Publications
1003 results found
Chin S-T, Boughton BA, Gay MCL, et al., 2024, Unravelling inulin molecules in food sources using a matrix-assisted laser desorption/ionization magnetic resonance mass spectrometry (MALDI-MRMS) pipeline., Food Res Int, Vol: 184
Inulin, a polysaccharide characterized by a β-2,1 fructosyl-fructose structure terminating in a glucosyl moiety, is naturally present in plant roots and tubers. Current methods provide average degrees of polymerization (DP) but lack information on the distribution and absolute concentration of each DP. To address this limitation, a reproducible (CV < 10 %) high throughput (<2 min/sample) MALDI-MRMS approach capable of characterizing and quantifying inulin molecules in plants using matched-matrix consisting of α-cyano-4-hydroxycinnamic acid butylamine salt (CHCA-BA), chicory inulin-12C and inulin-13C was developed. The method identified variation in chain lengths and concentration of inulin across various plant species. Globe artichoke hearts, yacón and elephant garlic yielded similar concentrations at 15.6 g/100 g dry weight (DW), 16.8 g/100 g DW and 17.7 g/100 g DW, respectively, for DP range between 9 and 22. In contrast, Jerusalem artichoke demonstrated the highest concentration (53.4 g/100 g DW) within the same DP ranges. Jerusalem artichoke (DPs 9-32) and globe artichoke (DPs 9-36) showed similar DP distributions, while yacón and elephant garlic displayed the narrowest and broadest DP ranges (DPs 9-19 and DPs 9-45, respectively). Additionally, qualitative measurement for all inulin across all plant samples was feasible using the peak intensities normalized to Inulin-13C, and showed that the ratio of yacón, elephant garlic and Jerusalem was approximately one, two and three times that of globe artichoke. This MALDI-MRMS approach provides comprehensive insights into the structure of inulin molecules, opening avenues for in-depth investigations into how DP and concentration of inulin influence gut health and the modulation of noncommunicable diseases, as well as shedding light on refining cultivation practices to elevate the beneficial health properties associated with spec
Lodge S, Litton E, Gray N, et al., 2024, Stratification of Sepsis Patients on Admission into the Intensive Care Unit According to Differential Plasma Metabolic Phenotypes., J Proteome Res, Vol: 23, Pages: 1328-1340
Delayed diagnosis of patients with sepsis or septic shock is associated with increased mortality and morbidity. UPLC-MS and NMR spectroscopy were used to measure panels of lipoproteins, lipids, biogenic amines, amino acids, and tryptophan pathway metabolites in blood plasma samples collected from 152 patients within 48 h of admission into the Intensive Care Unit (ICU) where 62 patients had no sepsis, 71 patients had sepsis, and 19 patients had septic shock. Patients with sepsis or septic shock had higher concentrations of neopterin and lower levels of HDL cholesterol and phospholipid particles in comparison to nonsepsis patients. Septic shock could be differentiated from sepsis patients based on different concentrations of 10 lipids, including significantly lower concentrations of five phosphatidylcholine species, three cholesterol esters, one dihydroceramide, and one phosphatidylethanolamine. The Supramolecular Phospholipid Composite (SPC) was reduced in all ICU patients, while the composite markers of acute phase glycoproteins were increased in the sepsis and septic shock patients within 48 h admission into ICU. We show that the plasma metabolic phenotype obtained within 48 h of ICU admission is diagnostic for the presence of sepsis and that septic shock can be differentiated from sepsis based on the lipid profile.
