994 results found
Lonati C, Berezhnoy G, Lawler N, et al., 2023, Urinary phenotyping of SARS-CoV-2 infection connects clinical diagnostics with metabolomics and uncovers impaired NAD+ pathway and SIRT1 activation., Clin Chem Lab Med
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.
Serrano-Contreras JI, Lindon JC, Frost G, et al., 2023, Implementation of pure shift 1 H NMR in metabolic phenotyping for structural information recovery of biofluid metabolites with complex spin systems., NMR Biomed
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.
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
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
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
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
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
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.
Loo RL, Chan Q, Nicholson JK, et al., 2022, Balancing the equation: a natural history of trimethylamine and trimethylamine-N-oxide., Journal of Proteome Research, Vol: 21, Pages: 560-589, ISSN: 1535-3893
Trimethylamine (TMA) and its N-oxide (TMAO) are ubiquitous in prokaryote and eukaryote organisms as well as in the environment, reflecting their fundamental importance in evolutionary biology, and their diverse biochemical functions. Both metabolites have multiple biological roles including cell-signaling. Much attention has focused on the significance of serum and urinary TMAO in cardiovascular disease risk, yet this is only one of the many facets of a deeper TMA-TMAO partnership that reflects the significance of these metabolites in multiple biological processes spanning animals, plants, bacteria, and fungi. We report on analytical methods for measuring TMA and TMAO and attempt to critically synthesize and map the global functions of TMA and TMAO in a systems biology framework.
Masuda R, Lodge S, Whiley L, et al., 2022, Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection., Anal Chem
SARS-CoV-2 infection causes a significant reduction in lipoprotein-bound serum phospholipids give rise to supramolecular phospholipid composite (SPC) signals observed in diffusion and relaxation edited 1H NMR spectra. To characterize the chemical structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent analytical techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 positive and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR experiment. This is of specific interest in relation to understanding the potential for in
Nitschke P, Lodge S, Kimhofer T, et al., 2022, J-edited dIffusional proton nuclear magnetic resonance spectroscopic measurement of glycoprotein and supramolecular phospholipid biomarkers of inflammation in human serum., Analytical Chemistry, Vol: 94, Pages: 1333-1341, ISSN: 0003-2700
Proton nuclear magnetic resonance (NMR) N-acetyl signals (Glyc) from glycoproteins and supramolecular phospholipids composite peak (SPC) from phospholipid quaternary nitrogen methyls in subcompartments of lipoprotein particles) can give important systemic metabolic information, but their absolute quantification is compromised by overlap with interfering resonances from lipoprotein lipids themselves. We present a J-Edited DIffusional (JEDI) proton NMR spectroscopic approach to selectively augment signals from the inflammatory marker peaks Glyc and SPCs in blood serum NMR spectra, which enables direct integration of peaks associated with molecules found in specific compartments. We explore a range of pulse sequences that allow editing based on peak J-modulation, translational diffusion, and T2 relaxation time and validate them for untreated blood serum samples from SARS-CoV-2 infected patients (n = 116) as well as samples from healthy controls and pregnant women with physiological inflammation and hyperlipidemia (n = 631). The data show that JEDI is an improved approach to selectively investigate inflammatory signals in serum and may have widespread diagnostic applicability to disease states associated with systemic inflammation.
