Intestinal microbiota changes are associated with the development of obesity. However, studies in humans have generated conflicting results due to high inter-individual heterogeneity in terms of ...diet, age, and hormonal factors, and the largely unexplored influence of gender. In this work, we aimed to identify differential gut microbiota signatures associated with obesity, as a function of gender and changes in body mass index (BMI). Differences in the bacterial community structure were analyzed by 16S sequencing in 39 men and 36 post-menopausal women, who had similar dietary background, matched by age and stratified according to the BMI. We observed that the abundance of the Bacteroides genus was lower in men than in women (P<0.001, Q = 0.002) when BMI was > 33. In fact, the abundance of this genus decreased in men with an increase in BMI (P<0.001, Q<0.001). However, in women, it remained unchanged within the different ranges of BMI. We observed a higher presence of Veillonella (84.6% vs. 47.2%; X2 test P = 0.001, Q = 0.019) and Methanobrevibacter genera (84.6% vs. 47.2%; X2 test P = 0.002, Q = 0.026) in fecal samples in men compared to women. We also observed that the abundance of Bilophila was lower in men compared to women regardless of BMI (P = 0.002, Q = 0.041). Additionally, after correcting for age and sex, 66 bacterial taxa at the genus level were found to be associated with BMI and plasma lipids. Microbiota explained at P = 0.001, 31.17% variation in BMI, 29.04% in triglycerides, 33.70% in high-density lipoproteins, 46.86% in low-density lipoproteins, and 28.55% in total cholesterol. Our results suggest that gut microbiota may differ between men and women, and that these differences may be influenced by the grade of obesity. The divergence in gut microbiota observed between men and women might have a dominant role in the definition of gender differences in the prevalence of metabolic and intestinal inflammatory diseases.
BACKGROUNDEndothelial dysfunction is a crucial step in atherosclerosis development, and its severity is determinant for the risk of cardiovascular recurrence. Diet may be an effective strategy to ...protect the endothelium, although there is no consensus about the best dietary model. The CORonary Diet Intervention with Olive oil and cardiovascular PREVention (CORDIOPREV) study is an ongoing prospective, randomized, single-blind, controlled trial in 1,002 coronary heart disease (CHD) patients, whose primary objective is to compare the effect of 2 healthy dietary patterns (low-fat versus Mediterranean diet) on the incidence of cardiovascular events. Here, we report the results of one secondary outcome of the CORDIOPREV study: to evaluate the effect of these diets on endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery. METHODS AND FINDINGSFrom the total participants taking part in the CORDIOPREV study, 805 completed endothelial function study at baseline and were randomized to follow a Mediterranean diet (35% fat, 22% monounsaturated fatty acids MUFAs, and <50% carbohydrates) or a low-fat diet (28% fat, 12% MUFAs, and >55% carbohydrates), with endothelial function measurement repeated after 1 year. As secondary objectives and to explore different underlying mechanisms in the modulation of endothelial function, we quantified endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) and evaluated, in 24 preselected patients, in vitro cellular processes related to endothelial damage (reactive oxygen species, apoptosis, and senescence) and endothelial repair (cell proliferation and angiogenesis), as well as other modulators (micro-RNAs miRNAs and proteins). Patients who followed the Mediterranean diet had higher FMD (3.83%; 95% confidence interval CI: 2.91-4.23) compared with those in the low-fat diet (1.16%; 95% CI: 0.80 to 1.98) with a difference between diets of 2.63% (95% CI: 1.89-3.40, p = 0.011), even in those patients with severe endothelial dysfunction. We observed higher EPC levels (group difference: 1.64%; 95% CI: 0.79-2.13, p = 0.028) and lower EMPs (group difference: -755 EMPs/μl; 95% CI: -1,010 to -567, p = 0.015) after the Mediterranean diet compared with the low-fat diet in all patients. We also observed lower intracellular reactive oxygen species (ROS) production (group difference: 11.1; 95% CI: 2.5 to 19.6, p = 0.010), cellular apoptosis (group difference: -20.2; 95% CI: -26.7 to -5.11, p = 0.013) and senescence (18.0; 95% CI: 3.57 to 25.1, p = 0.031), and higher cellular proliferation (group difference: 11.3; 95% CI: 4.51 to 13.5, p = 0.011) and angiogenesis (total master segments length, group difference: 549; 95% CI: 110 to 670, p = 0.022) after the Mediterranean diet than the low-fat diet. Each dietary intervention was associated with distinct changes in the epigenetic and proteomic factors that modulate biological process associated with endothelial dysfunction. The evaluation of endothelial function is a substudy of the CORDIOPREV study. As in any substudy, these results should be treated with caution, such as the potential for false positives because of the exploratory nature of the analyses. CONCLUSIONSOur results suggest that the Mediterranean diet better modulates endothelial function compared with a low-fat diet and is associated with a better balance of vascular homeostasis in CHD patients, even in those with severe endothelial dysfunction. CLINICAL TRIAL REGISTRATIONURL, http://www.cordioprev.es/index.php/en. clinicaltrials.gov number NCT00924937.
