Gut microbiota has been implicated in major diseases affecting the human population and has also been linked to triglycerides and high-density lipoprotein levels in the circulation. Recent ...development in metabolomics allows classifying the lipoprotein particles into more details. Here, we examine the impact of gut microbiota on circulating metabolites measured by Nuclear Magnetic Resonance technology in 2309 individuals from the Rotterdam Study and the LifeLines-DEEP cohort. We assess the relationship between gut microbiota and metabolites by linear regression analysis while adjusting for age, sex, body-mass index, technical covariates, medication use, and multiple testing. We report an association of 32 microbial families and genera with very-low-density and high-density subfractions, serum lipid measures, glycolysis-related metabolites, ketone bodies, amino acids, and acute-phase reaction markers. These observations provide insights into the role of microbiota in host metabolism and support the potential of gut microbiota as a target for therapeutic and preventive interventions.
Background and Aims
Previous small studies have appraised the gut microbiome (GM) in steatosis, but large‐scale studies are lacking. We studied the association of the GM diversity and composition, ...plasma metabolites, predicted functional metagenomics, and steatosis.
Approach and Results
This is a cross‐sectional analysis of the prospective population‐based Rotterdam Study. We used 16S ribosomal RNA gene sequencing and determined taxonomy using the SILVA reference database. Alpha diversity and beta diversity were calculated using the Shannon diversity index and Bray–Curtis dissimilarities. Differences were tested across steatosis using permutational multivariate analysis of variance. Hepatic steatosis was diagnosed by ultrasonography. We subsequently selected genera using regularized regression. The functional metagenome was predicted based on the GM using Kyoto Encyclopedia of Genes and Genomes pathways. Serum metabolomics were assessed using high‐throughput proton nuclear magnetic resonance. All analyses were adjusted for age, sex, body mass index, alcohol, diet, and proton‐pump inhibitors. We included 1,355 participants, of whom 472 had steatosis. Alpha diversity was lower in steatosis (P = 1.1∙10−9), and beta diversity varied across steatosis strata (P = 0.001). Lasso selected 37 genera of which three remained significantly associated after adjustment (Coprococcus3: β = −65; Ruminococcus Gauvreauiigroup: β = 62; and Ruminococcus Gnavusgroup: β = 45, Q‐value = 0.037). Predicted metagenome analyses revealed that pathways of secondary bile‐acid synthesis and biotin metabolism were present, and D‐alanine metabolism was absent in steatosis. Metabolic profiles showed positive associations for aromatic and branched chain amino acids and glycoprotein acetyls with steatosis and R. Gnavusgroup, whereas these metabolites were inversely associated with alpha diversity and Coprococcus3.
Conclusions
We confirmed, on a large‐scale, the lower microbial diversity and association of Coprococcus and Ruminococcus Gnavus with steatosis. We additionally showed that steatosis and alpha diversity share opposite metabolic profiles.
Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research ...Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).
Abstract
Background
People living with chronic obstructive pulmonary disease (COPD) have an increased risk of experiencing cardiovascular (CV) events, particularly after an exacerbation. Such CV ...burden is not yet known for incident COPD patients. We examined the risk of severe CV events in incident COPD patients in periods following either moderate and/or severe exacerbations.
Methods
Persons aged ≥ 40 years with an incident COPD diagnosis from the PHARMO Data Network were included. Exposed time periods included 1–7, 8–14, 15–30, 31–180 and 181–365 days following an exacerbation. Moderate exacerbations were defined as those managed in outpatient settings; severe exacerbations as those requiring hospitalisation. The outcome was a composite of time to first severe CV event (acute coronary syndrome, heart failure decompensation, cerebral ischaemia, or arrhythmia) or death. Hazard ratios (HR) were estimated for association between each exposed period and outcome.
Results
8020 patients with newly diagnosed COPD were identified. 2234 patients (28%) had ≥ 1 exacerbation, 631 patients (8%) had a non-fatal CV event, and 461 patients (5%) died during a median follow-up of 36 months. The risk of experiencing the composite outcome was increased following a moderate/severe exacerbation as compared to time periods of stable disease range of HR: from 15.3 (95% confidence interval 11.8–20.0) in days 1–7 to 1.3 (1.0–1.8) in days 181–365. After a moderate exacerbation, the risk was increased over the first 180 days HR 2.5 (1.3–4.8) in days 1–7 to 1.6 (1.3–2.1) in days 31–180. After a severe exacerbation, the risk increased substantially and remained higher over the year following the exacerbation HR 48.6 (36.9–64.0) in days 1–7 down to 1.6 (1.0–2.6) in days 181–365. Increase in risk concerned all categories of severe CV events.
Conclusions
Among incident COPD patients, we observed a substantial risk increase of severe CV events or all-cause death following either a moderate or severe exacerbation of COPD. Increase in risk was highest in the initial period following an exacerbation. These findings highlight the significant cardiopulmonary burden among people living with COPD even with a new diagnosis.
