Adiposity is associated with expansion of the genus Dialister in rheumatoid arthritis patients.

OBJECTIVE: To analyze the intestinal microbiota of patients with rheumatoid arthritis (RA) and obesity and a higher percentage of fatty tissue. METHODS: Nested case-control study of 80 RA patients and 80 age and sex-matched controls. Obesity was defined as a body mass index ≥ 30, and body composition using dual-energy x-ray absorptiometry. The gut microbiota was analyzed using 16 S rRNA gene sequencing; bioinformatics analysis was performed using QIIME2 and PICRUSt. Other variables included averaged 28-joint Disease Activity Score (DAS28-ESR), cytokines and adipokines. Two multivariate were constructed with obesity and fat mass index (FMI). RESULTS: Obesity was more frequent in RA patients than in controls (36.3 % vs 25.1 %; p = 0.026), as was a higher FMI value (mean [SE]=11.6 [3.9] vs 10.2 [3.9]; p = 0.032). Alpha and beta diversity analysis revealed differences in gut microbiota between RA patients with and without obesity. Dialister and Odoribacter were more abundant in RA patients with obesity than in RA patients without obesity, while the genus Clostridium was more abundant in RA patients without obesity. The factors associated with obesity in RA patients were age (OR [95 % CI], 1.09 [1.02-1.17]), mean DAS28-ESR (OR [95 % CI], 1.46 [1.12-1.67]), leptin levels (OR [95 % CI], 1.06 [1.01-1.10]), the genus Dialister (OR [95 % CI], 1.03 [1.01-1.07]), and the genus Clostridium (OR [95 % CI], 0.013 [0.00-0.36]). The associations observed for FMI were similar. CONCLUSIONS: In patients with RA, obesity, and a higher percentage of fatty tissue, intestinal microbiota differed from that of controls and of the other patients. The genus Dialister was associated with obesity and FMI.

Influence of Factors Altering Gastric Microbiota on Bariatric Surgery Metabolic Outcomes.

Little is known about the influence of gastric microbiota on host metabolism, even though the stomach plays an important role in the production of hormones involved in body weight regulation and glucose homeostasis. Proton pump inhibitors (PPIs) and Helicobacter pylori alter gut microbiota, but their impact on gastric microbiota in patients with obesity and the influence of these factors on the metabolic response to bariatric surgery is not fully understood. Forty-one subjects with morbid obesity who underwent sleeve gastrectomy were included in this study. The H. pylori group was established by the detection of H. pylori using a sequencing-based method (n = 16). Individuals in whom H. pylori was not detected were classified according to PPI treatment. Gastric biopsy specimens were obtained during surgery and were analyzed by a high-throughput-sequencing method. Patients were evaluated at baseline and 3, 6, and 12 months after surgery. ß-Diversity measures were able to cluster patients according to their gastric mucosa-associated microbiota composition. H. pylori and PPI treatment are presented as two important factors for gastric mucosa-associated microbiota. H. pylori reduced diversity, while PPIs altered ß-diversity. Both factors induced changes in the gastric mucosa-associated microbiota composition and its predicted functions. PPI users showed lower percentages of change in the body mass index (BMI) in the short term after surgery, while the H. pylori group showed higher glucose levels and lower percentages of reduction in body weight/BMI 1 year after surgery. PPIs and H. pylori colonization could modify the gastric mucosa-associated microbiota, altering its diversity, composition, and predicted functionality. These factors may have a role in the metabolic evolution of patients undergoing bariatric surgery. IMPORTANCE The gut microbiota has been shown to have an impact on host metabolism. In the stomach, factors like proton pump inhibitor treatment and Helicobacter pylori haven been suggested to alter gut microbiota; however, the influence of these factors on the metabolic response to bariatric surgery has not been fully studied. In this study, we highlight the impact of these factors on the gastric microbiota composition. Moreover, proton pump inhibitor treatment and the presence of Helicobacter pylori could have an influence on bariatric surgery outcomes, mainly on body weight loss and glucose homeostasis. Deciphering the relationship between gastric hormones and gastric microbiota and their contributions to bariatric surgery outcomes paves the way to develop gut manipulation strategies to improve the metabolic success of bariatric surgery.

Gut Microbiota Metabolism of Bile Acids Could Contribute to the Bariatric Surgery Improvements in Extreme Obesity.

