Unraveling interindividual variation of trimethylamine N-oxide and its precursors at the population level

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.Molecular Epidemiolog

Sex differences in fat distribution influence the association between BMI and arterial stiffness

Contains fulltext : 182585.pdf (publisher's version ) (Closed access)CONTEXT AND OBJECTIVE: The increase in arterial stiffness in patients with the metabolic syndrome is strongly related to the amount of visceral adipose tissue. In clinical practice, anthropometric measurements such as BMI and waist circumference are commonly used to assess general and abdominal adiposity. Waist circumference is a composite measure of subcutaneous and visceral abdominal adipose tissue. As the distribution of intra-abdominal fat differs between men and women, we investigated the sex-specific associations between different anthropometric measures for general and abdominal obesity with arterial stiffness. METHODS: A cross-sectional descriptive study was performed in 1517 participants of the Nijmegen Biomedical Study, aged 50-70 years. After measurement of height, waist circumference and hip circumference, the following indices were calculated: BMI, waist-hip ratio and waist-height ratio (WHtR). Arterial stiffness was assessed by measurement of carotid-femoral pulse wave velocity (PWV). The association between the anthropometric indices and vascular stiffness was investigated by linear regression analysis adjusting for the traditional cardiovascular risk factors. RESULTS: BMI, waist circumference, waist-hip ratio and WHtR correlated positively with PWV in univariate analysis both in men and women (all P < 0.016). Hip circumference was only associated with PWV in women (P < 0.001). After adjustment for age and heart rate, waist circumference and WHtR (standardized beta of 0.142 and 0.141, respectively, both P < 0.001) showed the strongest associations with PWV in men, whereas in women only BMI was associated with PWV (standardized beta of 0.177, P < 0.001). In men, WHtR was independently related to increased arterial stiffness, after adjustment for BMI and traditional cardiovascular risk factors. In women, in multivariate analyses, BMI remained significantly positively associated with PWV, whereas WHtR became negatively associated with PWV. CONCLUSION: Sex-related differences in adipose tissue distribution influence the association between anthropometric measures of obesity and vascular stiffness as measured with by PWV. We found that in men, WHtR showed the strongest association with PWV, whereas in women BMI was best associated with a higher PWV

Genetic and Microbial Associations to Plasma and Fecal Bile Acids in Obesity Relate to Plasma Lipids and Liver Fat Content

Contains fulltext : 226225.pdf (publisher's version ) (Open Access

Vasculometabolic and Inflammatory Effects of Aldosterone in Obesity

Contains fulltext : 220588.pdf (Publisher’s version ) (Open Access

Characterization of gut microbial structural variations as determinants of human bile acid metabolism

Contains fulltext : 242535.pdf (Publisher’s version ) (Closed access

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects

Contains fulltext : 232503.pdf (Publisher’s version ) (Open Access)The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19(+) B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19(+) B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine

Increased NEFA levels reduce blood Mg2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg2+

Contains fulltext : 201059.pdf (publisher's version ) (Open Access

Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk

Contains fulltext : 204147.pdf (publisher's version ) (Closed access)RATIONALE: Altered gut microbial composition has been linked to cardiovascular diseases (CVDs), but its functional links to host metabolism and immunity in relation to CVD development remain unclear. OBJECTIVES: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes, and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts. METHODS AND RESULTS: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based LLD (Lifelines DEEP) cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, sex, and body mass index, the gut microbiome could explain </=11.1% and 16.4% of the variation in plasma metabolites in the population-based and obesity cohorts, respectively. Obese-specific microbial associations were found for lipid compositions in the VLDL, IDL, and LDL lipoprotein subclasses. Bacterial L-methionine biosynthesis and a Ruminococcus species were associated to cardiovascular phenotypes in obese individuals, namely atherosclerosis and liver fat content, respectively. Integration of microbiome-diet-inflammation analysis in relation to metabolic risk score of CVD in the population cohort revealed 48 microbial pathways associated to CVD risk that were largely independent of diet and inflammation. Our data also showed that plasma levels rather than fecal levels of short-chain fatty acids were relevant to inflammation and CVD risk. CONCLUSIONS: This study presents the largest metagenome-based association study on plasma metabolism and microbiome relevance to diet, inflammation, CVD risk, and cardiometabolic phenotypes in both population-based and clinical obesity cohorts. Our findings identified novel bacterial species and pathways that associated to specific lipoprotein subclasses and revealed functional links between the gut microbiome and host health that provide a basis for developing microbiome-targeted therapy for disease prevention and treatment