aims to characterize mucosal lipid profiles in treatment-naïve UC patients and deep remission UC patients compared with healthy subjects.MethodsTreatment-naïve UC patients (n = 21), UC patients in deep remission (n = 12), and healthy volunteers (n = 14) were recruited. The state of deep remission was defined by histological and immunological remission defined by a normalized TNF-α gene expression. Mucosa biopsies were collected by colonoscopy. Lipid analysis was performed by means of ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS-MS). In total, 220 lipids from 11 lipid classes were identified.ResultsThe relative concentration of 122 and 36 lipids was altered in UC treatment-naïve patients and UC remission patients, respectively, compared with healthy controls. The highest number of significant variations was in the phosphatidylcholine (PC), ceramide (Cer), and sphingomyelin (SM) composition. Multivariate analysis revealed discrimination among the study groups based on the lipid profile. Furthermore, changes in phosphatidylethanolamine(38:3), Cer(d18:1/24:0), and Cer(d18:1/24:2) were most distinctive between the groups.ConclusionThis study revealed a discriminant mucosal lipid composition pattern between treatment-naïve UC patients, deep remission UC patients, and healthy controls. We report several distinctive lipids, which might be involved in the inflammatory response in UC, and could reflect the disease state.

scholarly journals Multi-omic Evaluation of Metabolic Alterations in Multiple Sclerosis Identifies Shifts in Aromatic Amino Acid Metabolism

2021 ◽  
Author(s):  
Kathryn C. Fitzgerald ◽  
Matthew D. Smith ◽  
Elias S. Sotirchos ◽  
Michael D. Kornberg ◽  
Morgan Douglas ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Amino Acid ◽  
Metabolic Pathways ◽  
Aromatic Amino Acid ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
P Value ◽  
Healthy Controls ◽  
Metabolic Dysfunction ◽  
Metabolic Alterations

ABSTRACTThe circulating metabolome is a product of interactions between the genome, epigenome, exposome and microbiome. The metabolome may be altered in people with multiple sclerosis (MS); however, existing metabolomics studies were relatively small or characterized a limited number of metabolites. Herein, we performed a multi-site study profiling the circulating metabolome to obtain relative abundances for 269 metabolites in a large cohort of MS patients and healthy controls. After adjusting for batch effects and extensive quality control, we created an overall metabolic dysfunction score, defined apriori sets of metabolites using known metabolic pathways, and derived novel networks of correlated metabolites using a weighted correlation network analysis (WGCNA). We assessed whether metabolic dysfunction, individual metabolites, metabolic pathways or WGCNA-identified module scores differed between people with MS versus healthy controls (HC) after adjusting for age, sex and race using generalized estimating equations (participants could provide multiple samples). In a subset of patients, information on disability status was also available. Similar models assessed the association between metabolites and metabolite sets with measures of disability. In people with MS, we identified striking abnormalities in a WGCNA-defined module enriched in aromatic amino acid (AAA) metabolites (FDR-adjusted p-value=2.77E-18) that are also strongly associated with disability (FDR-adjusted p-value for AAA module=1.01E-4). Consistent results were obtained using apriori-defined metabolite sets or in analyses of individual metabolites. The identified abnormalities likely relate to imbalances in gut microbial metabolism of AAAs resulting in reduced production of immunomodulatory metabolites and increased production of metabotoxins (indole acetate, phenylacetylglutamine, p-cresol sulfate, p-cresol glucuronide). Single cell RNA sequencing data analysis demonstrated altered AAA metabolism in CSF and blood derived monocyte cell populations, while treatment of human peripheral blood mononuclear cells with AAA-derived metabotoxins resulted in increased production of tumor necrosis factor-α. We identify novel metabolic alterations in people with MS potentially contributing to disease pathophysiology.

A Common Thrombomodulin Amino Acid Dimorphism Is Associated with Myocardial Infarction

1997 ◽  
Vol 77 (02) ◽  
pp. 248-251 ◽  
Author(s):  
Lena Norlund ◽  
Johan Holm ◽  
Bengt Zöller ◽  
Ann-Kristin Öhlin
Keyword(s):  
Myocardial Infarction ◽  
Amino Acid ◽  
Plasma Concentration ◽  
Acute Coronary Syndromes ◽  
Protein C ◽  
Integral Membrane Protein ◽  
Control Group ◽  
Healthy Controls ◽  
Coronary Syndromes ◽  
Premature Myocardial Infarction

SummaryEndothelial dysfunction and haemostatic imbalance are believed to be important aetiological factors in the development of acute coronary syndromes. Thrombomodulin (TM) is an integral membrane protein crucial for normal endothelial function and activation of the protein C anticoagulant pathway. We have investigated the importance of a common C/T dimorphism in the TM gene (nucleotide 1418) for development of premature myocardial infarction (MI). The C/T dimorphism predicts an Ala455 to Val replacement in the sixth EGF-like domain of TM. The dimorphism was investigated in 97 MI survivors and 159 healthy controls. The C allele was significantly more frequent among patients than controls (p = 0.035). The allele frequency for the C allele was 0.82 in the patients and 0.72 in the control group. The plasma concentration of TM was investigated among healthy controls but was not related to the C/T dimorphism. In conclusion, the association of the C allele with premature MI, suggests that the TM gene and the C/T dimorphism may be aetiological factors involved in the pathogenesis of MI. Possibly, the Ala455 to Val replacement may affect the function of the TM molecule and the activation of the protein C anticoagulant pathway.

Statistical Force-Field for Structural Modeling Using Chemical Cross-Linking/mass Spectrometry Distance Constraints

2018 ◽  
Author(s):  
Allan J. R. Ferrari ◽  
Fabio C. Gozzo ◽  
Leandro Martinez
Keyword(s):  
Mass Spectrometry ◽  
Amino Acid ◽  
Force Field ◽  
Protein Structures ◽  
Protein Structure Determination ◽  
Structural Modeling ◽  
Cross Linking ◽  
Amino Acid Residues ◽  
Distance Constraints ◽  
Chemical Cross Linking

<div><p>Chemical cross-linking/Mass Spectrometry (XLMS) is an experimental method to obtain distance constraints between amino acid residues, which can be applied to structural modeling of tertiary and quaternary biomolecular structures. These constraints provide, in principle, only upper limits to the distance between amino acid residues along the surface of the biomolecule. In practice, attempts to use of XLMS constraints for tertiary protein structure determination have not been widely successful. This indicates the need of specifically designed strategies for the representation of these constraints within modeling algorithms. Here, a force-field designed to represent XLMS-derived constraints is proposed. The potential energy functions are obtained by computing, in the database of known protein structures, the probability of satisfaction of a topological cross-linking distance as a function of the Euclidean distance between amino acid residues. The force-field can be easily incorporated into current modeling methods and software. In this work, the force-field was implemented within the Rosetta ab initio relax protocol. We show a significant improvement in the quality of the models obtained relative to current strategies for constraint representation. This force-field contributes to the long-desired goal of obtaining the tertiary structures of proteins using XLMS data. Force-field parameters and usage instructions are freely available at http://m3g.iqm.unicamp.br/topolink/xlff <br></p></div><p></p><p></p>

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