Bariatric surgery is the only procedure to obtain and maintain weight loss in the long term, although the mechanisms driving these benefits are not completely understood. In the last years, gut microbiota has emerged as one of the drivers through its metabolites, especially secondary bile acids. In the current study, we have compared the gut microbiota and the bile acid pool, as well as anthropometric and biochemical parameters, of patient with morbid obesity who underwent bariatric surgery by two different techniques, namely Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Gut microbiota populations differed after the respective procedures, particularly with respect to the Enterobacteriaceae family. Both techniques resulted in changes in the bile acids pool, but RYGB was the procedure which suffered the greatest changes, with a reduction in most of their levels. Blautia and Veillonella were the two genera that more relationships showed with secondary bile acids, indicating a possible role in their formation and inhibition, respectively. Correlations with the anthropometric and biochemical variables showed that secondary bile acids could have a role in the amelioration of the glucose and HDL-cholesterol levels. Thus, we have observed a possible relationship between the interaction of the bile acids pool metabolized by the gut microbiota in the metabolic improvements obtained by bariatric surgery in the frame of morbid obesity, deserving further investigation in greater cohorts to decipher the role of each bile acid in the homeostasis of the host for their possible use in the development of microbiota-based therapeutics, such as new drugs, postbiotics or probiotics.

Helicobacter pylori Eradication Therapy Affect the Gut Microbiota and Ghrelin Levels.

Background: Antibiotic therapy used to eradicate Helicobacter pylori has been associated with changes in plasma ghrelin and alterations in the gut microbiota. On the other hand, changes in ghrelin levels have been related to changes in gut microbiota composition. Our aim was to evaluate the relationship between changes in the gut microbiota and ghrelin levels in H. pylori infected patients who received antibiotic treatment for its eradication. Methods: A prospective case-control study that included forty H. pylori-positive patients who received eradication therapy (omeprazole, clarithromycin, and amoxicillin) and twenty healthy H. pylori antigen-negative participants. Patients were evaluated, including clinical, anthropometric and dietary variables, before and 2 months after treatment. Gut microbiota composition was analyzed through 16S rRNA amplicon sequencing (IlluminaMiSeq). Results: Changes in gut microbiota profiles and decrease in ghrelin levels were identified after H. pylori eradication treatment. Gut bacteria such as Bifidobacterium longum, Bacteroides, Prevotella, Parabacteroides distasonis, and RS045 have been linked to ghrelin levels fasting and/or post meals. Changes in the abundance of Lachnospiraceae, its genus Blautia, as well as Prevotella stercorea, and Megasphaera have been inversely associated with changes in ghrelin after eradication treatment. Conclusions: Eradication treatment for H. pylori produces changes in the composition of the intestinal microbiota and ghrelin levels. The imbalance between lactate producers such as Blautia, and lactate consumers such as Megasphaera, Lachnospiraceae, or Prevotella, could trigger changes related to ghrelin levels under the alteration of the eradication therapy used for H. pylori. In addition, acetate producing bacteria such as B. longum, Bacteroides, and P. distasonis could also play an important role in ghrelin regulation.

Gut Microbiota: The Missing Link Between Helicobacter pylori Infection and Metabolic Disorders?

Helicobacter pylori (H. pylori) is a gram-negative bacterium that infects approximately 4.4 billion individuals worldwide. Although the majority of infected individuals remain asymptomatic, this bacterium colonizes the gastric mucosa causing the development of various clinical conditions as peptic ulcers, chronic gastritis and gastric adenocarcinomas and mucosa-associated lymphoid tissue lymphomas, but complications are not limited to gastric ones. Extradigestive pathologies, including metabolic disturbances such as diabetes, obesity and nonalcoholic fatty liver disease, have also been associated with H. pylori infection. However, the underlying mechanisms connecting H. pylori with extragastric metabolic diseases needs to be clarified. Notably, the latest studies on the topic have confirmed that H. pylori infection modulates gut microbiota in humans. Damage in the gut bacterial community (dysbiosis) has been widely related to metabolic dysregulation by affecting adiposity, host energy balance, carbohydrate metabolism, and hormonal modulation, among others. Taking into account that Type 2 diabetic patients are more prone to be H. pylori positive, gut microbiota emerges as putative key factor responsible for this interaction. In this regard, the therapy of choice for H. pylori eradication, based on proton pump inhibitor combined with two or more antibiotics, also alters gut microbiota composition, but consequences on metabolic health of the patients has been scarcely explored. Recent studies from our group showed that, despite decreasing gut bacterial diversity, conventional H. pylori eradication therapy is related to positive changes in glucose and lipid profiles. The mechanistic insights explaining these effects should also be addressed in future research. This review will deal with the role of gut microbiota as the linking factor between H. pylori infection and metabolic diseases, and discussed the impact that gut bacterial modulation by H. pylori eradication treatment can also have in host's metabolism. For this purpose, new evidence from the latest human studies published in more recent years will be analyzed.

