Publications
145 results found
Graham NSN, Blissitt G, Zimmerman K, et al., 2023, ADVANCE-TBI study protocol: traumatic brain injury outcomes in UK military personnel serving in Afghanistan between 2003 and 2014 - a longitudinal cohort study., BMJ Open, Vol: 13
INTRODUCTION: Outcomes of traumatic brain injury (TBI) are highly variable, with cognitive and psychiatric problems often present in survivors, including an increased dementia risk in the long term. Military personnel are at an increased occupational risk of TBI, with high rates of complex polytrauma including TBI characterising the UK campaign in Afghanistan. The ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE)-TBI substudy will describe the patterns, associations and long-term outcomes of TBI in the established ADVANCE cohort. METHODS AND ANALYSIS: The ADVANCE cohort comprises 579 military personnel exposed to major battlefield trauma requiring medical evacuation, and 566 matched military personnel without major trauma. TBI exposure has been captured at baseline using a standardised interview and registry data, and will be refined at first follow-up visit with the Ohio State Method TBI interview (a National Institute of Neurological Disorders and Stroke TBI common data element). Participants will undergo blood sampling, MRI and detailed neuropsychological assessment longitudinally as part of their follow-up visits every 3-5 years over a 20-year period. Biomarkers of injury, neuroinflammation and degeneration will be quantified in blood, and polygenic risk scores calculated for neurodegeneration. Age-matched healthy volunteers will be recruited as controls for MRI analyses. We will describe TBI exposure across the cohort, and consider any relationship with advanced biomarkers of injury and clinical outcomes including cognitive performance, neuropsychiatric symptom burden and function. The influence of genotype will be assessed. This research will explore the relationship between military head injury exposure and long-term outcomes, providing insights into underlying disease mechanisms and informing prevention interventions. ETHICS AND DISSEMINATION: The ADVANCE-TBI substudy has received a favourable opinion from the Ministry of Defence Research Eth
Liew F, Talwar S, Cross A, et al., 2023, SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination, EBioMedicine, Vol: 87, Pages: 1-14, ISSN: 2352-3964
Background:Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.Methods:In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.Findings:Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination.Interpretation:The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.Funding:This
Vink E, Davis C, MacLean A, et al., 2022, Viral coinfections in hospitalized Coronavirus disease 2019 patients recruited to the international severe acute respiratory and emerging infections consortium WHO clinical characterisation protocol UK study, Open Forum Infectious Diseases, Vol: 9, Pages: 1-10, ISSN: 2328-8957
BackgroundWe conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity.MethodsMultiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge.ResultsA coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity.ConclusionsViral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward.
Norris T, Razieh C, Zaccardi F, et al., 2022, Impact of cardiometabolic multimorbidity and ethnicity on cardiovascular/renal complications in patients with COVID-19, Heart, Vol: 108, Pages: 1200-1208, ISSN: 1355-6037
Objective Using a large national database of people hospitalised with COVID-19, we investigated the contribution of cardio-metabolic conditions, multi-morbidity and ethnicity on the risk of in-hospital cardiovascular complications and death.Methods A multicentre, prospective cohort study in 302 UK healthcare facilities of adults hospitalised with COVID-19 between 6 February 2020 and 16 March 2021. Logistic models were used to explore associations between baseline patient ethnicity, cardiometabolic conditions and multimorbidity (0, 1, 2, >2 conditions), and in-hospital cardiovascular complications (heart failure, arrhythmia, cardiac ischaemia, cardiac arrest, coagulation complications, stroke), renal injury and death.Results Of 65 624 patients hospitalised with COVID-19, 44 598 (68.0%) reported at least one cardiometabolic condition on admission. Cardiovascular/renal complications or death occurred in 24 609 (38.0%) patients. Baseline cardiometabolic conditions were independently associated with increased odds of in-hospital complications and this risk increased in the presence of cardiometabolic multimorbidity. For example, compared with having no cardiometabolic conditions, 1, 2 or ≥3 conditions was associated with 1.46 (95% CI 1.39 to 1.54), 2.04 (95% CI 1.93 to 2.15) and 3.10 (95% CI 2.92 to 3.29) times higher odds of any cardiovascular/renal complication, respectively. A similar pattern was observed for all-cause death. Compared with the white group, the South Asian (OR 1.19, 95% CI 1.10 to 1.29) and black (OR 1.53 to 95% CI 1.37 to 1.72) ethnic groups had higher risk of any cardiovascular/renal complication.Conclusions In hospitalised patients with COVID-19, cardiovascular complications or death impacts just under half of all patients, with the highest risk in those of South Asian or Black ethnicity and in patients with cardiometabolic multimorbidity.
