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.

Association Between Clonal Hematopoiesis Driver Mutations, Immune Cell Function, and the Vasculometabolic Complications of Obesity.

BACKGROUND: Obesity is accompanied by dysregulated inflammation, which can contribute to vasculometabolic complications including metabolic syndrome and atherosclerosis. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular diseases. We aimed to determine how CHIP is related to immune cell function, systemic inflammation, and vasculometabolic complications in obese individuals. METHODS AND RESULTS: Two hundred ninety-seven individuals with overweight and obesity, between the ages of 54 and 81 years, were recruited in a cross-sectional study. Clonal hematopoiesis driver mutations (CHDMs) were identified with an ultrasensitive targeted assay. Assessment of carotid artery atherosclerosis was performed with ultrasound. Detailed immunological parameters, including cytokine production capacity of peripheral blood mononuclear cells, and targeted plasma proteomics analysis, were studied. Adipose tissue inflammation was determined in subcutaneous fat biopsies. Individuals with CHIP had higher concentrations of circulating IL (interleukin)-6. Total number of leukocytes and neutrophils were higher in individuals with CHIP. In contrast, ex vivo cytokine production capacity of peripheral blood mononuclear cells was significantly lower in individuals with CHIP. Sex-stratified analysis showed that men with CHDMs had significantly higher leukocyte and neutrophil counts, and ex vivo cytokine production capacity was lower in women with CHDMs. Surprisingly, the presence of atherosclerotic plaques was significantly lower in individuals with CHDMs. There was no relation between CHIP and metabolic syndrome. CONCLUSIONS: In individuals with overweight or obesity, CHDMs are not associated with vasculometabolic complications, but rather with a lower presence of carotid plaques. CHDMs associate with increased circulating inflammatory markers and leukocyte numbers, but a lower peripheral blood mononuclear cell cytokine production capacity.

Host genetic regulation of human gut microbial structural variation.

Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established1-6, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship.

The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity.

Leptin is associated with cardiometabolic complications of obesity, such as metabolic syndrome and atherosclerosis. In obese men, the presence of metabolic syndrome is associated with higher circulating leptin and interleukin (IL)-6 concentrations and increased monocyte cytokine production capacity. Here, we investigated the effects of leptin on monocyte function and systemic inflammatory markers in obese individuals. We specifically explored whether leptin can induce long-term changes in innate immune function by inducing innate immune memory (also called trained immunity). We exposed human primary monocytes for 24 h to relevant leptin concentrations in vitro and measured cytokine production. In addition, after removing leptin, we incubated monocytes for 5 d in culture medium, and we restimulated them on day 6 to assess cytokine production capacity, phagocytosis, and foam cell formation. Direct stimulation with leptin did not induce cytokine production, but exposure to 50 ng/mL leptin augmented lipopolysaccharide- and R848-induced tumor necrosis factor α (TNF-α) production after 1 wk. In a separate in vivo study in a cohort of 302 obese subjects (body mass index [BMI] >27 kg/m2, 55 to 81 yr), we measured circulating leptin, inflammatory markers, and cytokine production upon ex vivo stimulation of isolated peripheral blood mononuclear cells. Circulating leptin concentrations positively correlated with circulating IL-1ß and IL-6, which was more pronounced in men than in women. Four single nucleotide polymorphisms in the leptin gene influenced circulating IL-6 concentrations in men, suggesting a direct effect of leptin on IL-6. In conclusion, in vitro, leptin does not directly stimulate monocytes to produce cytokines, yet induces long-term monocyte hyperresponsiveness, i.e. trained immunity. In obese subjects, leptin is associated with circulating IL-6 in a sex-dependent manner. The underlying mechanisms of the sex-specific effect of leptin on innate immune cells remain to be further investigated.

Stratification of Atherosclerosis based on Plasma Metabolic States.

CONTEXT: Atherosclerosis is a dominant cause of cardiovascular disease (CVD), including myocardial infarction and stroke. OBJECTIVE: To investigate metabolic states that are associated with the development of atherosclerosis. METHODS: Cross-sectional cohort study at a university hospital in the Netherlands. A total of 302 adult subjects with a body mass index (BMI) ≥ 27 kg/m2 were included. We integrated plasma metabolomics with clinical metadata to quantify the "atherogenic state" of each individual, providing a continuous spectrum of atherogenic states that ranges between nonatherogenic states to highly atherogenic states. RESULTS: Analysis of groups of individuals with different clinical conditions-such as metabolically healthy individuals with obesity, and individuals with metabolic syndrome-confirmed the generalizability of this spectrum; revealed a wide variation of atherogenic states within each condition; and allowed identification of metabolites that are associated with the atherogenic state regardless of the particular condition, such as gamma-glutamyl-glutamic acid and homovanillic acid sulfate. The analysis further highlighted metabolic pathways such as catabolism of phenylalanine and tyrosine and biosynthesis of estrogens and phenylpropanoids. Using validation cohorts, we confirmed variation in atherogenic states in healthy subjects (before atherosclerosis plaques become visible), and showed that metabolites associated with the atherogenic state were also associated with future CVD. CONCLUSION: Our results provide a global view of atherosclerosis risk states using plasma metabolomics.