Impact of Tumor LINE-1 Methylation Level and Neoadjuvant Treatment and Its Association with Colorectal Cancer Survival.

Recent studies suggest that long-interspersed nucleotide element-1 (LINE-1) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of LINE-1 methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect LINE-1 methylation. Thus, the aim of this study was to assess the prognostic value of tumor LINE-1 methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor LINE-1 methylation, as well as pathological and oncological variables. We also studied the association between LINE-1 methylation and pathological features, and finally, we assessed the overall and disease-free survival of LINE1 methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. LINE-1 was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area (p < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, LINE-1 methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated LINE-1 tumors than those with normal LINE-1 methylation (p = 0.004 and 0.0049, respectively). Indeed, LINE-1 was hypermethylated more in the treated patients than in the non-treated patients (p < 0.05). The present study showed that tumor LINE-1 hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor LINE-1 methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.

H. pylori Eradication Treatment Causes Alterations in the Gut Microbiota and Blood Lipid Levels.

Background: The gut microbiome plays an important role in the lipid metabolism. Antibiotic treatment causes changes in the intestinal microbiota. Our objective was to explore the relationship between changes in the intestinal microbiota and the level of plasma high density lipoprotein cholesterol (HDL) and low density lipoprotein cholesterol (LDL). Methods: Prospective case-control study with Helicobacter pylori-positive patients undergoing eradication therapy with omeprazole, clarithromycin, and amoxicillin. Stool and blood samples were obtained from 20 controls (H. pylori negative) and 40 patients before and 2 months after antibiotic treatment. Gut microbiota was determined through 16S rRNA amplicon sequencing (Illumina MiSeq). Results: Eradication treatment for H. pylori increased the HDL levels, and caused changes in gut microbiota profiles. An unfavorable lipid profiles (high LDL and low HDL levels) was associated with a low microbial richness and an increase of the Bacteroidetes phylum. Prevotella copri, Lachonobacterium, and Delsufovibrio were positively associated with HDL while Rikenellaceae was negatively associated with HDL after completing antibiotic treatment. Conclusions: Helicobacter pylori eradication treatment could improve lipid metabolism in relation with an increase in the HDL. Changes in the abundance of specific bacteria, such as P. copri, Lachonobacterium, Delsufovibrio, and Rikenellaceae could be associated with change in the plasma HDL levels.

Mucosa-associated microbiota in the jejunum of patients with morbid obesity: alterations in states of insulin resistance and metformin treatment.

BACKGROUND: Stool samples have been widely used to evaluate gut microbiota; however, little is known about the composition of human small intestinal microbiota and the alterations provoked by insulin resistance. OBJECTIVE: To describe the composition of jejunal microbiota in morbidly obese patients, as well as its link with insulin resistance and metformin treatment. SETTING: Virgen de la Victoria University Hospital and Regional University Hospital, Málaga, Spain. METHODS: Jejunal biopsies from 46 morbidly obese patients were analyzed by next-generation sequencing method. Patients were classified in the following 3 groups: low homeostasis model assessment of insulin resistance index (HOMA-IR) value, high HOMA-IR value, and metformin-treated type 2 diabetes patients (T2D-metf). RESULTS: Richness (q = .011) together with Proteobacteria (W = 2), Fusobacteria (W = 2), and Bacteroidetes (W = 1) phyla were significantly higher in high HOMA-IR compared with low HOMA-IR group. At family level, several differences were found between low HOMA-IR and T2D-metf group, being the most important the higher abundance of Halomonadacea in T2D-metf group (W = 22). PICRUSt analysis showed that predicted genes involved in trimethylamine-N-oxide biosynthesis pathway could be increased in jejunal microbiota of T2D-metf group compared with the low HOMA-IR group, while indole biosynthesis pathway could be increased in the low HOMA-IR group compared with the high HOMA-IR group. CONCLUSION: An increase in richness and an enrichment in Proteobacteria, Fusobacteria, and Bacteroidetes was observed in jejunal from morbidly obese patients with high insulin resistance. Halomonadaceae family was significantly increased in metformin-treated patients. Functional analysis of predicted metagenome suggests that trimethylamine-N-oxide biosynthesis pathway could be increased in the jejunal microbiota of T2D-meft group, while indole biosynthesis pathway could be increased in low HOMA-IR group. These results contribute to the increase in the scarce knowledge about the mucosal microbiota of the hardly accessible small intestine.

