Abstract
Context
Emerging evidence has related the gut microbiome and circulating metabolites to human obesity. Gut microbiota is responsible for several metabolic functions, and altered plasma ...metabolome might reflect differences in the gut microbiome.
Objective
To identify a plasma metabolite profile associated with body mass index (BMI) in a general population and investigate whether such metabolite profile is associated with distinct composition of the gut microbiota.
Design
Targeted profiling of 48 plasma metabolites was performed in a population of 920 Swedish adults (mean age, 39 years; 53% women) from the ongoing Malmö Offspring Study using targeted liquid chromatography–mass spectrometry. Gut microbiota was analyzed by sequencing the 16S ribosomal RNA gene (V1-V3 region) in fecal samples of 674 study participants.
Results
BMI was associated with 19 metabolites (P < 0.001 for all), of which glutamate provided the strongest direct association (P = 5.2e-53). By orthogonal partial least squares regression, a metabolite principal component predictive of BMI was constructed (PCBMI). In addition to glutamate, PCBMI was dominated by branched-chain amino acids (BCAAs) and related metabolites. Four gut microbiota genera (Blautia, Dorea, Ruminococcus, and SHA-98) were associated with both BMI and PCBMI (P < 8.0e-4 for all). When simultaneously regressing PCBMI and metabolite-associated gut bacteria against BMI, only PCBMI remained statistically significant.
Conclusions
We discovered associations between four gut microbiota genera (Blautia, Dorea, Ruminococcus, and SHA-98) and BMI-predictive plasma metabolites, including glutamate and BCAAs. Thus, these metabolites could be mediators between gut microbiota and obesity, pointing to potential future opportunities for targeting the gut microbiota in prevention of obesity.
We identified metabolites associated with BMI. The BMI-related metabolites were connected to four microbiota genera, suggesting a mediating role of the metabolites in the microbiota–obesity relationship.
Abstract
Context
Type 2 diabetes mellitus (T2DM) is accompanied by an increased risk for coronary artery disease (CAD), but the overlapping metabolic disturbances preceding both diseases are ...insufficiently described.
Objective
We hypothesized that alterations in metabolism occur years before clinical manifestation of T2DM and CAD and that these alterations are reflected in the plasma metabolome. We thus aimed to identify plasma metabolites that predict future T2DM and CAD.
Design
Through use of targeted liquid chromatography-mass spectrometry, 35 plasma metabolites (amino acid metabolites and acylcarnitines) were quantified in 1049 individuals without CAD and diabetes, drawn from a population sample of 5386 in the Malmö Preventive Project (mean age, 69.5 years; 31% women). The sample included 204 individuals who developed T2DM, 384 who developed CAD, and 496 who remained T2DM and CAD free during a mean follow-up of 6.1 years.
Results
In total, 16 metabolites were significantly associated with risk for developing T2DM according to logistic regression models. Glutamate (OR, 1.96; P = 5.4e-12) was the most strongly associated metabolite, followed by increased levels of branched-chain amino acids. Incident CAD was predicted by three metabolites: glutamate (OR, 1.28; P = 6.6e-4), histidine (OR, 0.76; P = 5.1e-4), and asparagine (OR, 0.80; P = 2.2e-3). Glutamate (OR, 1.48; P = 1.6e-8) and asparagine (OR, 0.75; P = 1.8e-5) were both associated with a composite endpoint of developing T2DM or CAD.
Conclusion
Several plasma metabolites were associated with incidence of T2DM and CAD; elevated glutamate and reduced asparagine levels were associated with both diseases. We thus discovered associations that might help shed additional light on why T2DM and CAD commonly co-occur.
Plasma glutamate and asparagine levels predict future cardiometabolic disease. These metabolite alterations might help shed additional light on why T2DM and CAD commonly co-occur.
We recently identified a health conscious food pattern (HCFP) associated with reduced risk of cardiometabolic disease. However, the molecular events linking the healthy food pattern to reduced risk ...of cardiometabolic disease are unknown. Our aim was to identify plasma metabolites associated with the HCFP and test if such metabolites predict cardiometabolic disease and mortality.
Using liquid-chromatography mass-spectrometry, 112 plasma metabolites were measured in 3236 participants without cardiovascular disease (CVD) and diabetes mellitus from the population-based Malmö Diet and Cancer study. Metabolites associated with the HCFP were identified using multivariable adjusted linear regressions followed by Bonferroni correction. The healthy dietary biomarkers were subsequently related to risk of cardiometabolic disease and mortality during long-term follow-up with multivariable adjusted Cox proportional hazards models.
During a median follow-up time of 21.4 years, 603 participants developed CVD, 362 developed diabetes mellitus and 843 participants died. Five healthy dietary biomarkers were associated with the HCFP at baseline (p<0.0004) and four predicted at least one of the studied end points (p<0.05). Ergothioneine was the metabolite most strongly connected to the HCFP and was associated with a lower risk of coronary disease (HR per 1 SD increment of ergothioneine, HR=0.85, p=0.01), cardiovascular mortality (HR=0.79, p=0.002) and overall mortality (HR=0.86, p=4e-5).