Whiley L, Lawler NG, Zeng AX, et al., 2024, Cross-Validation of Metabolic Phenotypes in SARS-CoV-2 Infected Subpopulations Using Targeted Liquid Chromatography-Mass Spectrometry (LC-MS)., J Proteome Res, Vol: 23, Pages: 1313-1327
To ensure biological validity in metabolic phenotyping, findings must be replicated in independent sample sets. Targeted workflows have long been heralded as ideal platforms for such validation due to their robust quantitative capability. We evaluated the capability of liquid chromatography-mass spectrometry (LC-MS) assays targeting organic acids and bile acids to validate metabolic phenotypes of SARS-CoV-2 infection. Two independent sample sets were collected: (1) Australia: plasma, SARS-CoV-2 positive (n = 20), noninfected healthy controls (n = 22) and COVID-19 disease-like symptoms but negative for SARS-CoV-2 infection (n = 22). (2) Spain: serum, SARS-CoV-2 positive (n = 33) and noninfected healthy controls (n = 39). Multivariate modeling using orthogonal projections to latent structures discriminant analyses (OPLS-DA) classified healthy controls from SARS-CoV-2 positive (Australia; R2 = 0.17, ROC-AUC = 1; Spain R2 = 0.20, ROC-AUC = 1). Univariate analyses revealed 23 significantly different (p < 0.05) metabolites between healthy controls and SARS-CoV-2 positive individuals across both cohorts. Significant metabolites revealed consistent perturbations in cellular energy metabolism (pyruvic acid, and 2-oxoglutaric acid), oxidative stress (lactic acid, 2-hydroxybutyric acid), hypoxia (2-hydroxyglutaric acid, 5-aminolevulinic acid), liver activity (primary bile acids), and host-gut microbial cometabolism (hippuric acid, phenylpropionic acid, indole-3-propionic acid). These data support targeted LC-MS metabolic phenotyping workflows for biological validation in independent sample sets.
Lonati C, Berezhnoy G, Lawler N, et al., 2024, Urinary phenotyping of SARS-CoV-2 infection connects clinical diagnostics with metabolomics and uncovers impaired NAD+ pathway and SIRT1 activation., Clin Chem Lab Med, Vol: 62, Pages: 770-788
OBJECTIVES: The stratification of individuals suffering from acute and post-acute SARS-CoV-2 infection remains a critical challenge. Notably, biomarkers able to specifically monitor viral progression, providing details about patient clinical status, are still not available. Herein, quantitative metabolomics is progressively recognized as a useful tool to describe the consequences of virus-host interactions considering also clinical metadata. METHODS: The present study characterized the urinary metabolic profile of 243 infected individuals by quantitative nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography mass spectrometry (LC-MS). Results were compared with a historical cohort of noninfected subjects. Moreover, we assessed the concentration of recently identified antiviral nucleosides and their association with other metabolites and clinical data. RESULTS: Urinary metabolomics can stratify patients into classes of disease severity, with a discrimination ability comparable to that of clinical biomarkers. Kynurenines showed the highest fold change in clinically-deteriorated patients and higher-risk subjects. Unique metabolite clusters were also generated based on age, sex, and body mass index (BMI). Changes in the concentration of antiviral nucleosides were associated with either other metabolites or clinical variables. Increased kynurenines and reduced trigonelline excretion indicated a disrupted nicotinamide adenine nucleotide (NAD+) and sirtuin 1 (SIRT1) pathway. CONCLUSIONS: Our results confirm the potential of urinary metabolomics for noninvasive diagnostic/prognostic screening and show that the antiviral nucleosides could represent novel biomarkers linking viral load, immune response, and metabolism. Moreover, we established for the first time a casual link between kynurenine accumulation and deranged NAD+/SIRT1, offering a novel mechanism through which SARS-CoV-2 manipulates host physiology.
Roberts JL, Whiley L, Gray N, et al., 2024, Rapid and Self-Administrable Capillary Blood Microsampling Demonstrates Statistical Equivalence with Standard Venous Collections in NMR-Based Lipoprotein Analysis., Anal Chem, Vol: 96, Pages: 4505-4513
We investigated plasma and serum blood derivatives from capillary blood microsamples (500 μL, MiniCollect tubes) and corresponding venous blood (10 mL vacutainers). Samples from 20 healthy participants were analyzed by 1H NMR, and 112 lipoprotein subfraction parameters; 3 supramolecular phospholipid composite (SPC) parameters from SPC1, SPC2, and SPC3 subfractions; 2 N-acetyl signals from α-1-acid glycoprotein (Glyc), GlycA, and GlycB; and 3 calculated parameters, SPC (total), SPC3/SPC2, and Glyc (total) were assessed. Using linear regression between capillary and venous collection sites, we explained that agreement (Adj. R2 ≥ 0.8, p < 0.001) was witnessed for 86% of plasma parameters (103/120) and 88% of serum parameters (106/120), indicating that capillary lipoprotein, SPC, and Glyc concentrations follow changes in venous concentrations. These results indicate that capillary blood microsamples are suitable for sampling in remote areas and for high-frequency longitudinal sampling of the majority of lipoproteins, SPCs, and Glycs.
