Publications
746 results found
Collier DA, Ferreira IATM, Kotagiri P, et al., 2021, Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2, NATURE, Vol: 596, Pages: 417-+, ISSN: 0028-0836
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- Citations: 368
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
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- Citations: 19
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.
Thompson A, Bourke C, Robertson R, et al., 2021, Understanding the role of the gut in undernutrition: what can technology tell us?, Gut, Vol: 70, Pages: 1580-1594, ISSN: 0017-5749
Gut function remains largely underinvestigated in undernutrition, despite its critical role in essential nutrient digestion, absorption and assimilation. In areas of high enteropathogen burden, alterations in gut barrier function and subsequent inflammatory effects are observable but remain poorly characterised. Environmental enteropathy (EE)—a condition that affects both gut morphology and function and is characterised by blunted villi, inflammation and increased permeability—is thought to play a role in impaired linear growth (stunting) and severe acute malnutrition. However, the lack of tools to quantitatively characterise gut functional capacity has hampered both our understanding of gut pathogenesis in undernutrition and evaluation of gut-targeted therapies to accelerate nutritional recovery. Here we survey the technology landscape for potential solutions to improve assessment of gut function, focussing on devices that could be deployed at point-of-care in low-income and middle-income countries (LMICs). We assess the potential for technological innovation to assess gut morphology, function, barrier integrity and immune response in undernutrition, and highlight the approaches that are currently most suitable for deployment and development. This article focuses on EE and undernutrition in LMICs, but many of these technologies may also become useful in monitoring of other gut pathologies.
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.
Martinez-Gili L, Pechlivanis A, Begum S, et al., 2021, PO-799: Response failure to ursodeoxycholic acid treatment in primary biliary cholangitis is associated with a distinct stool and urine secondary bile acid profile, International Liver Congress (ILC2021), Publisher: Elsevier, Pages: S404-S405, ISSN: 0168-8278
Posma JM, Garcia-Perez I, Frost G, et al., 2021, Nutriome-metabolome relationships provide insights into dietary intake and metabolism (vol 1, pg 426, 2020), NATURE FOOD, Vol: 2, Pages: 541-542
Li J, 2021, Roux-en-Y Gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype, Microbiome, Vol: 9, ISSN: 2049-2618
BACKGROUND: Bariatric surgery, used to achieve effective weight loss in individuals with severe obesity, modifies the gut microbiota and systemic metabolism in both humans and animal models. The aim of the current study was to understand better the metabolic functions of the altered gut microbiome by conducting deep phenotyping of bariatric surgery patients and bacterial culturing to investigate causality of the metabolic observations. METHODS: Three bariatric cohorts (n = 84, n = 14 and n = 9) with patients who had undergone Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or laparoscopic gastric banding (LGB), respectively, were enrolled. Metabolic and 16S rRNA bacterial profiles were compared between pre- and post-surgery. Faeces from RYGB patients and bacterial isolates were cultured to experimentally associate the observed metabolic changes in biofluids with the altered gut microbiome. RESULTS: Compared to SG and LGB, RYGB induced the greatest weight loss and most profound metabolic and bacterial changes. RYGB patients showed increased aromatic amino acids-based host-bacterial co-metabolism, resulting in increased urinary excretion of 4-hydroxyphenylacetate, phenylacetylglutamine, 4-cresyl sulphate and indoxyl sulphate, and increased faecal excretion of tyramine and phenylacetate. Bacterial degradation of choline was increased as evidenced by altered urinary trimethylamine-N-oxide and dimethylamine excretion and faecal concentrations of dimethylamine. RYGB patients' bacteria had a greater capacity to produce tyramine from tyrosine, phenylalanine to phenylacetate and tryptophan to indole and tryptamine, compared to the microbiota from non-surgery, normal weight individuals. 3-Hydroxydicarboxylic acid metabolism and urinary excretion of primary bile acids, serum BCAAs and dimethyl sulfone were also perturbed following bariatric surgery. CONCLUSION: Altered bacterial composition and metabolism contribute to metabolic observations in biofluid