Effect of Synbiotic Supplementation in a Very-Low-Calorie Ketogenic Diet on Weight Loss Achievement and Gut Microbiota: A Randomized Controlled Pilot Study.

SCOPE: Little is known about the changes that a very-low-calorie ketogenic diet (VLCKD) produces in gut microbiota or the effect of synbiotics during the diet. The aim of this study is to evaluate changes in gut microbiota produced by a VLCKD and synbiotic supplementation. METHODS AND RESULTS: A randomized, single-blind, parallel-design trial is conducted in 33 obese patients who follow a weight-loss program (PnK-Method) that include a VLCKD followed by a low-calorie diet (LCD). Subjects are randomly allocated to three groups: one supplemented with synbiotics, a second group supplemented with a placebo during the VLCKD and synbiotics during the LCD phase, and a control group given a placebo. Although symbiotic administration do not produce an effect on microbial diversity, an increase in short-chain fatty aciding producing bacteria and anti-inflammatory mediator signals such as Odoribacter and Lachnospira is shown. The administration of Bifidobacterium animalis subsp. lactis and prebiotics fiber during the LCD is significantly associated with the percentage of weight loss and change in glucose, C-reactive protein and lipopolysaccharide-binding protein. CONCLUSIONS: VLCKD produces important changes in gut microbiota. The administration of synbiotics during VLCKD can improve weight loss through the amelioration of inflammation, which may be mediated by the gut microbiota.

H. pylori Eradication Treatment Alters Gut Microbiota and GLP-1 Secretion in Humans.

Changes in the intestinal microbial community and some metabolic disturbances, including obesity and type2 diabetes, are related. Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis. Microbiota have been linked to incretin secretion. Antibiotic use causes changes in microbial diversity and composition. Our aim was to evaluate the relationship between microbiota changes and GLP-1 secretion. A prospective case-control study with a Helicobacter pylori-positive patient model involving subjects under eradication therapy (omeprazole, clarithromycin, and amoxicillin). Forty patients with H. pylori infection and 20 matched participants, but negative for H. pylori antigen. Patients were evaluated before and two months after treatment. We analyzed anthropometric measurements, carbohydrate metabolism, lipid profile, and C-reactive protein. Gut microbiota composition was analyzed through 16S rRNA amplicon sequencing (IlluminaMiSeq). Eradication treatment for H. pylori decreased bacterial richness (Chao1, p = 0.041). Changes in gut microbiota profiles were observed at phylum, family, genus and species levels. GLP-1 secretion and variables of carbohydrate metabolism were improved. Correlations were seen between GLP-1 changes and variations within microbial community abundances, specifically Bifidobacterium adolescentis, the Lachnobacterium genus, and Coriobacteriaceae family. A conventional treatment to eradicate H. pylori could improve carbohydrate metabolism possibly in relation with an increase in GLP-1 secretion. GLP-1 secretion may be related to alterations in intestinal microbiota, specifically Lachnobacterium, B. adolescentis and Coriobacteriaceae.

H. pylori eradication with antibiotic treatment causes changes in glucose homeostasis related to modifications in the gut microbiota.