Sala S, Nitschke P, Masuda R, et al., 2024, Integrative molecular structure elucidation and construction of an extended metabolic pathway associated with an ancient innate immune response in COVID-19 patients, Journal of Proteome Research, Vol: 23, Pages: 956-970, ISSN: 1535-3893
We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.
Serrano-Contreras JI, Lindon JC, Frost G, et al., 2024, Implementation of pure shift 1 H NMR in metabolic phenotyping for structural information recovery of biofluid metabolites with complex spin systems, NMR in Biomedicine, Vol: 37, ISSN: 0952-3480
NMR spectroscopy is a mainstay of metabolic profiling approaches to investigation of physiological and pathological processes. The one-dimensional proton pulse sequences typically used in phenotyping large numbers of samples generate spectra that are rich in information but where metabolite identification is often compromised by peak overlap. Recently developed pure shift (PS) NMR spectroscopy, where all J-coupling multiplicities are removed from the spectra, has the potential to simplify the complex proton NMR spectra that arise from biosamples and hence to aid metabolite identification. Here we have evaluated two complementary approaches to spectral simplification: the HOBS (band-selective with real-time acquisition) and the PSYCHE (broadband with pseudo-2D interferogram acquisition) pulse sequences. We compare their relative sensitivities and robustness for deconvolving both urine and serum matrices. Both methods improve resolution of resonances ranging from doublets, triplets and quartets to more complex signals such as doublets of doublets and multiplets in highly overcrowded spectral regions. HOBS is the more sensitive method and takes less time to acquire in comparison with PSYCHE, but can introduce unavoidable artefacts from metabolites with strong couplings, whereas PSYCHE is more adaptable to these types of spin system, although at the expense of sensitivity. Both methods are robust and easy to implement. We also demonstrate that strong coupling artefacts contain latent connectivity information that can be used to enhance metabolite identification. Metabolite identification is a bottleneck in metabolic profiling studies. In the case of NMR, PS experiments can be included in metabolite identification workflows, providing additional capability for biomarker discovery.
Dorado E, Doria ML, Nagelkerke A, et al., 2024, Extracellular vesicles as a promising source of lipid biomarkers for breast cancer detection in blood plasma., J Extracell Vesicles, Vol: 13
Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication in cancer, from development to metastasis. EV-based liquid biopsy is a promising strategy for cancer diagnosis as EVs can be found in cancer patients' body fluids. In this study, the lipid composition of breast cancer-derived EVs was studied as well as the potential of blood plasma EVs for the identification of lipid biomarkers for breast cancer detection. Initially, an untargeted lipidomic analysis was carried out for a panel of cancerous and non-cancerous mammary epithelial cells and their secreted EVs. We found that breast cancer-derived EVs are enriched in sphingolipids and glycerophospholipids compared to their parental cells. The initial in vitro study showed that EVs and their parental cells can be correctly classified (100% accuracy) between cancerous and non-cancerous, as well as into their respective breast cancer subtypes, based on their lipid composition. Subsequently, an untargeted lipidomic analysis was carried out for blood plasma EVs from women diagnosed with breast cancer (primary or progressive metastatic breast cancer) as well as healthy women. Correspondingly, when blood plasma EVs were analysed, breast cancer patients and healthy women were correctly classified with an overall accuracy of 93.1%, based on the EVs' lipid composition. Similarly, the analysis of patients with primary breast cancer and healthy women showed an overall accuracy of 95% for their correct classification. Furthermore, primary and metastatic breast cancers were correctly classified with an overall accuracy of 89.5%. This reveals that the blood plasma EVs' lipids may be a promising source of biomarkers for detection of breast cancer. Additionally, this study demonstrates the usefulness of untargeted lipidomics in the study of EV lipid composition and EV-associated biomarker discovery studies. This is a proof-of-concept study and a starting point for further analysis on the