Sex-specific association of visceral and subcutaneous adipose tissue volumes with systemic inflammation and innate immune cells in people living with obesity.

BACKGROUND AND AIMS: Obesity predisposes to metabolic and cardiovascular diseases. Adipose tissue inflammation and systemic inflammation contribute to these complications. There are strong sex differences in adipose tissue distribution and in systemic inflammation. Women have more subcutaneous adipose tissue (SAT) and less visceral adipose tissue (VAT) than men. We explored the sex differences in the association between the different adipose compartments and inflammatory markers that are important in cardiometabolic disease pathophysiology. METHODS: Single-center observational cohort study with 302 individuals with a BMI ≥ 27 kg/m2. We were unable to acquire MRI data from seven individuals and from another 18 the MRI data were not usable, resulting in 277 people (155 men, 122 women), aged 55-81 years. INTERVENTION: We performed the following measurements: abdominal magnetic resonance imaging to measure VAT, and SAT (deep and superficial) volumes; circulating leukocyte counts and cytokine production capacity of peripheral blood mononuclear cells (PBMCs), circulating cytokines, adipokines, and targeted proteomics; abdominal sSAT biopsies for histology and gene expression. RESULTS: Only in women, (s)SAT volume was associated with circulating leukocytes, monocytes, and neutrophils. Circulating IL-6 and IL-18BP were associated with SAT volume in women and VAT in men. Several circulating proteins, including monocyte-colony-stimulating factor 1 and hepatocyte growth factor, are associated with sSAT in women and VAT in men. Only in women, SAT volume is associated with SAT expression of inflammatory proteins, including leptin, CD68, TNFα and IL-1α. CONCLUSION: In women living with obesity, abdominal SAT volume, especially sSAT, is associated with circulating leukocytes and inflammatory proteins. In men, these parameters mainly show associations with VAT volume. This could be because only in women, sSAT volume is associated with sSAT expression of inflammatory proteins. These findings underscore that future research on adipose tissue in relation to cardiometabolic and cardiovascular disease should take sex differences into account.

Traditional Cardiovascular Risk Factors Are Stronger Related to Carotid Intima-Media Thickness Than to Presence of Carotid Plaques in People Living With HIV.

Background Cardiovascular disease is a major cause of morbidity and mortality in people living with HIV, who are at higher risk than the general population. We assessed, in a large cohort of people living with HIV, which cardiovascular, HIV-specific, and lipoproteomic markers were associated with carotid intima-media thickness (cIMT) and carotid plaque presence. We also studied guideline adherence on lipid-lowering medication in individuals with high and very high risk for cardiovascular disease. Methods and Results In 1814 individuals with a median (interquartile range) age of 53 (44-60) years, we found a carotid plaque in 909 (50.1%) and a median (interquartile range) intima-media thickness of 0.66 (0.57-0.76) mm. Ultrasonography was used for the assessment of cIMT and plaque presence. Univariable and multivariable regression models were used for associations with cIMT and presence of plaques. Age, Black race, body mass index, type 2 diabetes, and smoking (pack years) were all positively associated with higher cIMT. Levels of high-density lipoprotein cholesterol, specifically medium and large high-density lipoprotein subclasses, were negatively associated with higher cIMT. Only age and prior myocardial infarction were positively related to the presence of a carotid plaque. Lipid-lowering treatment was prescribed in one-third of people living with HIV, who are at high and very high risk for cardiovascular disease. Conclusions Traditional cardiovascular risk factors were significantly associated with higher cIMT but not with carotid plaques, except for age. HIV-specific factors were not associated with both ultrasound measurements. Future studies are needed to elucidate which factors contribute to plaque formation. Improvement of guideline adherence on prescription of lipid-lowering treatment in high- and very high-risk patients for cardiovascular disease is recommended. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03994835.

Sex-specific Association Between Adipose Tissue Inflammation and Vascular and Metabolic Complications of Obesity.