Introduction:
High mortality rates of approximately 20% within 1 year after treatment are observed for patients with proximal femoral fractures. This preliminary study explores the prognostic value ...of a previously constructed mortality risk score based on a set of 14 metabolites for the survival and functional recovery in patients with proximal femoral fractures.
Materials and Methods:
A prospective observational cohort study was conducted including patients admitted with a proximal femoral fracture. The primary outcome was patient survival, and the recovery of independence in activities of daily living was included as a secondary outcome. The mortality risk score was constructed for each patient and its prognostic value was tested for the whole population.
Results:
Data was available form 136 patients. The mean age of all patients was 82.1 years, with a median follow-up of 6 months. Within this period, 19.0% of all patients died and 51.1% recovered to their prefracture level of independence. The mortality score was significantly associated with mortality (HR, 2.74; 95% CI, 1.61-4.66; P < 0.001), but showed only a fair prediction accuracy (AUC = 0.68) and a borderline significant comparison of the mortality score tertile groups in survival analyses (P = 0.049). No decisive associations were found in any of the analyses for the functional recovery of patients.
Discussion:
These findings support the previously determined prognostic value of the mortality risk score. However, the independent prognostic value when adjusted for potential confounding factors is yet to be assessed. Also, a risk score constructed for this specific patient population might achieve higher accuracies for the prediction of survival and functional recovery.
Conclusions:
A modest prediction accuracy was observed for the mortality risk score in this population. More elaborate studies are needed to validate these findings and develop a tailored model for clinical purposes in this patient population.
Trimethylamine N‐oxide (TMAO) is a circulating microbiome‐derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels ...of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO‐to‐precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in‐depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio HR 1.17, 95% CI 1.07; 1.28) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome‐wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO‐to‐precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish‐TMAO, meat‐carnitine, and plant‐based food‐betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.
Measurements of trimethylamine N‐oxide and its precursors in plasma samples from five population cohorts identified an association between choline concentrations and cardiovascular disease. The interindividual variability of metabolite concentrations was determined by common genetic variation, dietary patterns, and the gut microbial composition of the population.
Highlights
Exploration of microbiome‐related metabolites (trimethylamine N‐oxide TMAO, choline, betaine,
l‐carnitine, and deoxycarnitine) in 7834 participants from five population cohorts.
Cardiovascular risk was associated with elevated choline concentrations, but not with TMAO concentrations.
Characterization of the genetic architecture behind metabolite concentration variability.
Identification of gut microbial taxonomic abundance associated with metabolite's plasma concentration levels.
Fish intake is the major dietary driver of TMAO concentrations, and betaine is related to grains and vegetable intake.
Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify ...rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (
-value < 1.42 × 10
, minor allele frequency of 0.2-0.5%) in the ERF study. Eight of these variants (in
,
,
,
,
, and
) were located on chromosome 11q22.3 that contains
, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (
-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in
(
-
= 1.48 × 10
), which has previously been associated with age. Additionally, a novel rare variant in the known
locus showed suggestive evidence for association (
-value = 1.18 × 10
) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.
Carotid intima-media thickness (cIMT) is an established heritable marker for subclinical atherosclerosis. In this study, we aim to identify rare variants with large effects driving differences in ...cIMT by performing genome-wide linkage analysis of individuals in the extremes of cIMT trait distribution (>90th percentile) in a large family-based study from a genetically isolated population in the Netherlands. Linked regions were subsequently explored by fine-mapping using exome sequencing. We observed significant evidence of linkage on chromosomes 2p16.3 rs1017418, heterogeneity LOD (HLOD) = 3.35, 19q13.43 (rs3499, HLOD = 9.09), 20p13 (rs1434789, HLOD = 4.10), and 21q22.12 (rs2834949, HLOD = 3.59). Fine-mapping using exome sequencing data identified a non-coding variant (rs62165235) in
gene under the linkage peak at chromosome 2 that is likely to have a regulatory function. The variant was associated with quantitative cIMT in the family-based study population (effect = 0.27,
-value = 0.013). Furthermore, we identified several genes under the linkage peak at chromosome 21 highly expressed in tissues relevant for atherosclerosis. To conclude, our linkage analysis identified four genomic regions significantly linked to cIMT. Further analyses are needed to demonstrate involvement of identified candidate genes in development of atherosclerosis.
Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived ...metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.
ABSTRACT
Analyzing the type and frequency of patient‐specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial ...planning, and improved clinical care. Locus‐specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT‐NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid‐intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read‐through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
Analysing the type and frequency of patient specific mutations giving rise to Duchenne Muscular Dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning and improved clinical care. We describe the development and analysis of the TREAT‐NMD DMD Global database (http://umd.be/TREAT_DMD/). We analysed and reported genetic data for 7149 DMD mutations held within the database. Additionally, we identified mutations within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read‐through therapies.
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