Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.

Chronic inflammation is involved in the onset and development of many diseases, including obesity, atherosclerosis, type 2 diabetes, osteoarthritis, autoimmune and degenerative diseases, asthma, periodontitis, and cirrhosis. The inflammation process is mediated by chemokines, cytokines, and different inflammatory cells. Although the molecules and mechanisms that regulate this primary defense mechanism are not fully understood, recent findings offer a putative role of noncoding RNAs, especially microRNAs (miRNAs), in the progression and management of the inflammatory response. These noncoding RNAs are crucial for the stability and maintenance of gene expression patterns that characterize some cell types, tissues, and biologic responses. Several miRNAs, such as miR-126, miR-132, miR-146, miR-155, and miR-221, have emerged as important transcriptional regulators of some inflammation-related mediators. Additionally, little is known about the involvement of long noncoding RNAs, long intergenic noncoding RNAs, and circular RNAs in inflammation-mediated processes and the homeostatic imbalance associated with metabolic disorders. These noncoding RNAs are emerging as biomarkers with diagnosis value, in prognosis protocols, or in the personalized treatment of inflammation-related alterations. In this context, this review summarizes findings in the field, highlighting those noncoding RNAs that regulate inflammation, with emphasis on recognized mediators such as TNF-a, IL-1, IL-6, IL-18, intercellular adhesion molecule 1, VCAM-1, and plasminogen activator inhibitor 1. The down-regulation or antagonism of the noncoding RNAs and the administration of exogenous miRNAs could be, in the near future, a promising therapeutic strategy in the treatment of inflammation-related diseases.-Marques-Rocha, J. L., Samblas, M., Milagro, F. I., Bressan, J., Martínez, J. A., Marti, A. Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J. 29, 3595-3611 (2015). www.fasebj.org

Diet-induced obesity is associated to an imbalance in the normal gut microbiota composition.Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability and, when reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans-resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high-fat sucrose diet (HFS) and in turn, improve gut health. Wistar rats were randomized into four groups fed a HFS diet supplemented or not with trans-resveratrol (15 mg/kg BW/day), quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body-weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans-resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance.Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet-induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium 1 cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS dietinduced gut microbiota dysbiosis. In contrast, trans-resveratrol supplementation alone or in combination with quercetin, scarcely modified the profile of gut bacteria, but acted at intestinal level altering the mRNA expression of tight-junction proteins (TJPs) and inflammation associated genes.

Gut microbiota plays a key role in host physiology and metabolism. Indeed, the relevance of a well-balanced gut microbiota composition to an individual´s health status is essential for the person's well-being. Currently, investigations are focused on analyzing the effects of pre-and probiotics as new therapeutic tools to counteract the disruption of intestinal bacterial balance occurring in several diseases. Polyphenols exert a wide range of beneficial health effects. However, although specific attention has been paid in recent years to the function of this "biological entity" in the metabolism of polyphenols, less is known about the modulatory capacity of these bioactive compounds on gut microbiota composition. This review provides an overview of the latest investigations carried out with pure polyphenols, extracts rich in polyphenols and polyphenol-rich dietary sources (such as cocoa, tea, wine, soy products and fruits), and critically discusses the consequences to gut microbiota composition which are produced.

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Diverse evidence suggests that the gut microbiota is involved in the development of obesity and associated comorbidities. It has been reported that the composition of the gut microbiota differs in obese and lean subjects, suggesting that microbiota dysbiosis can contribute to changes in body weight. However, the mechanisms by which the gut microbiota participates in energy homeostasis are unclear. Gut microbiota can be modulated positively or negatively by different lifestyle and dietary factors. Interestingly, complex interactions between genetic background, gut microbiota, and diet have also been reported concerning the risk of developing obesity and metabolic syndrome features. Moreover, microbial metabolites can induce epigenetic modifications (i.e., changes in DNA methylation and micro-RNA expression), with potential implications for health status and susceptibility to obesity. Also, microbial products, such as short-chain fatty acids or membrane proteins, may affect host metabolism by regulating appetite, lipogenesis, gluconeogenesis, inflammation, and other functions. Metabolomic approaches are being used to identify new postbiotics with biological activity in the host, allowing discovery of new targets and tools for incorporation into personalized therapies. This review summarizes the current understanding of the relations between the human gut microbiota and the onset and development of obesity. These scientific insights are paving the way to understanding the complex relation between obesity and microbiota. Among novel approaches, prebiotics, probiotics, postbiotics, and fecal microbiome transplantation could be useful to restore gut dysbiosis.