CONTEXT: Adipose tissue (AT) inflammation predisposes to insulin resistance and metabolic syndrome in obesity. OBJECTIVE: To investigate the association between adipocyte size, AT inflammation, systemic inflammation, and metabolic and atherosclerotic complications of obesity in a sex-specific manner. DESIGN: Cross-sectional cohort study. SETTING: University hospital in the Netherlands. PARTICIPANTS: A total of 302 adult subjects with a body mass index (BMI) ≥ 27 kg/m2. MAIN OUTCOME MEASURES: We obtained subcutaneous abdominal fat biopsies and systematically assessed, in a sex-specific manner, associations of several parameters of AT inflammation (including adipocyte size, macrophage content, crown-like structures, and gene expression) to biomarkers of systemic inflammation, leukocyte number and function, and to the presence of metabolic syndrome, insulin resistance, and carotid atherosclerotic plaques, assessed with ultrasound. RESULTS: Adipocyte size was associated with metabolic syndrome and AT macrophage content with insulin resistance. In contrast, none of the AT parameters was associated with carotid atherosclerosis, although mRNA expression of the anti-inflammatory IL-37 was associated with a lower intima-media thickness. We revealed profound sex-specific differences, with an association between BMI and adipocyte size, and between adipocyte size and metabolic syndrome in men only. Also, only men showed an association between adipocyte size, AT expression of leptin and MCP-1, and AT macrophage numbers, and between AT inflammation (crown-like structure number) and several circulating inflammatory proteins, including high specificity C-reactive protein, and IL-6. CONCLUSIONS: Inflammation in abdominal subcutaneous adipose tissue is more related to the metabolic than the atherosclerotic complications of obesity, and there are profound sex-specific differences in the association between BMI, adipocyte size, AT inflammation, and systemic inflammation, which are much stronger in men than women.

Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family.

Objective: Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters. Methods: Uptake of 1 nM of iodothyronines or sulfated iodothyronines in COS1 cells expressing SLC22 proteins was performed. Results: We first tested 25 mouse (m) SLC22 proteins for TH uptake and found that the majority of the organic anion transporter (OAT) clade were capable of 3,3',5-triiodothyronine and/or thyroxine (T4) transport. Based on phylogenetic tree analysis of the mouse and human (h) SLC22 family, we selected eight hSLC22s that grouped with the newly identified mouse TH transporters. Of these, four tested positive for uptake of one or more substrates, particularly hSLC22A11 showed robust (3-fold over control) uptake of T4. Uptake of sulfated iodothyronines was strongly (up to 17-fold) induced by some SLC22s, most notably SLC22A8, hSLC22A9, mSLC22A27 and mSLC22A29. Finally, the zebrafish orthologues of SLC22A6/8 drOatx and drSlc22a6l also transported almost all (sulfated) iodothyronines tested. The OAT inhibitors lesinurad and probenecid inhibited most SLC22 proteins. Conclusions: Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology.

Individualized dosing of evinacumab is predicted to yield reductions in drug expenses.

BACKGROUND: Evinacumab is a first-in-class inhibitor of angiopoietin-like protein 3 (ANGPTL3) for treatment of the rare disease homozygous familial hypercholesterolemia (HoFH). With projected drug costs of $450,000 per person per year, the question rises if cost-efficacy of evinacumab can be further improved. OBJECTIVES: To develop an individualized dosing regimen te reduce drug expenses. METHODS: Using the clinical and pharmacological data as provided by the license holder, we developed an alternative dosing regimen in silico based on the principles of reduction of wastage by dosing based on weight bands rather than a linear milligram per kilogram body weight (mg/kg) dosing regimen, as well as dose individualization guided by low density lipoprotein cholesterol (LDL-C) response. RESULTS: We found that the average quantity of drug used for a dose could be reduced by 34% without predicted loss in efficacy (LDL-C reduction 24 weeks after treatment initiation). CONCLUSION: Dose reductions without compromising efficacy seem feasible. We call for implementation and prospective evaluation of this strategy to reduce treatment costs of HoFH.

Systematic analysis of relationships between plasma branched-chain amino acid concentrations and cardiometabolic parameters: an association and Mendelian randomization study.