Bergamaschi L, Mescia F, Turner L, et al., 2021, Longitudinal analysis reveals that delayed bystander CD8<sub>+</sub> T cell activation and early immune pathology distinguish severe COVID-19 from mild disease, IMMUNITY, Vol: 54, Pages: 1257-+, ISSN: 1074-7613
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- Citations: 127
Kimhofer T, Lodge S, Whiley L, et al., 2021, Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection (vol 19, pg 4442, 2020), JOURNAL OF PROTEOME RESEARCH, Vol: 20, Pages: 3400-3400, ISSN: 1535-3893
Holmes E, Wist J, Masuda R, et al., 2021, Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome, Journal of Proteome Research, Vol: 20, Pages: 3315-3329, ISSN: 1535-3893
Calder N, Walsh K, Olupot-Olupot P, et al., 2021, Modifying gut integrity and microbiome in children with severe acute malnutrition using LEgume-Based Feeds [MIMBLE]: A pilot trial, Cell Reports Medicine, Vol: 2, Pages: 1-17, ISSN: 2666-3791
Case fatality among African children with severe acute malnutrition remains high. We report a 3-arm pilot trial in 58 Ugandan children, comparing feeds targeting disordered gastrointestinal function containing cowpea (CpF, n = 20) or inulin (InF, n = 20) with conventional feeds (ConF, n = 18). Baseline measurements of gut permeability (lactulose:mannitol ratio 1.19 ± SD 2.00), inflammation (fecal calprotectin 539.0 μg/g, interquartile range [IQR] 904.8), and satiety (plasma polypeptide YY 62.6 pmol/l, IQR 110.3) confirm gastrointestinal dysfunction. By day 28, no differences are observable in proportion achieving weight gain >5 g/kg/day (87%, 92%, 86%; p > 0.05), mortality (16%, 30%, 17%; p > 0.05), or edema resolution (83%, 54%, 91%; p > 0.05) among CpF, InF, and ConF. Decreased fecal bacterial richness from day 1 (abundance-based coverage estimator [ACE] 53.2) to day 7 (ACE 40.8) is observed only in ConF (p = 0.025). Bifidobacterium relative abundance increases from day 7 (5.8% ± 8.6%) to day 28 (10.9% ± 8.7%) in CpF (corrected p = 1.000). Legume-enriched feeds support aspects of gut function and the microbiome. Trial registration PACTR201805003381361.
Hoyles L, Mayneris-Perxachs J, Cardellini M, et al., 2021, Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome, Microbiome, Vol: 9, Pages: 1-18, ISSN: 2049-2618
Background: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear.Results: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The
Lawler NG, Gray N, Kimhofer T, et al., 2021, Systemic perturbations in amine and kynurenine metabolism associated with acute SARS-CoV-2 infection and inflammatory cytokine responses, Journal of Proteome Research, Vol: 20, Pages: 2796-2811, ISSN: 1535-3893
We performed quantitative metabolic phenotyping of blood plasma in parallel with cytokine/chemokine analysis from participants who were either SARS-CoV-2 (+) (n = 10) or SARS-CoV-2 (-) (n = 49). SARS-CoV-2 positivity was associated with a unique metabolic phenotype and demonstrated a complex systemic response to infection, including severe perturbations in amino acid and kynurenine metabolic pathways. Nine metabolites were elevated in plasma and strongly associated with infection (quinolinic acid, glutamic acid, nicotinic acid, aspartic acid, neopterin, kynurenine, phenylalanine, 3-hydroxykynurenine, and taurine; p < 0.05), while four metabolites were lower in infection (tryptophan, histidine, indole-3-acetic acid, and citrulline; p < 0.05). This signature supports a systemic metabolic phenoconversion following infection, indicating possible neurotoxicity and neurological disruption (elevations of 3-hydroxykynurenine and quinolinic acid) and liver dysfunction (reduction in Fischer’s ratio and elevation of taurine). Finally, we report correlations between the key metabolite changes observed in the disease with concentrations of proinflammatory cytokines and chemokines showing strong immunometabolic disorder in response to SARS-CoV-2 infection.