Ryan MJ, Raby E, Whiley L, et al., 2023, Nonsevere burn induces a prolonged systemic metabolic phenotype indicative of a persistent inflammatory response postinjury, Journal of Proteome Research, ISSN: 1535-3893
Globally, burns are a significant cause of injury that can cause substantial acute trauma as well as lead to increased incidence of chronic comorbidity and disease. To date, research has primarily focused on the systemic response to severe injury, with little in the literature reported on the impact of nonsevere injuries (<15% total burn surface area; TBSA). To elucidate the metabolic consequences of a nonsevere burn injury, longitudinal plasma was collected from adults (n = 35) who presented at hospital with a nonsevere burn injury at admission, and at 6 week follow up. A cross-sectional baseline sample was also collected from nonburn control participants (n = 14). Samples underwent multiplatform metabolic phenotyping using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry to quantify 112 lipoprotein and glycoprotein signatures and 852 lipid species from across 20 subclasses. Multivariate data modeling (orthogonal projections to latent structures-discriminate analysis; OPLS-DA) revealed alterations in lipoprotein and lipid metabolism when comparing the baseline control to hospital admission samples, with the phenotypic signature found to be sustained at follow up. Univariate (Mann-Whitney U) testing and OPLS-DA indicated specific increases in GlycB (p-value < 1.0e-4), low density lipoprotein-2 subfractions (variable importance in projection score; VIP > 6.83e-1) and monoacyglyceride (20:4) (p-value < 1.0e-4) and decreases in circulating anti-inflammatory high-density lipoprotein-4 subfractions (VIP > 7.75e-1), phosphatidylcholines, phosphatidylglycerols, phosphatidylinositols, and phosphatidylserines. The results indicate a persistent systemic metabolic phenotype that occurs even in cases of a nonsevere burn injury. The phenotype is indicative of an acute inflammatory profile that continues to be sustained postinjury, suggesting an impact on systems health beyond the site of injury. The phenotypes contained metabo
Wist J, Nitschke P, Masuda R, et al., 2023, A-216 Measuring Inflammation and Cardiovascular Markers at Benchtop NMR using Diffusion and Relaxation Edited Experiments, Clinical Chemistry, Vol: 69, ISSN: 0009-9147
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Metabolic phenotyping is an established tool in systems medicine that captures a profile of one’s individual health status and reflects the interaction between genes and external stressors. It uses analytical platforms such as NMR or MS to acquire molecular profiles, and modelling to extract actionable knowledge. Applying these techniques to a cohort of Australians infected by SARS-CoV-2 revealed a strong alteration in regions of 1D NMR spectra associated with lipoproteins and glycoproteins, and referred as Supramolecular Phospholipid Composite SPC (δ = 3.2 ppm) and Glyc (δ = 2.07 ppm). The latter is an established marker of inflammation. These results were later confirmed using larger cohorts from Spain (n = 525) and the UK (n = 1022). The urgent need for very rapid testing, at the early stage of the pandemic, prompted the development of bespoke NMR experiments able to measure this lipoproteins/glycoproteins signature without requiring complex modelling.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Physico-chemical properties of lipoprotein particles, such as diffusion, transverse and longitudinal relaxation rates, differ from low molecular weight metabolites. Therefore, an edited experiment JEDI (PGPE) was designed that combines diffusion, relaxation and scalar coupling editing blocks to produce a lipoprotein profile devoid of chemical noise (overlapping peaks) and where peaks give quantitative results.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The SPC peak was further broken down into 3 sub-regions that are related to the mai
Lodge S, Lawler NGG, Gray N, et al., 2023, Integrative Plasma Metabolic and Lipidomic Modelling of SARS-CoV-2 Infection in Relation to Clinical Severity and Early Mortality Prediction, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24, ISSN: 1661-6596
Begum S, Lodge S, Hall D, et al., 2023, Cardiometabolic disease risk markers are increased following burn injury in children, FRONTIERS IN PUBLIC HEALTH, Vol: 11
Chin S-T, Hoerlendsberger G, Wong KW, et al., 2023, Targeted lipidomics coupled with machine learning for authenticating the provenance of chicken eggs, FOOD CHEMISTRY, Vol: 410, ISSN: 0308-8146
