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.
Aim and objective
Emerging translational evidence suggests that epigenetic alterations (DNA methylation, miRNA expression, and histone modifications) occur after external stimuli and may contribute ...to exacerbated inflammation and the risk of suffering several diseases including diabetes, cardiovascular diseases, cancer, and neurological disorders. This review summarizes the current knowledge about the harmful effects of high-fat/high-sugar diets, micronutrient deficiencies (folate, manganese, and carotenoids), obesity and associated complications, bacterial/viral infections, smoking, excessive alcohol consumption, sleep deprivation, chronic stress, air pollution, and chemical exposure on inflammation through epigenetic mechanisms. Additionally, the epigenetic phenomena underlying the anti-inflammatory potential of caloric restriction,
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-3 PUFA, Mediterranean diet, vitamin D, zinc, polyphenols (i.e., resveratrol, gallic acid, epicatechin, luteolin, curcumin), and the role of systematic exercise are discussed.
Methods
Original and review articles encompassing epigenetics and inflammation were screened from major databases (including PubMed, Medline, Science Direct, Scopus, etc.) and analyzed for the writing of the review paper.
Conclusion
Although caution should be exercised, research on epigenetic mechanisms is contributing to understand pathological processes involving inflammatory responses, the prediction of disease risk based on the epigenotype, as well as the putative design of therapeutic interventions targeting the epigenome.
•Obese individuals have an increased risk to develop neurodegenerative diseases.•Obesity is usually accompanied by low-grade systemic inflammation.•Systemic and central inflammation may be a link ...between obesity and Alzheimer's disease.•Alteration in the microbiota-gut-brain axis may be involved in cognitive decline.•Antiinflammatory and antiobesity drugs could be useful in cognitive decline management.
Obesity prevalence is increasing steadily throughout the world's population in most countries and in parallel the prevalence of metabolic disorders including cardiovascular diseases and type 2 diabetes is also rising, but less is reported about excessive adiposity relationship with poorer cognitive performance, cognitive decline and dementia. Some human clinical studies have evidenced that obesity is related to the risk of the development of mild cognitive impairment, in the form of short-term memory and executive function deficits, as well as dementia and Alzheimer's disease. The precise mechanisms that underlie the connections between obesity and the risk of cognitive impairment are still largely unknown but potential avenues of further research include insulin resistance, the gut-brain axis, and systemic mediators and central inflammation processes. A common feature of metabolic diseases is a chronic and low-grade activation of the inflammatory system. This inflammation may eventually spread from peripheral tissue to the brain, and recent reports suggest that neuroinflammation is an important causal mechanism in cognitive decline. This inflammatory status could be triggered by changes in the gut microbiota composition. Consumption of diets high in fat and sugar influences the microbiota composition, which may lead to an imbalanced microbial population in the gut. Thus, it has recently been hypothesized that the gut microbiota could be part of a mechanistic link between the consumption of high fat and other unbalanced diets and impaired cognition, termed ‘gut-brain axis’. The present review will aim at providing an integrative analysis of the effects of obesity and unbalanced diets on cognitive performance and discusses some of the potential mechanisms involved, namely inflammation and changes in gut-brain axis. Moreover, the review aims to analyze anti-inflammatory drugs that have been tested for the treatment of cognition and obesity, recently approved anti-obesity drugs that could also have an impact on central nervous system, and bioactive food compounds that modulate gut microbiota and could have an impact through the gut-brain axis. In this era of precision nutrition medicine, it is imperative to identify the various metabolic-neurocognitive phenotypes in order to understand the processes that drive these diseases so that targeted therapeutic strategies to prevent and successfully manage these complex, multifactorial diseases could be designed and developed.
The knowledge on the mechanisms through which the metabolites produced by the gut microbiota (postbiotics) prevent diseases, induce therapeutic responses, and behave differently in response to ...dietary and environmental changes, is one of the major challenges in nutrition research and paves the route for the development of new therapeutic strategies against non-communicable diseases.
In this review, the main mechanisms by which postbiotics provide a link between nutrition, microbiota, and human health are discussed. Postbiotics are the repertoire of metabolites produced in the fermentation process of dietary components (mainly fibers and polyphenols, but also complex carbohydrates, proteins, and lipids), as well as the endogenous components generated by bacteria-host interactions that influence human health.
