An integrated analysis of bile acid metabolism in humans with severe obesity.

BACKGROUND AND AIMS: Bile acids (BA) are vital regulators of metabolism. BAs are AQ6 secreted in the small intestine, reabsorbed, and transported back to the liver, where they can modulate metabolic functions. There is a paucity of data regarding the portal BA composition in humans. This study aimed to address this knowledge gap by investigating portal BA composition and the relation with peripheral and fecal BA dynamics in conjunction with the gut microbiome. APPROACH AND RESULTS: Thirty-three individuals from the BARIA cohort were included. Portal plasma, peripheral plasma, and feces were collected. BA and C4 levels were measured employing mass spectrometry. FGF19 was measured using ELISA. Gut microbiota composition was determined through metagenomics analysis on stool samples. Considerable diversity in the portal BA composition was observed. The majority (n = 26) of individuals had a 9-fold higher portal than peripheral BA concentration. In contrast, 8 individuals showed lower portal BA concentration compared with peripheral and had higher levels of unconjugated and secondary BA in this compartment, suggesting more distal origin. The altered portal BA profile was associated with altered gut microbiota composition. In particular, taxa within Bacteroides were reduced in abundance in the feces of these individuals. CONCLUSIONS: Characterization of the portal BA composition in relation to peripheral and fecal BA increased insight into the dynamics of BA metabolism in individuals with obesity. Peripheral BA composition was much more diverse due to microbial metabolism. About 24% of the portal samples was surprisingly low in total BA; the underlying mechanism requires further exploration.

Glycodeoxycholic acid inhibits primary bile acid synthesis with minor effects on glucose- and lipid homeostasis in humans.

BACKGROUND: Bile acids play vital roles in control of lipid-, glucose-, and energy metabolism by activating Takeda G protein-coupled receptor 5 (TGR5) and Farnesoid X receptor (FXR), the latter promoting production of the endocrine-acting fibroblast growth factor 19 (FGF19). Short-term administration of single bile acids has been reported to enhance plasma levels of GLP-1 and to enhance energy expenditure. However, prolonged bile acid supplementation, e.g. of chenodeoxycholic acid (CDCA) for gallstone dissolution, has been reported to have adverse effects. STUDY DESIGN: In this proof-of-concept study, we assessed the safety and metabolic effects of oral glycine-conjugated deoxycholic acid (GDCA) administration at 10 mg/kg/day using regular and slow-release capsules (mimicking physiological bile acid release) over 30 days in two groups of each 10 healthy lean men respectively. MAIN FINDINGS: GDCA increased postprandial total bile acid and FGF19 concentrations while suppressing those of the primary bile acids CDCA and cholic acid. Plasma levels of 7α-hydroxy-4-cholesten-3-one were reduced, indicating repressed hepatic bile acid synthesis. There were minimal effects on indices of lipid-, glucose-, and energy metabolism. No serious adverse events were reported during GDCA administration in either capsule types, although 50% of participants showed mild increases in plasma levels of liver transaminases and 80% (regular capsules) and 50% (slow-release capsules) of participants experienced gastrointestinal adverse events. CONCLUSION: GDCA administration leads to elevated FGF19 levels and effectively inhibits primary bile acid synthesis, supporting therapy compliance and its effectiveness. However, effects on lipid, glucose- and energy metabolism were minimal, indicating that expanding the pool of this relatively hydrophobic bile acid does not impact energy metabolism in healthy subjects.

Novel Proteome Targets Marking Insulin Resistance in Metabolic Syndrome.

CONTEXT/OBJECTIVE: In order to better understand which metabolic differences are related to insulin resistance in metabolic syndrome (MetSyn), we used hyperinsulinemic-euglycemic (HE) clamps in individuals with MetSyn and related peripheral insulin resistance to circulating biomarkers. DESIGN/METHODS: In this cross-sectional study, HE-clamps were performed in treatment-naive men (n = 97) with MetSyn. Subjects were defined as insulin-resistant based on the rate of disappearance (Rd). Machine learning models and conventional statistics were used to identify biomarkers of insulin resistance. Findings were replicated in a cohort with n = 282 obese men and women with (n = 156) and without (n = 126) MetSyn. In addition to this, the relation between biomarkers and adipose tissue was assessed by nuclear magnetic resonance imaging. RESULTS: Peripheral insulin resistance is marked by changes in proteins related to inflammatory processes such as IL-1 and TNF-receptor and superfamily members. These proteins can distinguish between insulin-resistant and insulin-sensitive individuals (AUC = 0.72 ± 0.10) with MetSyn. These proteins were also associated with IFG, liver fat (rho 0.36, p = 1.79 × 10-9) and visceral adipose tissue (rho = 0.35, p = 6.80 × 10-9). Interestingly, these proteins had the strongest association in the MetSyn subgroup compared to individuals without MetSyn. CONCLUSIONS: MetSyn associated with insulin resistance is characterized by protein changes related to body fat content, insulin signaling and pro-inflammatory processes. These findings provide novel targets for intervention studies and should be the focus of future in vitro and in vivo studies.