Koller KR, Wilson A, Normolle DP, et al., 2021, Dietary fibre to reduce colon cancer risk in Alaska Native people: the Alaska FIRST randomised clinical trial protocol., BMJ Open, Vol: 11, Pages: 1-9, ISSN: 2044-6055
INTRODUCTION: Diet, shown to impact colorectal cancer (CRC) risk, is a modifiable environmental factor. Fibre foods fermented by gut microbiota produce metabolites that not only provide food for the colonic epithelium but also exert regulatory effects on colonic mucosal inflammation and proliferation. We describe methods used in a double-blinded, randomised, controlled trial with Alaska Native (AN) people to determine if dietary fibre supplementation can substantially reduce CRC risk among people with the highest reported CRC incidence worldwide. METHODS AND ANALYSES: Eligible patients undergoing routine screening colonoscopy consent to baseline assessments and specimen/data collection (blood, urine, stool, saliva, breath and colon mucosal biopsies) at the time of colonoscopy. Following an 8-week stabilisation period to re-establish normal gut microbiota post colonoscopy, study personnel randomise participants to either a high fibre supplement (resistant starch, n=30) or placebo (digestible starch, n=30) condition, repeating stool sample collection. During the 28-day supplement trial, each participant consumes their usual diet plus their supplement under direct observation. On day 29, participants undergo a flexible sigmoidoscopy to obtain mucosal biopsy samples to measure the effect of the supplement on inflammatory and proliferative biomarkers of cancer risk, with follow-up assessments and data/specimen collection similar to baseline. Secondary outcome measures include the impact of a high fibre supplement on the oral and colonic microbiome and biofluid metabolome. ETHICS AND DISSEMINATION: Approvals were obtained from the Alaska Area and University of Pittsburgh Institutional Review Boards and Alaska Native Tribal Health Consortium and Southcentral Foundation research review bodies. A data safety monitoring board, material transfer agreements and weekly study team meetings provide regular oversight throughout the study. Study findings will first be shared with AN
Masuda R, Lodge S, Nitschke P, et al., 2021, Integrative Modeling of Plasma Metabolic and Lipoprotein Biomarkers of SARS-CoV-2 Infection in Spanish and Australian COVID-19 Patient Cohorts, JOURNAL OF PROTEOME RESEARCH, Vol: 20, Pages: 4139-4152, ISSN: 1535-3893
Gray N, Lawler NG, Zeng AX, et al., 2021, Diagnostic potential of the plasma lipidome in infectious disease: application to acute SARS-CoV-2 infection, Metabolites, Vol: 11, Pages: 1-17, ISSN: 2218-1989
Improved methods are required for investigating the systemic metabolic effects of SARS-CoV-2 infection and patient stratification for precision treatment. We aimed to develop an effective method using lipid profiles for discriminating between SARS-CoV-2 infection, healthy controls, and non-SARS-CoV-2 respiratory infections. Targeted liquid chromatography–mass spectrometry lipid profiling was performed on discovery (20 SARS-CoV-2-positive; 37 healthy controls; 22 COVID-19 symptoms but SARS-CoV-2negative) and validation (312 SARS-CoV-2-positive; 100 healthy controls) cohorts. Orthogonal projection to latent structure-discriminant analysis (OPLS-DA) and Kruskal–Wallis tests were applied to establish discriminant lipids, significance, and effect size, followed by logistic regression to evaluate classification performance. OPLS-DA reported separation of SARS-CoV-2 infection from healthy controls in the discovery cohort, with an area under the curve (AUC) of 1.000. A refined panel of discriminant features consisted of six lipids from different subclasses (PE, PC, LPC, HCER, CER, and DCER). Logistic regression in the discovery cohort returned a training ROC AUC of 1.000 (sensitivity = 1.000, specificity = 1.000) and a test ROC AUC of 1.000. The validation cohort produced a training ROC AUC of 0.977 (sensitivity = 0.855, specificity = 0.948) and a test ROC AUC of 0.978 (sensitivity = 0.948, specificity = 0.922). The lipid panel was also able to differentiate SARS-CoV-2-positive individuals from SARS-CoV-2-negative individuals with COVID-19-like symptoms (specificity = 0.818). Lipid profiling and multivariate modelling revealed a signature offering mechanistic insights into SARS-CoV-2, with strong predictive power, and the potential to facilitate effective diagnosis and clinical management.
Wei GZ, Martin KA, Xing PY, et al., 2021, Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor, Proceedings of the National Academy of Sciences, Vol: 118, Pages: 1-10, ISSN: 0027-8424
While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR−/−) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR–mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
Dorado E, Doria ML, Nagelkerke A, et al., 2021, Lipidomic analysis of extracellular vesicles and its potential for the identification of body fluid-based biomarkers for breast cancer diagnosis., Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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