Collier DA, De Marco A, Ferreira IATM, et al., 2021, Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies, NATURE, Vol: 593, Pages: 136-+, ISSN: 0028-0836
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- Citations: 39
Gallagher K, Catesson A, Griffin JL, et al., 2021, Metabolomic analysis in inflammatory bowel disease: a systematic review, Journal of Crohns & Colitis, Vol: 15, Pages: 813-826, ISSN: 1873-9946
BACKGROUND AND AIMS: The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are chronic, idiopathic gastrointestinal (GI) diseases. Whilst their precise etiology is unknown, it is thought to involve a complex interaction between genetic predisposition and an abnormal host immune response to environmental exposures, likely microbial. Microbial dysbiosis has frequently been documented in IBD. Metabolomics (the study of small molecular intermediates and end products of metabolism in biological samples) provides a unique opportunity to characterize disease-associated metabolic changes and may be of particular use in quantifying gut microbial metabolism. Numerous metabolomic studies have been undertaken in inflammatory bowel disease populations, identifying consistent alterations in a range of molecules across several biological matrices. This systematic review aims to summarize these findings. METHODS: A comprehensive, systematic search was carried out using Medline and EMBASE. All studies were reviewed by two authors independently using predefined exclusion criteria. A total of sixty-four relevant papers were quality assessed and included in the review. RESULTS: Consistent metabolic perturbations were identified, including increases in levels of branched chain amino acids and lipid classes across stool, serum, plasma and tissue biopsy samples, and reduced levels of microbially modified metabolites in both urine (such as hippurate) and stool (such as secondary bile acids). CONCLUSIONS: This review provides a summary of metabolomic research in IBD to date, highlighting underlying themes of perturbed gut microbial metabolism and mammalian-microbial co-metabolism associated with disease status.
Kemp SA, Collier DA, Datir RP, et al., 2021, SARS-CoV-2 evolution during treatment of chronic infection, NATURE, Vol: 592, Pages: 277-+, ISSN: 0028-0836
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- Citations: 417
Posma JM, Stamler J, Garcia-Perez I, et al., 2021, Urinary metabolic phenotype of blood pressure, 19TH INTERNATIONAL SHR SYMPOSIUM SHR, Publisher: Lippincott, Williams & Wilkins, Pages: E70-E70, ISSN: 0263-6352
Objective: Metabolic phenotyping (metabolomics) captures systems-level information on metabolic processes by simultaneously measuring hundreds of metabolites using spectroscopic techniques. Concentrations of these metabolites are affected by genetic (host, microbiome), environmental and dietary factors and may provide insights into biochemical pathways underlying raised blood pressure (BP) in populations.Design and method: Two separate, timed 24hr urine specimens were obtained from 2,031 women and men, aged 40–59, from 8 USA population samples in the INTERMAP Study. Proton Nuclear Magnetic Resonance (1H NMR) was used to characterize a urinary metabolic signature; this was unaffected by diurnal variability and sampling time as it captures end-products of metabolism over a 24hr period. Demographic, population, medical, lifestyle and anthropometric factors were accounted for in regression models to define a urinary metabolic phenotype associated with BP.Results: 29 structurally identified urinary metabolites covaried with systolic BP (SBP), after adjustment for demographic variables, and 18 metabolites with diastolic BP (DBP), with 16 metabolites overlapping between SBP and DBP. These included metabolites related to energy metabolism, renal function, diet and gut microbiota. After adjustment for medical and lifestyle covariates, 22/14 metabolites remained associated with SBP/DBP. Joint covariate-metabolite penalized regression models identified Body Mass Index, age and family history as most important contributors, with 14 metabolites, including gut microbial co-metabolites, also included in the model. Metabolites were mapped in a symbiotic metabolic reaction network, that includes reactions mediated by 3,344 commensal gut microbial species, to highlight affected pathways (Figure). Significant single nucleotide polymorphisms (SNPs) from genome-wide association studies on cardiometabolic risk factors were mapped to genes in this network. This revealed multiple sub