BACKGROUND: Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids that are associated with an increased risk of cardiometabolic diseases (CMD). However, there are still only limited insights into potential direct associations between BCAAs and a wide range of CMD parameters, especially those remaining after correcting for covariates and underlying causal relationships. METHODS: To shed light on these relationships, we systematically characterized the associations between plasma BCAA concentrations and a large panel of 537 CMD parameters (including atherosclerosis-related parameters, fat distribution, plasma cytokine concentrations and cell counts, circulating concentrations of cardiovascular-related proteins and plasma metabolites) in 1400 individuals from the Dutch population cohort LifeLines DEEP and 294 overweight individuals from the 300OB cohort. After correcting for age, sex, and BMI, we assessed associations between individual BCAAs and CMD parameters. We further assessed the underlying causality using Mendelian randomization. RESULTS: A total of 838 significant associations were detected for 409 CMD parameters. BCAAs showed both common and specific associations, with the most specific associations being detected for isoleucine. Further, we found that obesity status substantially affected the strength and direction of associations for valine, which cannot be corrected for using BMI as a covariate. Subsequent univariable Mendelian randomization (UVMR), after removing BMI-associated SNPs, identified seven significant causal relationships from four CMD traits to BCAA levels, mostly for diabetes-related parameters. However, no causal effects of BCAAs on CMD parameters were supported. CONCLUSIONS: Our cross-sectional association study reports a large number of associations between BCAAs and CMD parameters. Our results highlight some specific associations for isoleucine, as well as obesity-specific effects for valine. MR-based causality analysis suggests that altered BCAA levels can be a consequence of diabetes and alteration in lipid metabolism. We found no MR evidence to support a causal role for BCAAs in CMD. These findings provide evidence to (re)evaluate the clinical importance of individual BCAAs in CMD diagnosis, prevention, and treatment.

Development and validation of a decision support tool for the diagnosis of acute heart failure: systematic review, meta-analysis, and modelling study.

OBJECTIVES: To evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with clinical characteristics. DESIGN: Individual patient level data meta-analysis and modelling study. SETTING: Fourteen studies from 13 countries, including randomised controlled trials and prospective observational studies. PARTICIPANTS: Individual patient level data for 10 369 patients with suspected acute heart failure were pooled for the meta-analysis to evaluate NT-proBNP thresholds. A decision support tool (Collaboration for the Diagnosis and Evaluation of Heart Failure (CoDE-HF)) that combines NT-proBNP with clinical variables to report the probability of acute heart failure for an individual patient was developed and validated. MAIN OUTCOME MEASURE: Adjudicated diagnosis of acute heart failure. RESULTS: Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure (73.3% (2286/3119) and 29.0% (1802/6208) in those with and without previous heart failure, respectively). The negative predictive value of the guideline recommended rule-out threshold of 300 pg/mL was 94.6% (95% confidence interval 91.9% to 96.4%); despite use of age specific rule-in thresholds, the positive predictive value varied at 61.0% (55.3% to 66.4%), 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), in patients aged <50 years, 50-75 years, and >75 years, respectively. Performance varied in most subgroups, particularly patients with obesity, renal impairment, or previous heart failure. CoDE-HF was well calibrated, with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively). In patients without previous heart failure, the diagnostic performance was consistent across all subgroups, with 40.3% (2502/6208) identified at low probability (negative predictive value of 98.6%, 97.8% to 99.1%) and 28.0% (1737/6208) at high probability (positive predictive value of 75.0%, 65.7% to 82.5%) of having acute heart failure. CONCLUSIONS: In an international, collaborative evaluation of the diagnostic performance of NT-proBNP, guideline recommended thresholds to diagnose acute heart failure varied substantially in important patient subgroups. The CoDE-HF decision support tool incorporating NT-proBNP as a continuous measure and other clinical variables provides a more consistent, accurate, and individualised approach. STUDY REGISTRATION: PROSPERO CRD42019159407.

[Transient loss of consciousness]. / Wegrakingen.

Although transient loss of consciousness (TLOC) is a common problem, hospital care for patients with TLOC is characterised by high rates of no diagnosis and misdiagnosis, accompanied by unnecessary hospital admissions and tests. We attribute these problems to increasing specialisation as well as to a blind spot for vasovagal syncope, a condition not claimed by any specialty. We suggest that all doctors seeing patients with TLOC, both in primary and secondary care, should be familiar with the presentations of the relatively harmless vasovagal syncope and the alarm symptoms of potentially life-threatening cardiac syncope. In this article we present some practical pointers to recognise these conditions and answer some frequently-asked questions regarding the diagnosis and treatment of TLOC.