We identified that higher ergothioneine was an independent marker of lower risk of cardiometabolic disease and mortality, which potentially can be induced by a specific healthy dietary intake.
Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of ...diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.
Abstract
Context
Metabolomics has the potential to generate biomarkers that can facilitate understanding relevant pathways in the pathophysiology of type 2 diabetes (T2DM).
Methods
Nontargeted ...metabolomics was performed, via liquid chromatography–mass spectrometry, in a discovery case-cohort study from the Malmö Preventive Project (MPP), which consisted of 698 metabolically healthy participants, of whom 202 developed T2DM within a follow-up time of 6.3 years. Metabolites that were significantly associated with T2DM were replicated in the population-based Malmö Diet and Cancer–Cardiovascular Cohort (MDC-CC) (N = 3423), of whom 402 participants developed T2DM within a follow-up time of 18.2 years.
Results
Using nontargeted metabolomics, we observed alterations in nine metabolite classes to be related to incident T2DM, including 11 identified metabolites. N2,N2-dimethylguanosine (DMGU) (OR = 1.94; P = 4.9e-10; 95% CI, 1.57 to 2.39) was the metabolite most strongly associated with an increased risk, and beta-carotene (OR = 0.60; P = 1.8e-4; 95% CI, 0.45 to 0.78) was the metabolite most strongly associated with a decreased risk. Identified T2DM-associated metabolites were replicated in MDC-CC. Four metabolites were significantly associated with incident T2DM in both the MPP and the replication cohort MDC-CC, after adjustments for traditional diabetes risk factors. These included associations between three metabolites, DMGU, 7-methylguanine (7MG), and 3-hydroxytrimethyllysine (HTML), and incident T2DM.
Conclusions
We used nontargeted metabolomics in two Swedish prospective cohorts comprising >4000 study participants and identified independent, replicable associations between three metabolites, DMGU, 7MG, and HTML, and future risk of T2DM. These findings warrant additional studies to investigate a potential functional connection between these metabolites and the onset of T2DM.
Plasma levels of metabolites DMGU, 7MG, and HTML are associated with incident T2DM in two prospective cohorts comprising >4000 patients.
The global burden of cardiovascular disease and type 2 diabetes could be decreased by improving dietary factors, but identification of groups suitable for interventional approaches can be difficult. ...Reporting of dietary intake is prone to errors, and measuring of metabolites has shown promise in determining habitual dietary intake. Our aim is to create a metabolic signature that is associated with healthy eating and test if it associates with type 2 diabetes and coronary artery disease risk.
Using plasma metabolite data consisting of 111 metabolites, partial least square (PLS) regression was used to identify a metabolic signature associated with a health conscious food pattern in the Malmö Offspring Study (MOS, n = 1538). The metabolic signature's association with dietary intake was validated in the Malmö Diet and Cancer study (MDC, n = 2521). The associations between the diet-associated metabolic signature and incident type 2 diabetes and coronary artery disease (CAD) were tested using Cox regression in MDC and logistic regression in Malmö Preventive Project (MPP, n = 1083). Modelling was conducted unadjusted (model 1), adjusted for potential confounders (model 2) and additionally for potential mediators (model 3).
The metabolic signature was associated with lower risk for type 2 diabetes in both MDC (hazard ratio: 0.58, 95% CI 0.52-0.66, per 1 SD increment of the metabolic signature) and MPP (odds ratio: 0.54, 95% CI 0.44-0.65 per 1 SD increment of the metabolic signature) in model 2. The results were attenuated but remained significant in model 3 in both MDC (hazard ratio 0.73, 95% CI 0.63-0.83) and MPP (odds ratio 0.70, 95% CI 0.55-0.88). The diet-associated metabolic signature was also inversely associated with lower risk of CAD in both MDC and MPP in model 1, but the association was non-significant in model 3.
In this proof-of-concept study, we identified a healthy diet-associated metabolic signature, which was inversely associated with future risk for type 2 diabetes and coronary artery disease in two different cohorts. The association with diabetes was independent of traditional risk factors and might illustrate an effect of health conscious dietary intake on cardiometabolic health.
Dyslipidemia is a hallmark of cardiovascular disease but is characterized by crude measurements of triglycerides, HDL- and LDL cholesterol. Lipidomics enables more detailed measurements of plasma ...lipids, which may help improve risk stratification and understand the pathophysiology of cardiovascular disease.
Lipidomics was used to measure 184 lipids in plasma samples from the Malmö Diet and Cancer – Cardiovascular Cohort (N = 3865), taken at baseline examination. During an average follow-up time of 20.3 years, 536 participants developed coronary artery disease (CAD). Least absolute shrinkage and selection operator (LASSO) were applied to Cox proportional hazards models in order to identify plasma lipids that predict CAD.
Eight plasma lipids improved prediction of future CAD on top of traditional cardiovascular risk factors. Principal component analysis of CAD-associated lipids revealed one principal component (PC2) that was associated with risk of future CAD (HR per SD increment =1.46, C·I = 1.35–1.48, P < 0.001). The risk increase for being in the highest quartile of PC2 (HR = 2.33, P < 0.001) was higher than being in the top quartile of systolic blood pressure. Addition of PC2 to traditional risk factors achieved an improvement (2%) in the area under the ROC-curve for CAD events occurring within 10 (P = 0.03), 15 (P = 0.003) and 20 (P = 0.001) years of follow-up respectively.