BACKGROUND: H. pylori infection and eradication cause perturbations of the gut microbiome. The gut microbiota has been identified as a potential contributor to metabolic diseases. We evaluate whether these alterations in intestinal microbiota composition produced by H. pylori infection and its posterior eradication with antibiotic treatment could be associated with glucose homeostasis in metabolically healthy subjects. METHODS: Forty adult patients infected with H. pylori and 20 control subjects were recruited. The infected subjects were evaluated before and two months after eradication treatment (omeprazole, clarithromycin, amoxicillin). The microbiota composition in fecal samples was determined by 16S rRNA gene (V3-V4) sequencing using Illumina Miseq. RESULTS: Patients (pre- and post-H. pylori eradication) showed a decreased bacterial richness and diversity with respect to controls. There was an improvement in glucose homeostasis in subjects two months after H. pylori eradication treatment. Changes in the amount of Rikenellaceae, Butyricimonas, E. biforme, B. fragilis, and Megamonas were inversely associated with changes in the glucose level or related parameters (Hb1ac) in H. pylori eradication subjects. CONCLUSIONS: H. pylori infection and eradication with antibiotic treatment causes alteration of the human gut microbiome. The increase in SCFA-producing bacteria and glucose-removing bacteria, specifically members of Megamonas, Rikenellaceae and Butyricimonas, has been related with an improvement in glucose homeostasis after H. pylori eradication with antibiotic treatment.

Gut microbiota specific signatures are related to the successful rate of bariatric surgery.

Bariatric surgery (BS) success rates vary in the long-time. A better understanding of weight-loss response may help improve the outcomes of BS. Gut microbiome could be implicated in the successful rate of BS. The aim of the study is to analyze the role of gut microbiome in the successful rate of BS. This is a cross-sectional study of a prospective cohort of 24 patients who underwent gastric bypass. Patients were classified based on excess weight loss (EWL) as: Success (EWL50% at nadir weight and throughout follow-up), Primary Failure (EWL<50% at nadir weight and thereafter), and Weight Regain (EWL>50% at nadir weight, but <50% at last follow-up visit). Gut microbiome analysis was assessed by High Throughput Sequencing. Cholesterol metabolism was shown as the most affected parameter among groups. Studied groups registered minor changes between their gut microbiome abundances, with Butyrivibrio, Lachnospira and Sarcina among them. However, Success group shared a more diverse core microbiome than the other groups. We showed evidence of a possible role of gut microbiome in the cholesterol metabolism, possibly through bile acids, relative to the success or failure of BS outcomes. Acinetobacter and Serratia, from Primary Failure core microbiome, could have implications in its successful rate. Sarcina abundance was presented as the best genera related to the body mass index (BMI) post-surgery. Gut microbiota could mediate, at least partially, the success rate of BS through their interaction with the bile acids milieu. Further studies are necessary to validate this probe of concept.

Decreased blood pressure is related to changes in NF-kB promoter methylation levels after bariatric surgery.

BACKGROUND: Obesity is characterized by a chronic, low-grade inflammation, and bariatric surgery is proposed as an effective treatment for reducing the obesity-related co-morbidities. Epigenetic modifications could be involved in the metabolic improvement after surgery. OBJECTIVE: The main aim of this study was to evaluate whether DNA methylation pattern from genes related to inflammation and insulin response is associated with the metabolic improvement after bariatric surgery in morbidly obese patients and if these changes depend on the surgical procedure. SETTING: University hospital, Spain. METHODS: We studied 60 severely obese patients; 31 underwent Roux-en-Y gastric bypass and 29 underwent laparoscopic sleeve gastrectomy. All patients were examined before and at 6 months after bariatric surgery. DNA methylation profile of genes related to the inflammatory response and insulin sensitivity was measured by pyrosequencing. RESULTS: The promoter methylation levels of the NFKB1 gene were increased significantly after surgery (2.16 ± .9 versus 2.8 ± 1.03). The decrease in blood pressure, both systolic and diastolic, after surgery was significantly associated with the changes in the promoter methylation levels of the NFKB1 gene (ß = -.513, P = .003 and ß = -.543, P = .004, respectively). A decrease in inflammation status, measured by high sensitivity C-reactive protein values, was associated with changes in SLC19A1 methylation levels. CONCLUSION: Our study shows for the first time an association between NFKB1 methylation levels and blood pressure after bariatric surgery, highlighting the possible function of this gene in the regulation of arterial pressure. Regarding SLC19A1, this gene could position as a potential target linking inflammation and insulin resistance.