•The gut microbiota is related to the development of metabolic diseases, whose incidence is sexually dimorphic.•The incidence of metabolic diseases depends on gonadal status; for example, it ...increases after menopause.•We show differences in the composition of the gut microbiota between genders and people of different hormonal status.•Menopause alters the Firmicutes/Bacteroidetes ratio and may reduce the saccharolytic activity of the gut microbiota.
We explore the differences in the gut microbiota associated with gender and hormonal status.
We included 76 individuals in this study: 17 pre-menopausal women, 19 men matched by age, as a control group for the pre-menopausal women, 20 post-menopausal women and 20 men matched by age as a control group for the post-menopausal women; all 4 groups were also matched by body mass index (BMI) and nutritional background.
We analyzed the differences in the gut microbiota, endotoxemia, intestinal incretins, pro-inflammatory cytokines, and plasma levels of energy homeostasis regulatory hormones between pre- and post-menopausal women and compared them with their respective male control groups.
We found a higher Firmicutes/Bacteroidetes ratio, a higher relative abundance of Lachnospira and Roseburia, and higher GLP-1 plasma levels in pre-menopausal women than in post-menopausal women, who had similar levels to men. In contrast, we observed a lower relative abundance of the Prevotella, Parabacteroides and Bilophila genera, and IL-6 and MCP-1 plasma levels in pre-menopausal women than in post-menopausal women, who had similar levels to the men. We also found higher GiP and leptin plasma levels in women than in men, irrespective of the menopausal status of the women. In addition, adiponectin levels were higher in pre-menopausal women than in their corresponding age-matched male control group.
Our results suggest that the differences in the composition of gut microbiota between genders and between women of different hormonal status may be related to the sexual dimorphism observed in the incidence of metabolic diseases and their co-morbidities.
Scope
The consumption of two healthy diets (Mediterranean (MED) and low‐fat (LF) diets) may restore the gut microbiome dysbiosis in obese patients depending on the degree of metabolic dysfunction.
...Methods and results
The differences in bacterial community at baseline and after 2 years of dietary intervention of 106 subjects from the CORDIOPREV study were analyzed, 33 of whom were obese patients with severe metabolic disease (5 criteria for metabolic syndrome) (MetS‐OB), 32 obese patients without metabolic dysfunction (2 or less criteria for metabolic syndrome) (NonMetS‐OB) and 41 non‐obese subjects (NonMetS‐NonOB). Our study showed a marked dysbiosis in people with severe metabolic disease (Met‐OB), compared with obese people without MetS (NonMetS‐OB) and non‐obese people (NonMetS‐NonOB). This disbiotic pattern was reversed by consumption of both MED (35% of calories as fat (22% MUFA fat, 6% PUFA fat and <10% saturated fat) or LF (<30% total fat (<10% saturated fat, 12%–14% MUFA fat and 6–8% PUFA fat) diets, whereas no significant microbiota changes were observed in NonMetS‐NonOB and NonMetS‐OB groups.
Conclusion
Our results suggest that the chronic intake of two healthy dietary patterns partially restores the gut microbiome dysbiosis in obese patients with coronary heart disease, depending on the degree of metabolic dysfunction.
A dysbiotic pattern in gut microbiota is found in obese people with metabolic dysfunction whereas the gut microbiota of obese people without metabolic disease is only partially altered as compared with non‐obese people. This dysbiosis is reversed by the chronic consumption of both Mediterranean or low‐fat diets, shaping microbiota to the pattern found in metabolically healthy people. However, no relevant microbiota changes were observed after the dietary intervention in non‐obese and obese people without metabolic dysfunction.