Lodge S, Nitschke P, Kimhofer T, et al., 2021, Diffusion and relaxation edited proton NMR spectroscopy of plasma reveals a high-fidelity supramolecular biomarker signature of SARS-CoV-2 infection, Analytical Chemistry, Vol: 93, Pages: 3976-3986, ISSN: 0003-2700
We have applied nuclear magnetic resonance spectroscopy based plasma phenotyping to reveal diagnostic molecular signatures of SARS-CoV-2 infection via combined diffusional and relaxation editing (DIRE). We compared plasma from healthy age-matched controls (n = 26) with SARS-CoV-2 negative non-hospitalized respiratory patients and hospitalized respiratory patients (n = 23 and 11 respectively) with SARS-CoV-2 rRT-PCR positive respiratory patients (n = 17, with longitudinal sampling time-points). DIRE data were modelled using principal component analysis and orthogonal projections to latent structures discriminant analysis (O-PLS-DA), with statistical cross-validation indices indicating excellent model generalization for the classification of SARS-CoV-2 positivity for all comparator groups (area under the receiver operator characteristic curve = 1). DIRE spectra show biomarker signal combinations conferred by differential concentrations of metabolites with selected molecular mobility properties. These comprise the following: (a) composite N-acetyl signals from α-1-acid glycoprotein and other glycoproteins (designated GlycA and GlycB) that were elevated in SARS-CoV-2 positive patients [p = 2.52 × 10–10 (GlycA) and 1.25 × 10–9 (GlycB) vs controls], (b) two diagnostic supramolecular phospholipid composite signals that were identified (SPC-A and SPC-B) from the –+N–(CH3)3 choline headgroups of lysophosphatidylcholines carried on plasma glycoproteins and from phospholipids in high-density lipoprotein subfractions (SPC-A) together with a phospholipid component of low-density lipoprotein (SPC–B). The integrals of the summed SPC signals (SPCtotal) were reduced in SARS-CoV-2 positive patients relative to both controls (p = 1.40 × 10–7) and SARS-CoV-2 negative patients (p = 4.52 × 10–8) but were not significantly different between controls and SARS-CoV-2 negative patients. The identity of the SPC signal comp
Barton W, Cronin O, GarciaPerez I, et al., 2021, The effects of sustained fitness improvement on the gut microbiome: A longitudinal, repeated measures case‐study approach, Translational Sports Medicine, Vol: 4, Pages: 174-192, ISSN: 2573-8488
The athlete gut microbiome differs from that of non‐athletes in its composition and metabolic function. Short‐term fitness improvement in sedentary adults does not replicate the microbiome characteristics of athletes. The objective of this study was to investigate whether sustained fitness improvement leads to pronounced alterations in the gut microbiome. This was achieved using a repeated‐measures, case‐study approach that examined the gut microbiome of two initially unfit volunteers undertaking progressive exercise training over a 6‐month period. Samples were collected every two weeks, and microbiome, metabolome, diet, body composition, and cardiorespiratory fitness data were recorded. Training culminated in both participants completing their respective goals (a marathon or Olympic‐distance triathlon) with improved body composition and fitness parameters. Increases in gut microbiota α‐diversity occurred with sustained training and fluctuations occurred in response to training events (eg, injury, illness, and training peaks). Participants’ BMI reduced during the study and was significantly associated with increased urinary measurements of N‐methyl nicotinate and hippurate, and decreased phenylacetylglutamine. These results suggest that sustained fitness improvements support alterations to gut microbiota and physiologically‐relevant metabolites. This study provides longitudinal analysis of the gut microbiome response to real‐world events during progressive fitness training, including intercurrent illness and injury.