Ryan MJ, Grant-St James A, Lawler NG, et al., 2023, Comprehensive Lipidomic Workflow for Multicohort Population Phenotyping Using Stable Isotope Dilution Targeted Liquid Chromatography-Mass Spectrometry, JOURNAL OF PROTEOME RESEARCH, Vol: 22, Pages: 1419-1433, ISSN: 1535-3893
Ruffieux H, Hanson AL, Lodge S, et al., 2023, A patient-centric modeling framework captures recovery from SARS-CoV-2 infection, NATURE IMMUNOLOGY, Vol: 24, Pages: 349-+, ISSN: 1529-2908
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Posma JM, Perez IG, Karaman I, et al., 2023, Host genomic influence on the gut microbial metabolite-blood pressure relationship, 29th Scientific Meeting of the International Society of Hypertension (Hypertension Kyoto 2022), Publisher: Lippincott, Williams & Wilkins, Pages: E240-E240, ISSN: 0263-6352
Kierath E, Ryan M, Holmes E, et al., 2023, Plasma lipidomics reveal systemic changes persistent throughout early life following a childhood burn injury., Burns Trauma, Vol: 11, ISSN: 2321-3868
BACKGROUND: Non-severe paediatric burns can result in poor long-term health outcomes. This occurs even in cases with good acute burn-related outcomes, including minimal scarring. The mechanisms that underpin the transition from non-severe burn to sustained negative long-term health impacts are currently unknown. However, sustained metabolic and immune changes have been observed in paediatric burn studies, suggesting these changes may be important.The plasma lipidome consists of a rich pool of bioactive metabolites that play critical roles in systemic processes including molecular signalling and inflammation. We hypothesised that changes in the plasma lipidome may reflect underlying changes in health status and be linked to long-term health after burn trauma. METHODS: This study analysed the lipidome in children who had previously experienced a non-severe burn, compared to non-injured controls. Thirty-three participants were recruited between the ages of 5 and 8 years who had experienced a non-severe burn between the ages of 1 and 3 years. Plasma samples were also collected from a non-injured, healthy, age and gender matched control group (n = 21). Plasma lipids were measured using reversed-phase liquid chromatographymass spectrometery (LC-MS). RESULTS: In total 838 reproducible lipid species from 19 sub-classes passed quality control procedures and progressed to statistical analysis. Analysis of individual lipid metabolites showed significantly higher concentrations of lysophosphatidylethanolamines and phosphatidylethanolamines, and significantly lower concentrations in myristic, palmitic and palmitoleic acids in the plasma of those who had experienced burn injury compared to controls. CONCLUSION: Long-term changes in the lipid profile may give insight into the mechanisms underlying poor long-term health subsequent to non-severe burn injury. Further work to investigate the relationship between long-term pathology and lipidomic changes may lea
Rowley CE, Lodge S, Egan S, et al., 2023, Altered dietary behaviour during pregnancy impacts systemic metabolic phenotypes., Front Nutr, Vol: 10, ISSN: 2296-861X
RATIONALE: Evidence suggests consumption of a Mediterranean diet (MD) can positively impact both maternal and offspring health, potentially mediated by a beneficial effect on inflammatory pathways. We aimed to apply metabolic profiling of serum and urine samples to assess differences between women who were stratified into high and low alignment to a MD throughout pregnancy and investigate the relationship of the diet to inflammatory markers. METHODS: From the ORIGINS cohort, 51 pregnant women were stratified for persistent high and low alignment to a MD, based on validated MD questionnaires. 1H Nuclear Magnetic Resonance (NMR) spectroscopy was used to investigate the urine and serum metabolite profiles of these women at 36 weeks of pregnancy. The relationship between diet, metabolite profile and inflammatory status was investigated. RESULTS: There were clear differences in both the food choice and metabolic profiles of women who self-reported concordance to a high (HMDA) and low (LMDA) Mediterranean diet, indicating that alignment with the MD was associated with a specific metabolic phenotype during pregnancy. Reduced meat intake and higher vegetable intake in the HMDA group was supported by increased levels of urinary hippurate (p = 0.044) and lower creatine (p = 0.047) levels. Serum concentrations of the NMR spectroscopic inflammatory biomarkers GlycA (p = 0.020) and GlycB (p = 0.016) were significantly lower in the HDMA group and were negatively associated with serum acetate, histidine and isoleucine (p < 0.05) suggesting a greater level of plant-based nutrients in the diet. Serum branched chain and aromatic amino acids were positively associated with the HMDA group while both urinary and serum creatine, urine creatinine and dimethylamine were positively associated with the LMDA group. CONCLUSION: Metabolic phenotypes of pregnant women who had a high alignment with the MD were signifi