Adipose tissue dysregulation in obesity strongly influences systemic metabolic homeostasis and is often linked to insulin resistance (IR). However, the molecular mechanisms underlying adipose tissue ...dysfunction in obesity are not fully understood. Herein, a proteomic analysis of subcutaneous (SC) and omental (OM) fat from lean subjects and obese individuals with different degrees of insulin sensitivity was performed to identify adipose tissue biomarkers related to obesity‐associated metabolic disease. Our results suggest that dysregulation of both adipose tissue extracellular matrix (ECM) organization and intracellular trafficking processes may be associated with IR in obesity. Thus, abnormal accumulation of the small leucine‐rich proteoglycan, lumican, as observed in SC fat of IR obese individuals, modifies collagen I organization, impairs adipogenesis and activates stress processes endoplasmic reticulum and oxidative stress in adipocytes. In OM fat, IR is associated with increased levels of the negative regulator of the Rab family of small GTPases, GDI2, which alters lipid storage in adipocytes by inhibiting insulin‐stimulated binding of the Rab protein, Rab18, to lipid droplets. Together, these results indicate that lumican and GDI2 might play depot‐dependent, pathogenic roles in obesity‐associated IR. Our findings provide novel insights into the differential maladaptive responses of SC and OM adipose tissue linking obesity to IR.
The Mediterranean diet has recently been the focus of considerable attention as a palatable model of a healthy diet. Its influence on many cardiovascular risk factors, combined with its proven effect ...in reducing the risk of cardiovascular events in primary prevention, has boosted scientific interest in this age-old nutritional model. Many of the underlying mechanisms behind its health-giving effects have been revealed, from the modulation of the microbiota to the function of high-density lipoproteins (HDL), and it seems to deliver its health benefits mainly by regulating several key mechanisms of atherosclerosis. In this review, we will review the evidence for its regulation of endothelial function, a key element in the early and late stages of atherosclerosis. In addition, we will assess studies which evaluate its effects on the functioning of different arterial territory vessels (mainly the microvascular, peripheral and central vascular beds), focusing mainly on the capillary, brachial and carotid arteries. Finally, we will evaluate the molecular mechanisms which may be involved.
Scope
Insulin resistance (IR) and chronic low‐grade inflammation are hallmarks of type 2 diabetes mellitus (T2DM). The “NOD‐like receptor pyrin domain containing‐3” (NLRP3) inflammasome component of ...innate immunity is a metabolic stress sensor modulated by dietary and genetics factors. The aim of this study was to evaluate the effects of the consumption of two diets for 3 years, Mediterranean (Med) and low fat, on glucose homeostasis in the 1002 coronary heart disease patients of the CORDIOPREV study, according to a genetic variant of NLRP3 inflammasome.
Methods and results
The study was conducted in the framework of the CORDIOPREV study, a randomized dietary intervention with Med and low‐fat diets. Single nucleotide polymorphisms (SNPs) located at inflammasome NLRP3 gene were genotyped by OpenArray platform. Nondiabetic CT+TT carriers of the rs4612666 SNP and AG+AA carriers of the rs10733113 SNP increased insulin sensitivity index (ISI) after 3 years of dietary intervention, whereas no effect was observed in diabetic patients. Further analysis by diet showed that the improvement of the ISI in nondiabetic rs10733113 AG+AA carriers was specific to the consumption of the Med diet.
Conclusion
Our results show that the benefits associated with a Med diet regarding glucose homeostasis in non‐T2DM patients depend on genetic variation in the inflammasome.
NLRP3 inflammasome activation specifically induces IL‐1β inflammation, which in turn leads to insulin resistance and progression of type 2 diabetes. It is shown that rs10733113 A allele carriers improve the insulin sensitivity after 3 years of Mediterranean (Med) diet consumption, presumably by dietary MUFA‐inflammasome gene variant interaction. Thus, the beneficial properties associated with Med diet in terms of glucose homeostasis may depend on an individual's genetic background.