Wu V, Tillner J, Jones E, et al., 2022, High resolution ambient MS imaging of biological samples by desorption electro-flow focussing ionization, Analytical Chemistry, Vol: 94, Pages: 10035-10044, ISSN: 0003-2700
In this study, we examine the suitability of desorption electro-flow focusing ionization (DEFFI) for mass spectrometry imaging (MSI) of biological tissue. We also compare the performance of desorption electrospray ionization (DESI) with and without the flow focusing setup. The main potential advantages of applying the flow focusing mechanism in DESI is its rotationally symmetric electrospray jet, higher intensity, more controllable parameters, and better portability due to the robustness of the sprayer. The parameters for DEFFI have therefore been thoroughly optimized, primarily for spatial resolution but also for intensity. Once the parameters have been optimized, DEFFI produces similar images to the existing DESI. MS images for mouse brain samples, acquired at a nominal pixel size of 50 μm, are comparable for both DESI setups, albeit the new sprayer design yields better sensitivity. Furthermore, the two methods are compared with regard to spectral intensity as well as the area of the desorbed crater on rhodamine-coated slides. Overall, the implementation of a flow focusing mechanism in DESI is shown to be highly suitable for imaging biological tissue and has potential to overcome some of the shortcomings experienced with the current geometrical design of DESI.
Habboub N, Manousou P, Forlano R, et al., 2022, Designing a polymetabolic risk score for non-alcoholic steatohepatitis patients by differentiating their metabolic profiles from healthy controls, JOURNAL OF HEPATOLOGY, Vol: 77, Pages: S179-S179, ISSN: 0168-8278
Serger E, Luengo-Gutierrez L, Chadwick JS, et al., 2022, The gut metabolite indole-3 propionate promotes nerve regeneration and repair, NATURE, Vol: 607, Pages: 585-+, ISSN: 0028-0836
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- Citations: 14
Habboub N, Forlano R, Goldin R, et al., 2022, EXAMINING THE CORRELATION OF HISTOLOGICAL FEATURES OF NAFLD WITH A POLYMETABOLIC RISK SCORE FOR PREDICTING PATIENTS WITH NAFLD, GASTROENTEROLOGY, Vol: 162, Pages: S1271-S1271, ISSN: 0016-5085
Menghini R, Hoyles L, Cardellini M, et al., 2022, ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids, MOLECULAR METABOLISM, Vol: 59, ISSN: 2212-8778
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- Citations: 1
Fromentin S, Forslund SK, Chechi K, et al., 2022, Microbiome and metabolome features of the cardiometabolic disease spectrum, Nature Medicine, Vol: 28, Pages: 303-+, ISSN: 1078-8956
Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages—acute coronary syndrome, chronic IHD and IHD with heart failure—and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
Talmor-Barkan Y, Bar N, Shaul AA, et al., 2022, Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease, NATURE MEDICINE, Vol: 28, Pages: 295-+, ISSN: 1078-8956
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- Citations: 13
Dejnirattisai W, Huo J, Zhou D, et al., 2022, SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses, Cell, Vol: 185, Pages: 467-484.e15, ISSN: 0092-8674
On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.
Belda E, Voland L, Tremaroli V, et al., 2022, Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism, GUT, Vol: 71, Pages: 2463-2480, ISSN: 0017-5749
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- Citations: 16
Forslund SK, Chakaroun R, Zimmermann-Kogadeeva M, et al., 2021, Combinatorial, additive and dose-dependent drug-microbiome associations, NATURE, Vol: 600, Pages: 500-+, ISSN: 0028-0836
de Silva TI, Liu G, Lindsey BB, et al., 2021, The impact of viral mutations on recognition by SARS-CoV-2 specific T cells., iScience, Vol: 24, Pages: 103353-103353, ISSN: 2589-0042
We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.
Nalpas N, Hoyles L, Anselm V, et al., 2021, An integrated workflow for enhanced taxonomic and functional coverage of the mouse fecal metaproteome., Gut Microbes, Vol: 13, Pages: 1-23, ISSN: 1949-0976
Intestinal microbiota plays a key role in shaping host homeostasis by regulating metabolism, immune responses and behavior. Its dysregulation has been associated with metabolic, immune and neuropsychiatric disorders and is accompanied by changes in bacterial metabolic regulation. Although proteomics is well suited for analysis of individual microbes, metaproteomics of fecal samples is challenging due to the physical structure of the sample, presence of contaminating host proteins and coexistence of hundreds of taxa. Furthermore, there is a lack of consensus regarding preparation of fecal samples, as well as downstream bioinformatic analyses following metaproteomics data acquisition. Here we assess sample preparation and data analysis strategies applied to mouse feces in a typical mass spectrometry-based metaproteomic experiment. We show that subtle changes in sample preparation protocols may influence interpretation of biological findings. Two-step database search strategies led to significant underestimation of false positive protein identifications. Unipept software provided the highest sensitivity and specificity in taxonomic annotation of the identified peptides of unknown origin. Comparison of matching metaproteome and metagenome data revealed a positive correlation between protein and gene abundances. Notably, nearly all functional categories of detected protein groups were differentially abundant in the metaproteome compared to what would be expected from the metagenome, highlighting the need to perform metaproteomics when studying complex microbiome samples.