Quality of life and coping in Dutch homozygous familial hypercholesterolemia patients: A qualitative study.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels leading to extremely premature atherosclerotic cardiovascular disease. Therefore, healthcare professionals consider HoFH to have major impact on patients' life. Remarkably, little is known on how patients deal with their condition. The aim of this study is to investigate how Dutch patients experience and cope with HoFH in daily life. METHODS: Adult patients with genetically confirmed HoFH, treated at the 3 specialized HoFH-centers in the Netherlands, were interviewed in-depth. Interview transcripts were analyzed according to grounded theory. Health-related quality of life (QoL) and coping were measured with the EuroQol (EQ)-5D-5L questionnaire and the Threatening Medical Situations Inventory (TMSI), respectively. RESULTS: 20 Dutch HoFH patients were interviewed: 50% women, median age 38 years, 60% with cardiovascular disease, 10% on apheresis. Coding of the transcripts resulted in a conceptual model, with disease perception as the central theme. Individual TMSI-results corresponded to the interviews, with most patients showing both monitoring (information-seeking behavior) and blunting (distractive strategies) coping styles. The median EQ-5D-5L health utility score (0.839) was only 5% below the Dutch population (0.887). Transient anxiety was reported when confronted with the consequences of HoFH in daily life. Patients reported high confidence in treatment by a dedicated HoFH center, which helped them cope with their disease. CONCLUSIONS: Dutch HoFH patients use a variety of effective coping mechanisms in such a way that their subjective QoL is only slightly affected. Healthcare professionals can use this knowledge to tailor their care to the specific needs of these patients.

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

Bile acids (BAs) facilitate intestinal fat absorption and act as important signaling molecules in host-gut microbiota crosstalk. BA-metabolizing pathways in the microbial community have been identified, but it remains largely unknown how the highly variable genomes of gut bacteria interact with host BA metabolism. We characterized 8,282 structural variants (SVs) of 55 bacterial species in the gut microbiomes of 1,437 individuals from two cohorts and performed a systematic association study with 39 plasma BA parameters. Both variations in SV-based continuous genetic makeup and discrete clusters showed correlations with BA metabolism. Metagenome-wide association analysis identified 809 replicable associations between bacterial SVs and BAs and SV regulators that mediate the effects of lifestyle factors on BA metabolism. This is the largest microbial genetic association analysis to demonstrate the impact of bacterial SVs on human BA composition, and it highlights the potential of targeting gut microbiota to regulate BA metabolism through lifestyle intervention.

Relationship between de novo lipogenesis and serum sex hormone binding globulin in humans.

OBJECTIVE: Obesity and liver fat are associated with decreased levels of serum sex hormone binding globulin (SHBG). Laboratory studies suggest that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans. DESIGN: A cross-sectional study examining the association between DNL, measured by stable isotopes, and serum SHBG, stratified by sex. PARTICIPANTS: Healthy men (n = 34) and women (n = 21) were combined from two cross-sectional studies. Forty-two per cent of participants had hepatic steatosis, and the majority were overweight (62%) or obese (27%). RESULTS: DNL was inversely associated with SHBG in women (ß: -0.015, 95% CI: -0.030; 0.000), but not in men (ß: 0.007, 95% CI: -0.005; 0.019) (p for interaction = .068). Adjustment for study population, age and body mass index did not materially change these results, although statistical significance was lost after adjustment for serum insulin. CONCLUSIONS: An inverse association between DNL and SHBG may explain the decreased SHBG levels that are observed in obesity, at least in women.

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

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.

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

Bile acids (BAs) are implicated in the etiology of obesity-related conditions such as non-alcoholic fatty liver disease. Differently structured BA species display variable signaling activities via farnesoid X receptor (FXR) and Takeda G protein-coupled BA receptor 1 (TGR5). This study profiles plasma and fecal BAs and plasma 7α-hydroxy-4-cholesten-3-one (C4) in 297 persons with obesity, identifies underlying genetic and microbial determinants, and establishes BA correlations with liver fat and plasma lipid parameters. We identify 27 genetic associations (p < 5 × 10-8) and 439 microbial correlations (FDR < 0.05) for 50 BA entities. Additionally, we report 111 correlations between BA and 88 lipid parameters (FDR < 0.05), mainly for C4 reflecting hepatic BA synthesis. Inter-individual variability in the plasma BA profile does not reflect hepatic BA synthetic pathways, but rather transport and metabolism within the enterohepatic circulation. Our study reveals genetic and microbial determinants of BAs in obesity and their relationship to disease-relevant lipid parameters that are important for the design of personalized therapies targeting BA-signaling pathways.

Gut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity.

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.

Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.

OBJECTIVE: Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m2 and half with a BMI>30 kg/m2, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity. CONCLUSIONS: We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.