A lipid pattern improve CAD prediction above traditional risk factors, highlighting that conventional lipid-measures insufficiently describe dyslipidemia that is present years before CAD. Identifying this hidden dyslipidemia may help motivate lifestyle and pharmacological interventions early enough to reach a substantial reduction in absolute risk.
•Lipidomics enables more detailed characterization of dyslipidemia.•A lipid signature predicts cardiovascular disease up to 20 years prior to disease.•The lipidomic prediction is independent of traditional cardiovascular risk factors.•Identifying this hidden dyslipidemia could motivate early preventive interventions.
Alterations in the human metabolome occur years before clinical manifestation of type 2 diabetes (T2DM). By contrast, there is little knowledge of how metabolite alterations in individuals with ...diabetes relate to risk of diabetes complications and premature mortality. Metabolite profiling was performed using liquid chromatography-mass spectrometry in 743 participants with T2DM from the population-based prospective cohorts The Malmö Diet and Cancer-Cardiovascular Cohort (MDC-CC) and The Malmö Preventive Project (MPP). During follow-up, a total of 175 new-onset cases of cardiovascular disease (CVD) and 298 deaths occurred. Cox regressions were used to relate baseline levels of plasma metabolites to incident CVD and all-cause mortality. A total of 11 metabolites were significantly (false discovery rate (fdr) <0.05) associated with all-cause mortality. Acisoga, acylcarnitine C10:3, dimethylguanidino valerate, homocitrulline, N2,N2-dimethylguanosine, 1-methyladenosine and urobilin were associated with an increased risk, while hippurate, lysine, threonine and tryptophan were associated with a decreased risk. Ten out of 11 metabolites remained significantly associated after adjustments for cardiometabolic risk factors. The associations between metabolite levels and incident CVD were not as strong as for all-cause mortality, although 11 metabolites were nominally significant (p < 0.05). Further examination of the mortality-related metabolites may shed more light on the pathophysiology linking diabetes to premature mortality.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with an unpredictable course. An observational study was set up using the French hospital discharge database to describe the reasons, ...outcomes and costs of hospitalisations related to this disease. Patients newly hospitalised for idiopathic pulmonary fibrosis (ICD-10 code: J84.1) in 2008 were identified and followed for 5 years. As J84.1 includes other fibrotic pulmonary diseases, an algorithm excluding age<50 years and presence of a differential diagnosis in the following year was defined. Overall, 6,476 patients were identified; of whom 30% were admitted through the emergency unit and 12% died during their first hospitalisation. Most of patients were hospitalised at least once for one or several acute events (n = 5,635; 87.0% of patients), of whom 36.5% of patients with an acute respiratory worsening (in-hospital mortality of 17.0% and median cost of €3,224; interquartile range (IQR €889-6,092)), 43.7% of patients with a respiratory infection (in-hospital mortality of 29.5% and median cost of €5,432 (IQR, €3,620-9,115)) and 51.7% of patients with a cardiac event (in-hospital mortality of 35.7% and median cost of €4,584 (IQR, €2,803-6,399)); 30.2% of these events occurred during the first hospitalisation. Finally, the 3-year in-hospital mortality crude rate was 36.8%. This study is the first providing extensive data on hospitalisations in patients with pulmonary fibrosis, mostly idiopathic, in France, demonstrating high burden and hospital cost.
Chronic immune activation persists in persons living with HIV-1 even though they are aviremic under antiretroviral therapy, and fuels comorbidities. In previous studies, we have revealed that ...virologic responders present distinct profiles of immune activation, and that one of these profiles is related to microbial translocation. In the present work, we tested in 140 HIV-1-infected adults under efficient treatment for a mean duration of eight years whether low-level viremia might be another cause of immune activation. We observed that the frequency of viremia between 1 and 20 HIV-1 RNA copies/mL (39.5 ± 24.7% versus 21.1 ± 22.5%, p = 0.033) and transient viremia above 20 HIV-1 RNA copies/mL (15.1 ± 16.9% versus 3.3 ± 7.2%, p = 0.005) over the 2 last years was higher in patients with one profile of immune activation, Profile E, than in the other patients. Profile E, which is different from the profile related to microbial translocation with frequent CD38+ CD8+ T cells, is characterized by a high level of CD4+ T cell (cell surface expression of CD38), monocyte (plasma concentration of soluble CD14), and endothelium (plasma concentration of soluble Endothelial Protein C Receptor) activation, whereas the other profiles presented low CD4:CD8 ratio, elevated proportions of central memory CD8+ T cells or HLA-DR+ CD4+ T cells, respectively. Our data reinforce the hypothesis that various etiological factors shape the form of the immune activation in virologic responders, resulting in specific profiles. Given the type of immune activation of Profile E, a potential causal link between low-level viremia and atherosclerosis should be investigated.
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