Masuda R, Wist J, Lodge S, et al., 2023, Plasma lipoprotein subclass variation in middle-aged and older adults: Sex-stratified distributions and associations with health status and cardiometabolic risk factors., J Clin Lipidol, Vol: 17, Pages: 677-687, ISSN: 1933-2874
BACKGROUND: Circulating lipids and lipoproteins mediate cardiovascular risk, however routine plasma lipid biochemistry provides limited information on pro-atherogenic remnant particles. OBJECTIVE: We analysed plasma lipoprotein subclasses including very low-density and intermediate-density lipoprotein (VLDL and IDL); and assessed their associations with health and cardiometabolic risk. METHODS: From 1,976 community-dwelling adults aged 45-67 years, 114/1071 women (10.6%) and 153/905 men (16.9%) were categorised as very healthy. Fasting plasma lipoprotein profiles comprising 112 parameters were measured using 1H nuclear magnetic resonance (NMR) spectroscopy, and associations with health status and cardiometabolic risk factors examined. RESULTS: HDL cholesterol was higher, and IDL and VLDL cholesterol and triglycerides lower, in very healthy women compared to other women, and women compared to men. IDL and VLDL cholesterol and triglyceride were lower in very healthy men compared to other men. HDL cholesterol and apolipoprotein (apo) A-I were inversely, and IDL and VLDL cholesterol, apoB-100, and apoB-100/apoA-I ratio directly associated with body mass index (BMI) in women and men. In women, LDL, IDL and VLDL cholesterol increased with age. Women with diabetes and cardiovascular disease had higher cholesterol, triglycerides, phospholipids and free cholesterol across IDL and VLDL fractions, with similar trends for men with diabetes. CONCLUSION: Lipoprotein subclasses and density fractions, and their lipid and apolipoprotein constituents, are differentially distributed by sex, health status and BMI. Very healthy women and men are distinguished by favorable lipoprotein profiles, particularly lower concentrations of VLDL and IDL, providing reference intervals for comparison with general populations and adults with cardiometabolic risk factors.
Yates JR, Cristea IM, Dong M-Q, et al., 2022, Want to Publish in <i>JPR</i>? This Is What You Need to Know!, JOURNAL OF PROTEOME RESEARCH, Vol: 21, Pages: 2837-2839, ISSN: 1535-3893
Gil-Redondo R, Conde R, Bizkarguenaga M, et al., 2022, An NMR-based model to investigate the metabolic phenoreversion of COVID-19 patients throughout a longitudinal study., Metabolites, Vol: 12, Pages: 1-15, ISSN: 2218-1989
After SARS-CoV-2 infection, the molecular phenoreversion of the immunological response and its associated metabolic dysregulation are required for a full recovery of the patient. This process is patient-dependent due to the manifold possibilities induced by virus severity, its phylogenic evolution and the vaccination status of the population. We have here investigated the natural history of COVID-19 disease at the molecular level, characterizing the metabolic and immunological phenoreversion over time in large cohorts of hospitalized severe patients (n = 886) and non-hospitalized recovered patients that self-reported having passed the disease (n = 513). Non-hospitalized recovered patients do not show any metabolic fingerprint associated with the disease or immune alterations. Acute patients are characterized by the metabolic and lipidomic dysregulation that accompanies the exacerbated immunological response, resulting in a slow recovery time with a maximum probability of around 62 days. As a manifestation of the heterogeneity in the metabolic phenoreversion, age and severity become factors that modulate their normalization time which, in turn, correlates with changes in the atherogenesis-associated chemokine MCP-1. Our results are consistent with a model where the slow metabolic normalization in acute patients results in enhanced atherosclerotic risk, in line with the recent observation of an elevated number of cardiovascular episodes found in post-COVID-19 cohorts.