Lodge S, Nitschke P, Loo RL, et al., 2021, Low volume in vitro diagnostic proton NMR spectroscopy of human blood plasma for lipoprotein and metabolite analysis: application to SARS-CoV-2 biomarkers., Journal of Proteome Research, Vol: 20, Pages: 1415-1423, ISSN: 1535-3893
The utility of low sample volume in vitro diagnostic (IVDr) proton nuclear magnetic resonance (1H NMR) spectroscopic experiments on blood plasma for information recovery from limited availability or high value samples was exemplified using plasma from patients with SARS-CoV-2 infection and normal controls. 1H NMR spectra were obtained using solvent-suppressed 1D, spin-echo (CPMG), and 2-dimensional J-resolved (JRES) spectroscopy using both 3 mm outer diameter SampleJet NMR tubes (100 μL plasma) and 5 mm SampleJet NMR tubes (300 μL plasma) under in vitro diagnostic conditions. We noted near identical diagnostic models in both standard and low volume IVDr lipoprotein analysis (measuring 112 lipoprotein parameters) with a comparison of the two tubes yielding R2 values ranging between 0.82 and 0.99 for the 40 paired lipoprotein parameters samples. Lipoprotein measurements for the 3 mm tubes were achieved without time penalty over the 5 mm tubes as defined by biomarker recovery for SARS-CoV-2. Overall, biomarker pattern recovery for the lipoproteins was extremely similar, but there were some small positive offsets in the linear equations for several variables due to small shimming artifacts, but there was minimal degradation of the biological information. For the standard untargeted 1D, CPMG, and JRES NMR experiments on the same samples, the reduced signal-to-noise was more constraining and required greater scanning times to achieve similar differential diagnostic performance (15 min per sample per experiment for 3 mm 1D and CPMG, compared to 4 min for the 5 mm tubes). We conclude that the 3 mm IVDr method is fit-for-purpose for quantitative lipoprotein measurements, allowing the preparation of smaller volumes for high value or limited volume samples that is common in clinical studies. If there are no analytical time constraints, the lower volume experiments are equally informative for untargeted profiling.
Lodge S, Nitschke P, Kimhofer T, et al., 2021, NMR spectroscopic windows on the systemic effects of SARS-CoV-2 infection on plasma lipoproteins and metabolites in relation to circulating cytokines., Journal of Proteome Research, Vol: 20, Pages: 1382-1396, ISSN: 1535-3893
To investigate the systemic metabolic effects of SARS-CoV-2 infection, we analyzed 1H NMR spectroscopic data on human blood plasma and co-modeled with multiple plasma cytokines and chemokines (measured in parallel). Thus, 600 MHz 1H solvent-suppressed single-pulse, spin-echo, and 2D J-resolved spectra were collected on plasma recorded from SARS-CoV-2 rRT-PCR-positive patients (n = 15, with multiple sampling timepoints) and age-matched healthy controls (n = 34, confirmed rRT-PCR negative), together with patients with COVID-19/influenza-like clinical symptoms who tested SARS-CoV-2 negative (n = 35). We compared the single-pulse NMR spectral data with in vitro diagnostic research (IVDr) information on quantitative lipoprotein profiles (112 parameters) extracted from the raw 1D NMR data. All NMR methods gave highly significant discrimination of SARS-CoV-2 positive patients from controls and SARS-CoV-2 negative patients with individual NMR methods, giving different diagnostic information windows on disease-induced phenoconversion. Longitudinal trajectory analysis in selected patients indicated that metabolic recovery was incomplete in individuals without detectable virus in the recovery phase. We observed four plasma cytokine clusters that expressed complex differential statistical relationships with multiple lipoproteins and metabolites. These included the following: cluster 1, comprising MIP-1β, SDF-1α, IL-22, and IL-1α, which correlated with multiple increased LDL and VLDL subfractions; cluster 2, including IL-10 and IL-17A, which was only weakly linked to the lipoprotein profile; cluster 3, which included IL-8 and MCP-1 and were inversely correlated with multiple lipoproteins. IL-18, IL-6, and IFN-γ together with IP-10 and RANTES exhibited strong positive correlations with LDL1-4 subfractions and negative correlations with multiple HDL subfractions. Collectively, these data show a distinct pattern indicative of a multilevel cellular immune resp
Seyfried F, Phetcharaburanin J, Glymenaki M, et al., 2021, Roux-en-Y gastric bypass surgery in Zucker rats induces bacterial and systemic metabolic changes independent of caloric restriction-induced weight loss, Gut Microbes, Vol: 13, Pages: 1-20, ISSN: 1949-0976