Wickenhagen A, Sugrue E, Lytras S, et al., 2021, A prenylated dsRNA sensor protects against severe COVID-19, Science, Vol: 374, Pages: 1-18, ISSN: 0036-8075
Nuzzo A, Guedj K, Curac S, et al., 2021, Accuracy of citrulline, I-FABP and d-lactate in the diagnosis of acute mesenteric ischemia, Scientific Reports, Vol: 11, Pages: 1-10, ISSN: 2045-2322
Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and D-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma D-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and D-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.
Drake TM, Riad AM, Fairfield CJ, et al., 2021, Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study, The Lancet, Vol: 398, Pages: 223-237, ISSN: 0140-6736
BACKGROUND: COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK. METHODS: We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities. FINDINGS: Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were
COVID-19 Host Genetics Initiative, 2021, Mapping the human genetic architecture of COVID-19, Nature, Vol: 600, Pages: 472-477, ISSN: 0028-0836
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Bermudez-Martin P, Becker JAJ, Caramello N, et al., 2021, The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota, Microbiome, Vol: 9, Pages: 1-23, ISSN: 2049-2618
BackgroundAutism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.ResultsMice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.ConclusionsThe microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.
Brial F, Chilloux J, Nielsen T, et al., 2021, Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health., Gut, Vol: 70, Pages: 2105-2114, ISSN: 0017-5749
OBJECTIVE: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health. DESIGN: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes. RESULTS: In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion. CONCLUSION: Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.
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
Letertre MPM, Myridakis A, Whiley L, et al., 2021, A targeted ultra performance liquid chromatography - Tandem mass spectrometric assay for tyrosine and metabolites in urine and plasma: Application to the effects of antibiotics on mice, JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, Vol: 1164, ISSN: 1570-0232
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Molinaro A, Lassen PB, Henricsson M, et al., 2020, Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology (vol 11, 5881, 2020), Nature Communications, Vol: 11, ISSN: 2041-1723
Giovanni SD, serger E, Chadwick J, et al., 2020, The intermittent fasting-dependent gut microbial metabolite indole-3 propionate promotes nerve regeneration and recovery after injury
<jats:title>Abstract</jats:title> <jats:p>The regenerative potential of mammalian peripheral nervous system (PNS) neurons after injury is critically limited by their slow axonal regenerative rate<jats:sup>1</jats:sup>. Since a delayed target re-innervation leads to irreversible loss of function of target organs<jats:sup>2</jats:sup>, accelerated axonal regeneration is required to enhance functional outcomes following injury. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms<jats:sup>3</jats:sup>. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration<jats:sup>4</jats:sup>. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and release of neurotrophins, can be activated by intermittent fasting (IF)<jats:sup>5,6</jats:sup>. IF has in turn been shown to increase synaptic plasticity<jats:sup>7,8</jats:sup> and neurogenesis<jats:sup>9</jats:sup>, partially sharing molecular mechanisms with axonal regeneration. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in the mouse via an unexpected mechanism that relies upon the gram + gut microbiome and an increase of the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by <jats:italic>Clostridium sporogenes</jats:italic> is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-d
Molinaro A, Bel Lassen P, Henricsson M, et al., 2020, Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology, Nature Communications, Vol: 11, ISSN: 2041-1723
Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.
Nalpas N, Hoyles L, Anselm V, et al., 2020, An integrated workflow for enhanced taxonomic and functional coverage of the mouse faecal metaproteome, Publisher: Cold Spring Harbor Laboratory
The intestinal microbiota plays a key role in shaping host homeostasis by regulating metabolism, immune responses and behaviour. Its dysregulation has been associated with metabolic, immune and neuropsychiatric disorders and is accompanied by changes in bacterial metabolic regulation. Although proteomics is well suited for analysis of individual microbes, metaproteomics of faecal samples is challenging due to the physical structure of the sample, presence of contaminating host proteins and coexistence of hundreds of species. Furthermore, there is a lack of consensus regarding preparation of faecal samples, as well as downstream bioinformatic analyses following metaproteomic data acquisition. Here we assess sample preparation and data analysis strategies applied to mouse faeces in a typical LC-MS/MS metaproteomic experiment. We show that low speed centrifugation (LSC) of faecal samples leads to high protein identification rates and a balanced taxonomic representation. During database search, protein sequence databases derived from matched mouse faecal metagenomes provided up to four times more MS/MS identifications compared to other database construction strategies, while a two-step database search strategy led to accumulation of false positive protein identifications. Comparison of matching metaproteome and metagenome data revealed a positive correlation between protein and gene abundances, as well as significant overlap and correlation in taxonomic representation. Notably, nearly all functional categories of detected protein groups were differentially abundant in the metaproteome compared to what would be expected from the metagenome, highlighting the need to perform metaproteomics when studying complex microbiome samples.
Mayneris-Perxachs J, Puig J, Burcelin R, et al., 2020, The APOA1bp-SREBF-NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients, CLINICAL NUTRITION, Vol: 39, Pages: 3408-3418, ISSN: 0261-5614
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Vieira-Silva S, Falony G, Belda E, et al., 2020, Statin therapy is associated with lower prevalence of gut microbiota dysbiosis, NATURE, Vol: 581, Pages: 310-+, ISSN: 0028-0836
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- Citations: 146
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