Quantifying the effect of nutritional interventions on metabolic resilience using personalized computational models.

The manifestation of metabolic deteriorations that accompany overweight and obesity can differ greatly between individuals, giving rise to a highly heterogeneous population. This inter-individual variation can impede both the provision and assessment of nutritional interventions as multiple aspects of metabolic health should be considered at once. Here, we apply the Mixed Meal Model, a physiology-based computational model, to characterize an individual's metabolic health in silico. A population of 342 personalized models were generated using data for individuals with overweight and obesity from three independent intervention studies, demonstrating a strong relationship between the model-derived metric of insulin resistance (ρ = 0.67, p < 0.05) and the gold-standard hyperinsulinemic-euglycemic clamp. The model is also shown to quantify liver fat accumulation and ß-cell functionality. Moreover, we show that personalized Mixed Meal Models can be used to evaluate the impact of a dietary intervention on multiple aspects of metabolic health at the individual level.

Networks of gut bacteria relate to cardiovascular disease in a multi-ethnic population: the HELIUS study.

AIMS: Gut microbiota have been linked to blood lipid levels and cardiovascular diseases (CVDs). The composition and abundance of gut microbiota trophic networks differ between ethnicities. We aim to evaluate the relationship between gut microbiotal trophic networks and CVD phenotypes. METHODS AND RESULTS: We included cross-sectional data from 3860 individuals without CVD history from 6 ethnicities living in the Amsterdam region participating in the prospective Healthy Life in Urban Setting (HELIUS) study. Genetic variants were genotyped, faecal gut microbiota were profiled, and blood and anthropometric parameters were measured. A machine learning approach was used to assess the relationship between CVD risk (Framingham score) and gut microbiota stratified by ethnicity. Potential causal relationships between gut microbiota composition and CVD were inferred by performing two-sample Mendelian randomization with hard CVD events from the Pan-UK Biobank and microbiome genome-wide association studies summary data from a subset of the HELIUS cohort (n = 4117). Microbial taxa identified to be associated with CVD by machine learning and Mendelian randomization were often ethnic-specific, but some concordance across ethnicities was found. The microbes Akkermansia muciniphila and Ruminococcaceae UCG-002 were protective against ischaemic heart disease in African-Surinamese and Moroccans, respectively. We identified a strong inverse association between blood lipids, CVD risk, and the combined abundance of the correlated microbes Christensenellaceae-Methanobrevibacter-Ruminococcaceae (CMR). The CMR cluster was also identified in two independent cohorts and the association with triglycerides was replicated. CONCLUSION: Certain gut microbes can have a potentially causal relationship with CVD events, with possible ethnic-specific effects. We identified a trophic network centred around Christensenellaceae, Methanobrevibacter, and various Ruminococcaceae, frequently lacking in South-Asian Surinamese, to be protective against CVD risk and associated with low triglyceride levels.

Diacylglycerols and Lysophosphatidic Acid, Enriched on Lipoprotein(a), Contribute to Monocyte Inflammation.

BACKGROUND: Oxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into additional proinflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a). METHODS: Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNA sequencing, ELISA, Western blot, and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions. RESULTS: Compared with healthy individuals with low/normal Lp(a) levels (median, 7 mg/dL [18 nmol/L]; n=13), individuals with elevated Lp(a) levels (median, 87 mg/dL [218 nmol/L]; n=12) demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in proinflammatory pathways related to leukocyte migration, chemotaxis, NF-κB (nuclear factor kappa B) signaling, and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL (interleukin)-6, IL-8, and IL-1ß after DG(40:6) and DG(38:4) stimulation, which was, in part, mediated via the NLRP3 (NOD [nucleotide-binding oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated colocalization of Lp(a) with M1 macrophages, and an enrichment of CD68+IL-18+TLR4+ (toll-like receptor) TREM2+ (triggering receptor expressed on myeloid cells) resident macrophages and CD68+CASP1+ (caspase) IL-1B+SELL+ (selectin L) inflammatory macrophages compared with patients with low Lp(a). Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]). CONCLUSIONS: Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is, in part, NLRP3 inflammasome dependent.

Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure.

BACKGROUND: Despite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current heart failure therapies. OBJECTIVES: We sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death. METHODS: We used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients. RESULTS: The mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro-B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients. CONCLUSIONS: A systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin.

Protein supplementation changes gut microbial diversity and derived metabolites in subjects with type 2 diabetes.

High-protein diets are promoted for individuals with type 2 diabetes (T2D). However, effects of dietary protein interventions on (gut-derived) metabolites in T2D remains understudied. We therefore performed a multi-center, randomized-controlled, isocaloric protein intervention with 151 participants following either 12-week high-protein (HP; 30Energy %, N = 78) vs. low-protein (LP; 10 Energy%, N = 73) diet. Primary objectives were dietary effects on glycemic control which were determined via glycemic excursions, continuous glucose monitors and HbA1c. Secondary objectives were impact of diet on gut microbiota composition and -derived metabolites which were determined by shotgun-metagenomics and mass spectrometry. Analyses were performed using delta changes adjusting for center, baseline, and kidney function when appropriate. This study found that a short-term 12-week isocaloric protein modulation does not affect glycemic parameters or weight in metformin-treated T2D. However, the HP diet slightly worsened kidney function, increased alpha-diversity, and production of potentially harmful microbiota-dependent metabolites, which may affect host metabolism upon prolonged exposure.

Bariatric surgery improves postprandial VLDL kinetics and restores insulin-mediated regulation of hepatic VLDL production.

Dyslipidemia in obesity results from excessive production and impaired clearance of triglyceride-rich (TG-rich) lipoproteins, which are particularly pronounced in the postprandial state. Here, we investigated the impact of Roux-en-Y gastric bypass (RYGB) surgery on postprandial VLDL1 and VLDL2 apoB and TG kinetics and their relationship with insulin-responsiveness indices. Morbidly obese patients without diabetes who were scheduled for RYGB surgery (n = 24) underwent a lipoprotein kinetics study during a mixed-meal test and a hyperinsulinemic-euglycemic clamp study before the surgery and 1 year later. A physiologically based computational model was developed to investigate the impact of RYGB surgery and plasma insulin on postprandial VLDL kinetics. After the surgery, VLDL1 apoB and TG production rates were significantly decreased, whereas VLDL2 apoB and TG production rates remained unchanged. The TG catabolic rate was increased in both VLDL1 and VLDL2 fractions, but only the VLDL2 apoB catabolic rate tended to increase. Furthermore, postsurgery VLDL1 apoB and TG production rates, but not those of VLDL2, were positively correlated with insulin resistance. Insulin-mediated stimulation of peripheral lipoprotein lipolysis was also improved after the surgery. In summary, RYGB resulted in reduced hepatic VLDL1 production that correlated with reduced insulin resistance, elevated VLDL2 clearance, and improved insulin sensitivity in lipoprotein lipolysis pathways.

Age and Diet Modulate the Insulin-Sensitizing Effects of Exercise: A Tracer-Based Oral Glucose Tolerance Test.

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance and mitochondrial lipid oxidation and also enhances insulin sensitivity (IS). It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests with tracers were conducted in mice ranging from 4 to 21 months of age, fed a low-fat diet (LFD) or high-fat diet (HFD) with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Values for an IS index derived for peripheral tissues (IS-P) and one for the liver (IS-L) were steeply decreased by aging and an HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In young animals fed an LFD, RW access enhanced the IS-P concomitantly with the muscle ß-oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease; however this only occurred in animals fed an LFD. Therefore, this study indicates that endurance exercise can improve the age-dependent decline in organ-specific IS if paired with a healthy diet. ARTICLE HIGHLIGHTS: Exercise is a known strategy to improve insulin sensitivity (IS), whereas aging and a lipid-rich diet decrease IS. Using a tracer-based oral glucose tolerance test, we investigated how exercise, age, and diet interact in the development of tissue-specific insulin resistance. Exercise (voluntary access to a running wheel) mainly improved IS in animals fed a low-fat diet. In these animals, exercise improved peripheral IS only at young age but fully prevented the age-dependent decline of hepatic IS. The prevention of age-dependent decline in IS by exercise is tissue-specific and blunted by a lipid-rich diet.

Age and diet modulate the insulin-sensitizing effects of exercise: a tracer-based oral glucose tolerance test.