Circulating microRNAs (miRNAs) have been proposed as biomarkers for type 2 diabetes (T2D). Adipose tissue (AT), for which dysfunction is widely associated with T2D development, has been reported as a ...major source of circulating miRNAs. However, the role of dysfunctional AT in the altered pattern of circulating miRNAs associated with T2D onset remains unexplored. Herein, we investigated the relationship between T2D-associated circulating miRNAs and AT function, as well as the role of preadipocytes and adipocytes as secreting cells of candidate circulating miRNAs. Among the plasma miRNAs related to T2D onset in the CORonary Diet Intervention with Olive oil and cardiovascular PREVention (CORDIOPREV) cohort, baseline miR-223-3p levels (diminished in patients who next developed T2D incident-T2D) were significantly related to AT insulin resistance (IR). Baseline serum from incident-T2D participants induced inflammation and IR in 3T3-L1 adipocytes. We demonstrated that tumor necrosis factor (TNF)-α inhibited miR-223-3p secretion while enhancing miR-223-3p intracellular accumulation in 3T3-L1 (pre)adipocytes. Overexpression studies showed that an intracellular increase of miR-223-3p impaired glucose and lipid metabolism in these cells. Our findings provide mechanistic insights into the alteration of circulating miRNAs preceding T2D, unveiling both preadipocytes and adipocytes as miR-223-3p-secreting cells and suggesting that inflammation promotes miR-223-3p intracellular accumulation, which might contribute to (pre)adipocyte dysfunction and body metabolic dysregulation.
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The relationship between adipose dysfunction and circulating miRNAs associated with T2D onset was investigated. Low circulating miR-223-3p related to adipose tissue insulin resistance index (ATIRI) in incident-T2D subjects. Both preadipocytes and adipocytes secrete miR-223-3p, and inflammation-induced intracellular miR-223-3p accumulation leads to cell dysfunction, which might contribute to body metabolic dysregulation.
Telomere Length (TL), a marker of cellular aging, holds promise as a biomarker to elucidate the molecular mechanism of diabetes. This study aimed to investigate whether shorter telomeres are ...associated with a higher risk of type 2 diabetes mellitus (T2DM) incidence in patients with coronary heart disease; and to determine whether the most suitable dietary patterns, particularly a Mediterranean diet or a low-fat diet, can mitigate the development of diabetes in these patients after a follow-up period of five years.
The CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive two healthy diets. Clinical investigators were masked to treatment assignment; participants were not. Quantitative-PCR was used to assess TL measurements.
1002 patients (59.5 ± 8.7 years and 82.5% men) were enrolled into Mediterranean diet (n = 502) or a low-fat diet (n = 500) groups. In this analysis, we included all 462 patients who did not have T2DM at baseline. Among them, 107 patients developed T2DM after a median of 60 months. Cox regression analyses showed that patients at risk of short telomeres (TL < percentile 20th) are more likely to experience T2DM than those at no risk of short telomeres (HR 1.65, p-value 0.023). In terms of diet, patients at high risk of short telomeres had a higher risk of T2DM incidence after consuming a low-fat diet compared to patients at no risk of short telomeres (HR 2.43, 95CI% 1.26 to 4.69, p-value 0.008), while no differences were observed in the Mediterranean diet group.
Patients with shorter TL presented a higher risk of developing T2DM. This association could be mitigated with a specific dietary pattern, in our case a Mediterranean diet, to prevent T2DM in patients with coronary heart disease.
Clinicaltrials.gov number NCT00924937.
SCOPE: To determine whether the insulin resistance that exists in metabolic syndrome (MetS) patients is modulated by dietary fat composition. METHODS AND RESULTS: Seventy‐five patients were randomly ...assigned to one of four diets for 12 wk: high‐saturated fatty acids (HSFAs), high‐MUFA (HMUFA), and two low‐fat, high‐complex carbohydrate (LFHCC) diets supplemented with long‐chain n‐3 (LFHCC n‐3) PUFA or placebo. At the end of intervention, the LFHCC n‐3 diet reduced plasma insulin, homeostasis model assessment of insulin resistance, and nonsterified fatty acid concentration (p < 0.05) as compared to baseline Spanish habitual (BSH) diet. Subcutaneous white adipose tissue (WAT) analysis revealed decreased EH‐domain containing‐2 mRNA levels and increased cbl‐associated protein gene expression with the LFHCC n‐3 compared to HSFA and HMUFA diets, respectively (p < 0.05). Moreover, the LFHCC n‐3 decreased gene expression of glyceraldehyde‐3‐phosphate dehydrogenase with respect to HMUFA and BSH diets (p < 0.05). Finally, proteomic characterization of subcutaneous WAT identified three proteins of glucose metabolism downregulated by the LFHCC n‐3 diet, including annexin A2. RT‐PCR analysis confirmed the decrease of annexin A2 (p = 0.027) after this diet. CONCLUSION: Our data suggest that the LFHCC n‐3 diet reduces systemic insulin resistance and improves insulin signaling in subcutaneous WAT of MetS patients compared to HSFA and BSH diets consumption.
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