Changes in SCD gene DNA methylation after bariatric surgery in morbidly obese patients are associated with free fatty acids.

Stearoyl CoA Desaturase-1 (SCD) is considered as playing an important role in the explanation of obesity. The aim of this study was to evaluate whether the DNA methylation SCD gene promoter is associated with the metabolic improvement in morbidly obese patients after bariatric surgery. The study included 120 subjects with morbid obesity who underwent a laparoscopic Roux-en Y gastric by-pass (RYGB) and a control group of 30 obese subjects with a similar body mass index (BMI) to that found in morbidly obese subjects six months after RYGB. Fasting blood samples were obtained before and at six months after RYGB. DNA methylation was measured by pyrosequencing technology. DNA methylation levels of the SCD gene promoter were lower in morbidly obese subjects before bariatric surgery but increased after RYGB to levels similar to those found in the control group. Changes of DNA methylation SCD gene were associated with the changes of free fatty acids levels (r = -0.442, p = 0.006) and HOMA-IR (r = -0.249, p = 0.035) after surgery. RYGB produces an increase in the low SCD methylation promoter levels found in morbidly obese subjects. This change of SCD methylation levels is associated with changes in FFA and HOMA-IR.

The role of vitamin D and VDR in carcinogenesis: Through epidemiology and basic sciences.

In the last two decades vitamin D (VD) research has demonstrated new extraskeletal actions of this pre-hormone, suggesting a protective role of this secosteroid in the onset, progression and prognosis of several chronic noncommunicable diseases, such as cardiovascular disease, diabetes mellitus or cancer. Regarding carcinogenesis, both preclinical and epidemiological evidence available show oncoprotective actions of VD and its receptor, the VDR. However, in late neoplastic stages the VD system (VDS) seems to be less functional, which appears to be due to an epigenetic silencing of the system. In preclinical experimental studies, VD presents oncoprotective actions through modulation of inflammation, cell proliferation, cell differentiation, angiogenesis, invasive and metastatic potential, apoptosis, miRNA expression regulation and modulation of the Hedgehog signalling pathway. Moreover, epidemiological evidence points towards an oncoprotective role of vitamin D and VDR in colorectal cancer. This association is more controversial with breast, ovarian and prostate cancers, although with a few adverse effects. Nonetheless, we should consider other factors to determine the benefit of increased serum concentration of VD. Much of the epidemiological evidence is still inconclusive, and we will have to wait for new, better-designed ongoing RCTs and their results to discern the real effect of vitamin D in cancer risk reduction and therapy. The objective of this literature review is to offer an up-to-date analysis of the role of the VD and VDR, in the onset, progression and prognosis of all types of cancer. We further discuss the available literature and suggest new hypotheses and future challenges in the field of VD research.

Methylation patterns of Vegfb promoter are associated with gene and protein expression levels: the effects of dietary fatty acids.

PURPOSE: We have investigated the epigenetic regulation by dietary fatty acids of Vegfb levels in rats' white adipose tissue and 3T3-L1 cells. METHODS: A group of rats were assigned to three diets, each one with a different composition of saturated, monounsaturated and polyunsaturated fatty acids. Samples of white adipose tissues were taken for the methylation and expression studies. Additionally, 3T3-L1 cells were treated with palmitic, oleic, and linoleic fatty acids. After treatment, cells were harvested and genetic material was extracted for the analysis of Vegfb levels. RESULTS: We report evidence of changes in the methylation levels of the CpG island at the Vegfb promoter and in the Vegfb expression levels in vivo and in vitro by dietary fatty acid, with the main contribution of the linoleic fatty acid. Vegfb promoter methylation levels were closely related to the Vegfb gene expression. CONCLUSION: According to our results, the regulation of Vegfb gene expression by dietary fatty acids may be mediated, at least in part, by epigenetic modifications on Vegfb promoter methylation. Considering the deep association between angiogenesis and tissue growth, we suggest the nutriepigenetic regulation of Vegfb as a key target in the control of the adipose tissue expansion.

Neonatal Androgen Exposure Causes Persistent Gut Microbiota Dysbiosis Related to Metabolic Disease in Adult Female Rats.