Mechanisms of Roux-en-Y gastric bypass (RYGB) surgery are not fully understood. This study aimed to investigate weight loss-independent bacterial and metabolic changes, as well as the absorption of bacterial metabolites and bile acids through the hepatic portal system following RYGB surgery. Three groups of obese Zucker (fa/fa) rats were included: RYGB (n = 11), sham surgery and body weight matched with RYGB (Sham-BWM, n = 5), and sham surgery fed ad libitum (Sham-obese, n = 5). Urine and feces were collected at multiple time points, with portal vein and peripheral blood obtained at the end of the study. Metabolic phenotyping approaches and 16S rRNA gene sequencing were used to determine the biochemical and bacterial composition of the samples, respectively. RYGB surgery-induced distinct metabolic and bacterial disturbances, which were independent of weight loss through caloric restriction. RYGB resulted in lower absorption of phenylalanine and choline, and higher urinary concentrations of host-bacterial co-metabolites (e.g., phenylacetylglycine, indoxyl sulfate), together with higher fecal trimethylamine, suggesting enhanced bacterial aromatic amino acid and choline metabolism. Short chain fatty acids (SCFAs) were lower in feces and portal vein blood from RYGB group compared to Sham-BWM, accompanied with lower abundances of Lactobacillaceae, and Ruminococcaceae known to contain SCFA producers, indicating reduced bacterial fiber fermentation. Fecal γ-amino butyric acid (GABA) was found in higher concentrations in RYGB than that in Sham groups and could play a role in the metabolic benefits associated with RYGB surgery. While no significant difference in urinary BA excretion, RYGB lowered both portal vein and circulating BA compared to Sham groups. These findings provide a valuable resource for how dynamic, multi-systems changes impact on overall metabolic health, and may provide potential therapeutic targets for developing downstream non-surgical treatment for
Jimenez B, Abellona MRU, Drymousis P, et al., 2021, Neuroendocrine neoplasms: identification of novel metabolic circuits of potential diagnostic utility, Cancers, Vol: 13, ISSN: 2072-6694
The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36–85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker 1H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.
Whiley L, Chappell KE, D'Hondt E, et al., 2021, Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer's disease, Alzheimers Research & Therapy, Vol: 13, Pages: 1-18, ISSN: 1758-9193
BackgroundBoth serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer’s disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls.MethodsMetabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations.ResultsResults revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced o
Gallagher K, Radhakrishnan ST, Li JV, et al., 2021, DEVELOPMENT OF A TARGETED METABOLOMIC URINE-BASED PANEL FOR INFLAMMATORY BOWEL DISEASE, Publisher: BMJ PUBLISHING GROUP, Pages: A114-A114, ISSN: 0017-5749
Kurbatova N, Garg M, Whiley L, et al., 2020, Urinary metabolic phenotyping for Alzheimer's disease, Scientific Reports, Vol: 10, ISSN: 2045-2322
Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer’s Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer’s Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer’s Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer’s Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer’s pathology in previous studies.
Lau CH, Taylor-Bateman V, Vorkas PA, et al., 2020, Metabolic signatures of gestational weight gain and postpartum weight loss in a lifestyle intervention study of overweight and obese women, Metabolites, Vol: 10, ISSN: 2218-1989
BACKGROUND: Overweight and obesity amongst women of reproductive age are increasingly common in developed economies and are shown to adversely affect birth outcomes and both childhood and adulthood health risks in the offspring. Metabolic profiling in conditions of overweight and obesity in pregnancy could potentially be applied to elucidate the molecular basis of the adverse effects of gestational weight gain (GWG) and postpartum weight loss (WL) on future risks for cardiovascular disease (CVD) and other chronic diseases. METHODS: Biofluid samples were collected from 114 ethnically diverse pregnant women with body mass index (BMI) between 25 and 40 kg/m2 from Chicago (US), as part of a randomized lifestyle intervention trial (Maternal Offspring Metabolics: Family Intervention Trial; NCT01631747). At 15 weeks, 35 weeks of gestation, and at 1 year postpartum, the blood plasma lipidome and metabolic profile of urine samples were analyzed by liquid chromatography mass spectrometry (LC-MS) and 1H nuclear magnetic resonance spectroscopy (1H NMR) respectively. RESULTS: Urinary 4-deoxyerythronic acid and 4-deoxythreonic acid were found to be positively correlated to BMI. Seventeen plasma lipids were found to be associated with GWG and 16 lipids were found to be associated with WL, which included phosphatidylinositols (PI), phosphatidylcholines (PC), lysophospholipids (lyso-), sphingomyelins (SM) and ether phosphatidylcholine (PC-O). Three phospholipids found to be positively associated with GWG all contained palmitate side-chains, and amongst the 14 lipids that were negatively associated with GWG, seven were PC-O. Six of eight lipids found to be negatively associated with WL contained an 18:2 fatty acid side-chain. CONCLUSIONS: Maternal obesity was associated with characteristic urine and plasma metabolic phenotypes, and phospholipid profile was found to be associated with both GWG and postpartum WL in metabolically healthy pregnant women with overweight/obesity. Postpartu