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests (OGTT) with a tracer were conducted in mice ranging from 4 to 21 months of age, fed a low- (LFD) or high-fat diet (HFD), with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Both insulin sensitivity indices derived for peripheral tissues and liver (IS-P and IS-L, respectively) were steeply decreased by aging and a HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In LFD young animals, RW access enhanced the IS-P concomitantly with the muscle ß- oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease, but only in LFD animals. This study indicates, therefore, that endurance exercise can improve the age-dependent decline in organ-specific IS mostly in the context of a healthy diet.

Self-organized metabotyping of obese individuals identifies clusters responding differently to bariatric surgery.

Weight loss through bariatric surgery is efficient for treatment or prevention of obesity related diseases such as type 2 diabetes and cardiovascular disease. Long term weight loss response does, however, vary among patients undergoing surgery. Thus, it is difficult to identify predictive markers while most obese individuals have one or more comorbidities. To overcome such challenges, an in-depth multiple omics analyses including fasting peripheral plasma metabolome, fecal metagenome as well as liver, jejunum, and adipose tissue transcriptome were performed for 106 individuals undergoing bariatric surgery. Machine leaning was applied to explore the metabolic differences in individuals and evaluate if metabolism-based patients' stratification is related to their weight loss responses to bariatric surgery. Using Self-Organizing Maps (SOMs) to analyze the plasma metabolome, we identified five distinct metabotypes, which were differentially enriched for KEGG pathways related to immune functions, fatty acid metabolism, protein-signaling, and obesity pathogenesis. The gut metagenome of the most heavily medicated metabotypes, treated simultaneously for multiple cardiometabolic comorbidities, was significantly enriched in Prevotella and Lactobacillus species. This unbiased stratification into SOM-defined metabotypes identified signatures for each metabolic phenotype and we found that the different metabotypes respond differently to bariatric surgery in terms of weight loss after 12 months. An integrative framework that utilizes SOMs and omics integration was developed for stratifying a heterogeneous bariatric surgery cohort. The multiple omics datasets described in this study reveal that the metabotypes are characterized by a concrete metabolic status and different responses in weight loss and adipose tissue reduction over time. Our study thus opens a path to enable patient stratification and hereby allow for improved clinical treatments.

Severe Dyslipidemia Mimicking Familial Hypercholesterolemia Induced by High-Fat, Low-Carbohydrate Diets: A Critical Review.

Emerging studies in the literature describe an association between high-fat, low-carbohydrate diets and severe hypercholesterolemia consistent with the levels observed in patients with (homozygous) familial hypercholesterolemia (FH). High levels of low-density lipoprotein cholesterol (LDL-C) may result from the reduced clearance of LDL particles from the circulation, the increased production of their precursor, or a combination of both. The increased intake of (saturated) fat and cholesterol, combined with limited to no intake of carbohydrates and fiber, are the main features of diets linked to hypercholesterolemia. However, several observations in previous studies, together with our observations from our lipid clinic, do not provide a definitive pathophysiological explanation for severe hypercholesterolemia. Therefore, we review these findings and possible pathophysiological explanations as well as opportunities for future research. Altogether, clinicians should rule out high-fat, low-carbohydrate diets as a possible cause for hypercholesterolemia in patients presenting with clinical FH in whom no mutation is found and discuss dietary modifications to durably reduce LDL-C levels and cardiovascular disease risk.

A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding.

Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice.

Microbiome-derived ethanol in nonalcoholic fatty liver disease.

To test the hypothesis that the gut microbiota of individuals with nonalcoholic fatty liver disease (NAFLD) produce enough ethanol to be a driving force in the development and progression of this complex disease, we performed one prospective clinical study and one intervention study. Ethanol was measured while fasting and 120 min after a mixed meal test (MMT) in 146 individuals. In a subset of 37 individuals and in an external validation cohort, ethanol was measured in portal vein blood. In an intervention study, ten individuals with NAFLD and ten overweight but otherwise healthy controls were infused with a selective alcohol dehydrogenase (ADH) inhibitor before an MMT. When compared to fasted peripheral blood, median portal vein ethanol concentrations were 187 (interquartile range (IQR), 17-516) times higher and increased with disease progression from 2.1 mM in individuals without steatosis to 8.0 mM in NAFL 21.0 mM in nonalcoholic steatohepatitis. Inhibition of ADH induced a 15-fold (IQR,1.6- to 20-fold) increase in peripheral blood ethanol concentrations in individuals with NAFLD, although this effect was abolished after antibiotic treatment. Specifically, Lactobacillaceae correlated with postprandial peripheral ethanol concentrations (Spearman's rho, 0.42; P < 10-5) in the prospective study. Our data show that the first-pass effect obscures the levels of endogenous ethanol production, suggesting that microbial ethanol could be considered in the pathogenesis of this highly prevalent liver disease.

Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans.

BACKGROUNDCytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.METHODSTo determine whether reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays.RESULTSMutation carriers had lower plasma 12α-hydroxylated/non-12α-hydroxylated BA and cholic acid (CA)/chenodeoxycholic acid (CDCA) ratios compared with age-, sex-, and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to mutation-carrier CA/CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We found that reduced CYP8B1 activity associates with increased insulin sensitivity in humans.CONCLUSIONOur findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.FUNDINGBiomedical Research Council/National Medical Research Council of Singapore.

Gut microbiome associations with host genotype vary across ethnicities and potentially influence cardiometabolic traits.

Previous studies in mainly European populations have reported that the gut microbiome composition is associated with the human genome. However, the genotype-microbiome interaction in different ethnicities is largely unknown. We performed a large fecal microbiome genome-wide association study of a single multiethnic cohort, the Healthy Life in an Urban Setting (HELIUS) cohort (N = 4,117). Mendelian randomization was performed using the multiethnic Pan-UK Biobank (N = 460,000) to dissect potential causality. We identified ethnicity-specific associations between host genomes and gut microbiota. Certain microbes were associated with genotype in multiple ethnicities. Several of the microbe-associated loci were found to be related to immune functions, interact with glutamate and the mucus layer, or be expressed in the gut or brain. Additionally, we found that gut microbes potentially influence cardiometabolic health factors such as BMI, cholesterol, and blood pressure. This provides insight into the relationship of ethnicity and gut microbiota and into the possible causal effects of gut microbes on cardiometabolic traits.

A systems biology approach to study non-alcoholic fatty liver (NAFL) in women with obesity.

Non-alcoholic fatty liver disease (NAFLD) is now the most frequent global chronic liver disease. Individuals with NAFLD exhibited an increased risk of all-cause mortality driven by extrahepatic cancers and liver and cardiovascular disease. Once the disease is established, women have a higher risk of disease progression and worse outcome. It is therefore critical to deepen the current knowledge on the pathophysiology of NAFLD in women. Here, we used a systems biology approach to investigate the contribution of different organs to this disease. We analyzed transcriptomics profiles of liver and adipose tissues, fecal metagenomes, and plasma metabolomes of 55 women with and without NAFLD. We observed differences in metabolites, expression of human genes, and gut microbial features between the groups and revealed that there is substantial crosstalk between these different omics sets. Multi-omics analysis of individuals with NAFLD may provide novel strategies to study the pathophysiology of NAFLD in humans.

[Laparoscopic cholecystolithotomy]. / Laparoscopische cholecystolithotomie.

Laparoscopic cholecystectomy is the standard treatment for upper abdominal complaints in the presence of gallbladder stones. This operation is a mediocre solution since only 63 % of the operated patients the symptoms become symptom free after one year. The laparoscopic cholecystolithotomy is an alternative procedure for removal of gallstones while preserving the gallbladder. This technique is being performed in Asia, but not in Western countries. The technique seems promising in patients after a bariatric procedure. These patients have a temporarily increased incidence of gallbladder stones. Laparoscopic cholecystectomy is associated with a an increased complication rate in these patients. But also non bariatric patients with symptomatic gallbladder stones might benefit from a laparoscopic cholecystolithotomy.

Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts.

Cellular senescence is an essentially irreversible growth arrest that occurs in response to various cellular stressors and may contribute to development of type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). In this article, we investigated whether chronically elevated insulin levels are associated with cellular senescence in the human liver. In 107 individuals undergoing bariatric surgery, hepatic senescence markers were assessed by immunohistochemistry as well as transcriptomics. A subset of 180 participants from the ongoing Finnish Kuopio OBesity Surgery (KOBS) study was used as validation cohort. We found plasma insulin to be highly associated with various markers of cellular senescence in liver tissue. The liver transcriptome of individuals with high insulin revealed significant upregulation of several genes associated with senescence: p21, TGFß, PI3K, HLA-G, IL8, p38, Ras, and E2F. Insulin associated with hepatic senescence independently of NAFLD and plasma glucose. By using transcriptomic data from the KOBS study, we could validate the association of insulin with p21 in the liver. Our results support a potential role for hyperinsulinemia in induction of cellular senescence in the liver. These findings suggest possible benefits of lowering insulin levels in obese individuals with insulin resistance.