Brignardello J, Fountana S, Posma JM, et al., 2022, Characterization of diet-dependent temporal changes in circulating short-chain fatty acid concentrations: a randomized crossover dietary trial, The American Journal of Clinical Nutrition, Vol: 116, Pages: 1368-1378, ISSN: 0002-9165
Background: Production of Short-chain fatty acids (SCFAs) from food is a complex and dynamic saccharolytic fermentation process mediated by both human and gut microbial factors. SCFA production and knowledge of the relationship between SCFA profiles and dietary patterns is lacking. Objective: Temporal changes in SCFA levels in response to two contrasting diets were investigated using a novel GC-MS method.Design: Samples were obtained from a randomized, controlled, crossover trial designed to characterize the metabolic response to four diets. Participants (n=19) undertook these diets during an inpatient stay (of 72-h). Serum samples were collected 2-h after breakfast (AB), lunch (AL) and dinner (AD) on day 3 and a fasting sample (FA) was obtained on day 4. 24-h urine samples were collected on day 3. In this sub-study, samples from the two extreme diets representing a diet with high adherence to WHO healthy eating recommendations and a typical Western diet were analyzed using a bespoke GC-MS method developed to detect and quantify 10 SCFAs and precursors in serum and urine samples. Results: Considerable inter-individual variation in serum SCFA concentrations was observed across all time points and temporal fluctuations were observed for both diets. Although the sample collection timing exerted a greater magnitude of effect on circulating SCFA concentrations, the unhealthy diet was associated with a lower concentration of acetic acid (FA: coefficient=-17.0; standard error (SE)=5.8; p-trend=0.00615), 2-methylbutyric acid (AL: coefficient=-0.1; SE=0.028; p-trend=4.13x10-4 and AD: coefficient =-0.1; SE:=0.028; p-trend=2.28x10-3) and 2-hydroxybutyric acid (FA: coefficient=-15.8; standard error=5.11; p-trend: 4.09x10-3). In contrast lactic acid was significantly higher in the unhealthy diet (AL: coefficient=750.2; standard error=315.2; p-trend=0.024 and AD: coefficient=1219.3; standard error=322.6; p-trend: 8.28x10-4). Conclusion: The GC-MS method allowed robust mapping of
Yau A, Fear MW, Gray N, et al., 2022, Enhancing the accuracy of surgical wound excision following burns trauma via application of Rapid Evaporative IonisationMass Spectrometry (REIMS), BURNS, Vol: 48, Pages: 1574-1583, ISSN: 0305-4179
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Letertre M, Bhatt A, Harvey M, et al., 2022, Characterizing the metabolic effects of the selective inhibition of gut microbial β-glucuronidases in mice, Scientific Reports, Vol: 12, ISSN: 2045-2322
The hydrolysis of xenobiotic glucuronides by gut bacterial glucuronidases reactivates previously detoxified compounds resulting in severe gut toxicity for the host. Selective bacterial β-glucuronidase inhibitors can mitigate this toxicity but their impact on wider host metabolic processes has not been studied. To investigate this the inhibitor 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4′,5′:4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine (UNC10201652, Inh 9) was administered to mice to selectively inhibit a narrow range of bacterial β-glucuronidases in the gut. The metabolomic profiles of the intestinal contents, biofluids, and several tissues involved in the enterohepatic circulation were measured and compared to control animals. No biochemical perturbations were observed in the plasma, liver or gall bladder. In contrast, the metabolite profiles of urine, colon contents, feces and gut wall were altered compared to the controls. Changes were largely restricted to compounds derived from gut microbial metabolism. This work establishes that inhibitors targeted towards bacterial β-glucuronidases modulate the functionality of the intestinal microbiota without adversely impacting the host metabolic system.
Sanabria J, Egan S, Masuda R, et al., 2022, Overview of the Nomenclature and Network of Contributors to the Development of Bioreactors for Human Gut Simulation Using Bibliometric Tools: A Fragmented Landscape, JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, Vol: 70, Pages: 11458-11467, ISSN: 0021-8561
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Nitschke P, Lodge S, Hall D, et al., 2022, Direct low field J-edited diffusional proton NMR spectroscopic measurement of COVID-19 inflammatory biomarkers in human serum., The Analyst, Vol: 147, Pages: 4213-4221, ISSN: 0003-2654
A JEDI NMR pulse experiment incorporating relaxational, diffusional and J-modulation peak editing has been implemented for a low field (80 MHz proton resonance frequency) spectrometer system to measure quantitatively two recently discovered plasma markers of SARS-CoV-2 infection and general inflammation. JEDI spectra capture a unique signature of two biomarker signals from acetylated glycoproteins (Glyc) and the supramolecular phospholipid composite (SPC) signals that are relatively enhanced by the combination of relaxation, diffusion and J-editing properties of the JEDI experiment that strongly attenuate contributions from the other molecular species in plasma. The SPC/Glyc ratio data were essentially identical in the 600 MHz and 80 MHz spectra obtained (R2 = 0.97) and showed significantly different ratios for control (n = 28) versus SARS-CoV-2 positive patients (n = 29) (p = 5.2 × 10-8 and 3.7 × 10-8 respectively). Simplification of the sample preparation allows for data acquisition in a similar time frame to high field machines (∼4 min) and a high-throughput version with 1 min experiment time could be feasible. These data show that these newly discovered inflammatory biomarkers can be measured effectively on low field NMR instruments that do not not require housing in a complex laboratory environment, thus lowering the barrier to clinical translation of this diagnostic technology.