Penney N, Barton W, Posma J, et al., 2020, Investigating the role of diet and exercise in gut microbe-hostcometabolism, mSystems, Vol: 5, Pages: 1-16, ISSN: 2379-5077
We investigated the individual and combined effects of diet and physical exercise on metabolism and the gut microbiome to establish how these lifestyle factors influence host-microbiome cometabolism. Urinary and fecal samples were collected from athletes and less active controls. Individuals were further classified according to an objective dietary assessment score of adherence to healthy dietary habits according to WHO guidelines, calculated from their proton nuclear magnetic resonance (1H-NMR) urinary profiles. Subsequent models were generated comparing extremes of dietary habits, exercise, and the combined effect of both. Differences in metabolic phenotypes and gut microbiome profiles between the two groups were assessed. Each of the models pertaining to diet healthiness, physical exercise, or a combination of both displayed a metabolic and functional microbial signature, with a significant proportion of the metabolites identified as discriminating between the various pairwise comparisons resulting from gut microbe-host cometabolism. Microbial diversity was associated with a combination of high adherence to healthy dietary habits and exercise and was correlated with a distinct array of microbially derived metabolites, including markers of proteolytic activity. Improved control of dietary confounders, through the use of an objective dietary assessment score, has uncovered further insights into the complex, multifactorial relationship between diet, exercise, the gut microbiome, and metabolism. Furthermore, the observation of higher proteolytic activity associated with higher microbial diversity indicates that increased microbial diversity may confer deleterious as well as beneficial effects on the host.
Gray N, Lawler NG, Yang R, et al., 2020, A simultaneous exploratory and quantitative amino acid and biogenic amine metabolic profiling platform for rapid disease phenotyping via UPLC-QToF-MS, Talanta, ISSN: 0039-9140
Metabolic phenotyping using mass spectrometry (MS) is being applied to ever increasing sample numbers in clinical and epidemiology studies. High-throughput and robust methods are being developed for the accurate measurement of metabolites associated with disease. Traditionally, quantitative assays have utilized triple quadrupole (QQQ) MS based methods; however, the use of such focused methods removes the ability to perform discovery-based metabolic phenotyping. An integrated workflow for the hybrid simultaneous quantification of 34 biogenic amines in combination with full scan high-resolution accurate mass (HRAM) exploratory metabolic phenotyping is presented. Primary and secondary amines are derivatized with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate prior to revered-phase liquid chromatographic separation and mass spectrometric detection. Using the HRAM-MS data, retrospective phenotypic data mining could be performed, demonstrating the versatility of HRAM-MS instrumentation in a clinical and molecular epidemiological environment. Quantitative performance was assessed using two MS detector platforms: Waters TQ-XS (QQQ; n = 3) and Bruker Impact II QToF (HRAMS-MS; n = 2) and three human biofluids (plasma, serum and urine). Finally, each platform was assessed using a certified external reference sample (NIST SRM 1950 plasma). Intra- and inter-day accuracy and precision were comparable between the QQQ and QToF instruments (<15%), with excellent linearity (R2 > 0.99) over the quantification range of 1–400 μmol L−1. Quantitative values were comparable across all instruments for human plasma, serum and urine samples, and calculated concentrations were verified against certified reference values for NIST SRM 1950 plasma as an external reference. As a real-life biological exemplar, the method was applied to plasma samples obtained from SARS-CoV-2 positive patients versus healthy controls. Both the QQQ and QToF approaches were equivalent in being ab
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