Alterations of gut microbiome have been proposed to play a role in metabolic disease, but the major determinants of microbiota composition remain ill defined. Nutritional and sex hormone challenges, especially during early development, have been shown to permanently alter adult female phenotype and contribute to metabolic disturbances. In this study, we implemented large-scale microbiome analyses to fecal samples from groups of female rats sequentially subjected to various obesogenic manipulations, including sex hormone perturbations by means of neonatal androgenization or adult ovariectomy (OVX), as a model of menopause, to establish whether these phenomena are related to changes in gut microbiota. Basic metabolic profiles concerning glucose/insulin homeostasis were also explored. The effects of the sex hormonal perturbations, either developmentally (androgenization) or in adulthood (OVX), clearly outshone the impact of nutritional interventions, especially concerning the gut microbiota profile. Notably, we observed a lower diversity in the androgenized group, with the highest Firmicutes to Bacteroidetes ratio, supporting the occurrence of durable alterations in gut microbiota composition, even in adulthood. Moreover, the elimination of adult ovarian secretions by OVX affected the richness of gut microbiota. Our data are the first to document the durable impact of sex steroid manipulations, and particularly early androgenization, on gut microbiota composition. Such dysbiosis is likely to contribute to the metabolic perturbations of conditions of obesity linked to gonadal dysfunction in the female.

Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci.

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Type 2 diabetes mellitus in relation to global LINE-1 DNA methylation in peripheral blood: a cohort study.

In the last years, epigenetic processes have emerged as a promising area of complex diseases research. DNA methylation measured in Long Interspersed Nucleotide Element 1 (LINE-1) sequences has been considered a surrogate marker for global genome methylation. New findings have suggested the potential involvement of epigenetic mechanisms in Type 2 diabetes (T2DM) as a crucial interface between the effects of genetic predisposition and environmental influences. Our study evaluated whether global DNA methylation predicted increased risk from T2DM or other carbohydrate metabolism disorders in a cohort study. We used a prospective cohort intervention study and a control group. We collected phenotypic, anthropometric, biochemical, and nutritional information from all subjects. Global LINE-1 DNA methylation was quantified by pyrosequencing technology. Subjects that did not improve their carbohydrate metabolism status showed lower levels of global LINE-1 DNA methylation (63.9 ± 1.7 vs. 64.7 ± 2.4) and they practiced less intense physical activity (5.8% vs. 21.5%). Logistic regression analyses showed a significant association between LINE-1 DNA methylation and metabolic status after adjustment for sex, age, BMI, and physical activity. Our study showed that lower LINE-1 DNA methylation levels were associated with a higher risk metabolic status worsening, independent of other classic risk factors. This finding highlights the potential role for epigenetic biomarkers as predictors of T2DM risk or other related metabolic disorders.

Plasma selenium levels and oxidative stress biomarkers: a gene-environment interaction population-based study.

The role of selenium exposure in preventing chronic disease is controversial, especially in selenium-repleted populations. At high concentrations, selenium exposure may increase oxidative stress. Studies evaluating the interaction of genetic variation in genes involved in oxidative stress pathways and selenium are scarce. We evaluated the cross-sectional association of plasma selenium concentrations with oxidative stress levels, measured as oxidized to reduced glutathione ratio (GSSG/GSH), malondialdehyde (MDA), and 8-oxo-7,8-dihydroguanine (8-oxo-dG) in urine, and the interacting role of genetic variation in oxidative stress candidate genes, in a representative sample of 1445 men and women aged 18-85 years from Spain. The geometric mean of plasma selenium levels in the study sample was 84.76 µg/L. In fully adjusted models the geometric mean ratios for oxidative stress biomarker levels comparing the highest to the lowest quintiles of plasma selenium levels were 0.61 (0.50-0.76) for GSSG/GSH, 0.89 (0.79-1.00) for MDA, and 1.06 (0.96-1.18) for 8-oxo-dG. We observed nonlinear dose-responses of selenium exposure and oxidative stress biomarkers, with plasma selenium concentrations above ~110 µg/L being positively associated with 8-oxo-dG, but inversely associated with GSSG/GSH and MDA. In addition, we identified potential risk genotypes associated with increased levels of oxidative stress markers with high selenium levels. Our findings support that high selenium levels increase oxidative stress in some biological processes. More studies are needed to disentangle the complexity of selenium biology and the relevance of potential gene-selenium interactions in relation to health outcomes in human populations.