Short-chain fatty acids denote a primary energy source for colonocytes, also acting on the gut-brain axis to reduce appetite and performing epigenetic roles. Polyamines promote homeostasis and affect epigenetic processes, apoptosis, and cell proliferation through interaction with proteins and nucleic acids. Bile acids are involved in glucose metabolism and modulation of the host immune response. p-Cresol features antimicrobial and antioxidant properties, but has been related to enteric pathogens, autism, and kidney diseases. The role of trimethylamine N-oxide (TMAO) in cardiovascular diseases is still under debate. Bacteriocins have antibiotic action against pathogens. The beneficial effects of polyphenols are demonstrated by their essentiality in the production of metabolites. Summarizing, metagenomic sequencing, intervention studies, and metabolomics are enabling to understand the modulation and effects of microbiota metabolic activity. However, in order to clearly elucidate the food-microbiota axis, the interplay among the host microbiota and the metabolites secreted by intestinal cells, and the intestine-liver-brain axis, the studies must be directed to the subject habitat.
•Postbiotics provide therapeutic benefits, preserve the integrity and improve the balance of the host microbiome.•Iron, calcium, phosphorus, and zinc are dependent on bacteria for the processes of absorption and/or maintenance in the body.•Bacteriocins from lactic acid bacteria have low or no cytotoxicity,can inhibit the growth of enteropathogenic bacteria.•Postbiotics are involved in the regulation of the immune, neurological, and physiological systems.
ABSTRACT
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‐α, 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
ABSTRACT
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.
•Results on the effects of low and non-calorie sweeteners on the gut microbiota are heterogeneous.•The gut microbial composition at baseline could mediate the microbial response to low and ...non-calorie sweeteners.•More human studies are needed to confirm the effects of sweeteners on the gut microbiota.
Use of non-nutritive sweeteners (NNSs) has increased worldwide in recent decades. However, evidence from preclinical studies shows that sweetener consumption may induce glucose intolerance through changes in the gut microbiota, which raises public health concerns. As studies conducted on humans are lacking, the aim of this review was to gather and summarize the current evidence on the effects of NNSs on human gut microbiota. Only clinical trials and cross-sectional studies were included in the review. Regarding NNSs (i.e, saccharin, sucralose, aspartame, and stevia), only two of five clinical trials showed significant changes in gut microbiota composition after the intervention protocol. These studies concluded that saccharin and sucralose impair glycemic tolerance. In three of the four cross-sectional studies an association between NNSs and the microbial composition was observed. All three clinical trials on polyols (i.e, xylitol) showed prebiotic effects on gut microbiota, but these studies had multiple limitations (publication date, dosage, duration) that jeopardize their validity. The microbial response to NNSs consumption could be strongly mediated by the gut microbial composition at baseline. Further studies in which the potential personalized microbial response to NNSs consumption is acknowledged, and that include longer intervention protocols, larger cohorts, and more realistic sweetener dosage are needed to broaden these findings.
Non-alcoholic fatty liver disease is a primary hepatic manifestation of obesity and an important adverse metabolic syndrome trait. Animal models of diet-induced obesity promote liver fat accumulation ...putatively associated with alterations in epigenetic profile. Dietary methyl donor-supplementation may protect against this disturbance during early developmental stages affecting the molecular basis of gene regulation. The aim of this study was to investigate the transcriptomic and epigenetic mechanisms implicated in liver fat accumulation as a result of an obesogenic diet and the putative preventive role of dietary methyl donors. Forty-eight male Wistar rats were assigned into four dietary groups for 8weeks; control, control methyl-donor-supplemented with a dietary cocktail containing betaine, choline, vitamin B12 and folic acid, high-fat-sucrose and high-fat-sucrose methyl-donor-supplemented. Liver fat accumulation induced by a HFS diet was prevented by methyl donor supplementation in HFS-fed animals. A liver mRNA microarray, subsequently validated by real time-qPCR, showed modifications in some biologically relevant genes involved in obesity development and lipid metabolism (Lepr, Srebf2, Agpat3 and Esr1). Liver global DNA methylation was decreased by methyl donor supplementation in control-fed animals. Methylation levels of specific CpG sites from Srebf2, Agpat3 and Esr1 promoter regions showed changes due to the obesogenic diet and the supplementation with methyl donors. Interestingly, Srebf2 CpG23_24 methylation levels (−167bp and −156bp with respect to the transcriptional start site) correlated with HDLc plasma levels, whereas Esr1 CpG14 (−2623bp) methylation levels were associated with body and liver weights and fat content. Furthermore HFS diet-induced liver fat accumulation was prevented by methyl donor supplementation. In conclusion, both obesogenic diet and methyl donor supplementation modified the mRNA hepatic profile as well as the methylation of specific gene promoters and total DNA.