Importance of the field: The increasing prevalence of type 2 diabetes mellitus and the negative clinical outcomes observed with the commercially available anti-diabetic drugs have led to the investigation of new therapeutic approaches focused on controlling postprandrial glucose levels. The use of carbohydrate digestive enzyme inhibitors from natural resources could be a possible strategy to block dietary carbohydrate absorption with less adverse effects than synthetic drugs. Areas covered in this review: This review covers the latest evidence regarding in vitro and in vivostudies in relation to pancreatic alpha-amylase inhibitors of plant origin, and presents bioactive compounds of phenolic nature that exhibit anti-amylase activity.What the reader will gain: The state of the art of the search for new pancreatic alpha amylase inhibitors of plant origin for the treatment of type 2 diabetes mellitus.Take home message: Pancreatic alpha-amylase inhibitors from traditional plant extracts are a promising tool for diabetes treatment. Many studies have confirmed the alpha-amylase inhibitory activity of plants and their bioactive compounds in vitro, but few studies corroborate these findings in rodents and very few in humans. Thus, despite some encouraging results, more research is required for developing a valuable anti-diabetic therapy using pancreatic alpha-amylase inhibitors of plant origin.Keywords: alpha-amylase; flavonoids; proanthocyanidins; tannins; type 2 diabetes mellitus 2 IntroductionDiabetes mellitus is one of the world´s major diseases, with an estimation of 347 million adults affected in 2011 (1). Type 2 diabetes mellitus, by far the most common type, is a metabolic disorder of multiple etiology characterized by carbohydrate, lipid and protein metabolic disorders that includes defects in insulin secretion, almost always with a major contribution of insulin resistance (2). These abnormalities could lead to lesions such as retinopathy, nephropathy, neuropathy, and angiopathy (3).In this context, the inhibition of carbohydrate digestive enzymes is considered a therapeutic tool for the treatment of type 2 diabetes (4). The most important digestive enzyme is pancreatic alpha-amylase (EC 3.2.1.1), a calcium metalloenzyme that catalyzes the hydrolysis of the alpha-1,4 glycosidic linkages of the starch, amylose, amylopectin, glycogen, and various maltodextrins and is responsible of most of starch digestion in humans. A second enzyme named alpha-glucosidase or maltase (EC 3.2.1.20) catalyzes the final step of the digestive process of carbohydrates acting upon 1,4-alpha bonds and giving as a result glucose (4).A positive correlation between human pancreatic alpha-amylase (HPA) activity and the increase in postprandial glucose levels has been shown, demonstrating the relevance of suppressing postprandial hyperglycemia (PPHG) in the treatment of type 2 diabetes (5). The ability of the alpha-amylase enzyme inhibitors to avoid dietary starch to be digested and absorbed in the organism has allowed to designat...

Epigenetics could contribute to explain individual differences in weight loss after an energy restriction intervention. Here, we identify novel potential epigenetic biomarkers of weight-loss comparing DNA methylation patterns of high and low responders to a 2 hypocaloric diet. Twenty-five overweight/obese men followed an 8-week caloric restriction intervention. DNA was isolated from peripheral blood mononuclear cells and treated with bisulfite. The basal and endpoint epigenetic differences between high and low responders were analysed by methylation microarray, which was also useful to compare the epigenetic changes due to the nutrition intervention. Subsequently, Sequenom EpiTYPER technology was used to validate several relevant CpGs and the surrounding regions.DNA methylation levels in several CpGs located in ATP10A and CD44 genes showed statistical baseline differences depending on the weight-loss outcome. At the treatment endpoint, DNA methylation levels of several CpGs on WT1 promoter were statistically more methylated in the high than in the low responders. Finally, different CpG sites from WT1 and ATP10A were significantly modified as a result of the intervention.In summary, hypocaloric diet-induced weight loss in humans could alter DNA methylation status of specific genes. Moreover, baseline DNA methylation patterns may be used as epigenetic markers that could help to predict weight loss.