Begum S, Johnson BZ, Morillon A-C, et al., 2022, Systemic long-term metabolic effects of acute non-severe paediatric burn injury, SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322
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Yeap BB, Marriott RJ, Manning L, et al., 2022, Higher premorbid serum testosterone predicts COVID-19-related mortality risk in men., European Journal of Endocrinology, Vol: 187, Pages: 159-170, ISSN: 0804-4643
Objective: Men are at greater risk from COVID-19 than women. Older, overweight men, and those with type 2 diabetes, have lower testosterone concentrations and poorer COVID-19-related outcomes. We analysed the associations of premorbid serum testosterone concentrations, not confounded by the effects of acute SARS-CoV-2 infection, with COVID-19-related mortality risk in men. Design: This study is a United Kingdom Biobank prospective cohort study of community-dwelling men aged 40-69 years. Methods: Serum total testosterone and sex hormone-binding globulin (SHBG) were measured at baseline (2006-2010). Free testosterone values were calculated (cFT). the incidence of SARS-CoV-2 infections and deaths related to COVID-19 were ascertained from 16 March 2020 to 31 January 2021 and modelled using time-stratified Cox regression. Results: In 159 964 men, there were 5558 SARS-CoV-2 infections and 438 COVID-19 deaths. Younger age, higher BMI, non-White ethnicity, lower educational attainment, and socioeconomic deprivation were associated with incidence of SARS-CoV-2 infections but total testosterone, SHBG, and cFT were not. Adjusting for potential confounders, higher total testosterone was associated with COVID-19-related mortality risk (overall trend P = 0.008; hazard ratios (95% CIs) quintile 1, Q1 vs Q5 (reference), 0.84 (0.65-1.12) Q2:Q5, 0.82 (0.63-1.10); Q3:Q5, 0.80 (0.66-1.00); Q4:Q5, 0.82 (0.75-0.93)). Higher SHBG was also associated with COVID-19 mortality risk (P = 0.008), but cFT was not (P = 0.248). Conclusions: Middle-aged to older men with the highest premorbid serum total testosterone and SHBG concentrations are at greater risk of COVID-19-related mortality. Men could be advised that having relatively high serum testosterone concentrations does not protect against future COVID-19-related mortality. Further investigation of causality and potential underlying mechanisms is warranted.
Mujagic Z, Kasapi M, Jonkers DMAE, et al., 2022, Integrated fecal microbiome–metabolome signatures reflect stress and serotonin metabolism in irritable bowel syndrome, Gut Microbes, Vol: 14, Pages: 1-20, ISSN: 1949-0976
To gain insight into the complex microbiome-gut-brain axis in irritable bowel syndrome (IBS) several modalities of biological and clinical data must be combined. We aimed to identify profiles of faecal microbiota and metabolites associated with IBS and to delineate specific phenotypes of IBS that represent potential pathophysiological mechanisms. Faecal metabolites were measured using proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy and gut microbiome using Shotgun Metagenomic Sequencing (MGS) in a combined dataset of 142 IBS patients and 120 healthy controls (HC) with extensive clinical, biological and phenotype information. Data were analysed using support vector classification and regression and kernel t-SNE. Microbiome and metabolome profiles could distinguish IBS and HC with an area-under-the-receiver-operator-curve (AUC) of 77.3% and 79.5%, respectively, but this could be improved by combining microbiota and metabolites to 83.6%. No significant differences in predictive ability of the microbiome-metabolome data were observed between the three classical, stool pattern-based, IBS subtypes. However, unsupervised clustering showed distinct subsets of IBS patients based on faecal microbiome-metabolome data. These clusters could be related plasma levels of serotonin and its metabolite 5-hydroxyindoleacetate, effects of psychological stress on gastrointestinal symptoms, onset of IBS after stressful events, medical history of previous abdominal surgery, dietary caloric intake and IBS symptom duration. Furthermore, pathways in metabolic reaction networks were integrated with microbiota data, that reflect the host-microbiome interactions in IBS. The identified microbiome-metabolome signatures for IBS, associated with altered serotonin metabolism and unfavourable stress-response related to gastrointestinal symptoms, support the microbiota-gut-brain link in the pathogenesis of IBS.
Nicholson JK, Jia W, Lasky-Su JA, et al., 2022, Metabolic Modeling in Health and Disease, JOURNAL OF PROTEOME RESEARCH, Vol: 21, Pages: 559-559, ISSN: 1535-3893
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