•Methyl donor supplementation protects against obesity-related liver fat accumulation.•Hepatic transcriptomic and epigenetic profiles were altered by diet and supplementation.•Hepatic DNA methylation marks were related with obesity and fatty liver features.
The combination of multiple omics approaches has emerged as an innovative holistic scope to provide a more comprehensive view of the molecular and physiological events underlying human diseases ...(including obesity, dyslipidemias, fatty liver, insulin resistance, and inflammation), as well as for elucidating unique and specific metabolic phenotypes. These omics technologies include genomics (polymorphisms and other structural genetic variants), epigenomics (DNA methylation, histone modifications, long non-coding RNA, telomere length), metagenomics (gut microbiota composition, enterotypes), transcriptomics (RNA expression patterns), proteomics (protein quantities), and metabolomics (metabolite profiles), as well as interactions with dietary/nutritional factors. Although more evidence is still necessary, it is expected that the incorporation of integrative omics could be useful not only for risk prediction and early diagnosis but also for guiding tailored dietary treatments and prognosis schemes. Some challenges include ethical and regulatory issues, the lack of robust and reproducible results due to methodological aspects, the high cost of omics methodologies, and high-dimensional data analyses and interpretation. In this review, we provide examples of system biology studies using multi-omics methodologies to unravel novel insights into the mechanisms and pathways connecting the genotype to clinically relevant traits and therapy outcomes for precision nutrition applications in health and disease.
Fecal microbiome disturbances are linked to different human diseases. In the case of obesity, gut microbiota seems to play a role in the development of low-grade inflammation. The purpose of the ...present study was to identify specific bacterial families and genera associated with an increased obesity-related inflammatory status, which would allow to build a regression model for the prediction of the inflammatory status of obese and overweight subjects based on fecal microorganisms.
A total of 361 volunteers from the Obekit trial (65 normal-weight, 110 overweight, and 186 obese) were classified according to four variables: waist/hip ratio (≥0.86 for women and ≥1.00 for men), leptin/adiponectin ratio (LAR, ≥3.0 for women and ≥1.4 for men), and plasma C-reactive protein (≥2 mg/L) and TNF levels (≥0.85 pg/mL). An inflammation score was designed to classify individuals in low (those subjects who did exceed the threshold value in 0 or 1 variable) or high inflammatory index (those subjects who did exceed the threshold value in 2 or more variables). Fecal 16 S rRNA sequencing was performed for all participants, and differential abundance analyses for family and genera were performed using the MicrobiomeAnalyst web-based platform.
Methanobacteriaceae, Christensenellaceae, Coriobacteriaceae, Bifidobacteriaceae, Catabacteriaceae, and Dehalobacteriaceae families, and Methanobrevibacter, Eggerthella, Gemmiger, Anaerostipes, and Collinsella genera were significantly overrepresented in subjects with low inflammatory index. Conversely, Carnobacteriaceae, Veillonellaceae, Pasteurellaceae, Prevotellaceae and Enterobacteriaceae families, and Granulicatella, Veillonella, Haemophilus, Dialister Parabacteroides, Prevotella, Shigella, and Allisonella genera were more abundant in subjects with a high inflammatory index. A regression model adjusted by BMI, sex, and age and including the families Coriobacteriaceae and Prevotellaceae and the genus Veillonella was developed.
A microbiota-based regression model was able to predict the obesity-related inflammatory status (area under the ROC curve = 0.8570 ± 0.0092 Harrell's optimism-correction) and could be useful in the precision management of inflammobesity.
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