Application of Gut Bacterial Profiling Information in Precision Nutrition for Obesity and Weight Loss Management.

BACKGROUND: It has been suggested that the dysfunction of the gut microbiome can have deleterious effects on the regulation of body weight and adiposity by affecting energy metabolism. In this context, gut bacterial profiling studies have contributed to characterize specific bacteria associated with obesity. This review covers the information driven by gut bacterial profiling analyses and emphasizes the potential application of this knowledge in precision nutrition strategies for obesity understanding and weight loss management. SUMMARY: Gut bacterial profiling studies have identified bacterial families that are more abundant in obese than in nonobese individuals (i.e., Prevotellaeae, Ruminococcaceae, and Veillonellaceae) as well as other families that have been repeatedly found more abundant in nonobese people (i.e., Christensenellaceae and Coriobacteriaceae), suggesting that an increase in their relative amount could be an interesting target in weight-loss treatments. Also, some gut-derived metabolites have been related to the regulation of body weight, including short-chain fatty acids, trimethylamine-N-oxide, and branched-chain and aromatic amino acids. Moreover, gut microbiota profiles may play a role in determining weight loss responses to specific nutritional treatments for the precise management of obesity. Thus, incorporating gut microbiota features may improve the performance of integrative models to predict weight loss outcomes. KEY MESSAGES: The application of gut bacterial profiling information is of great value for precision nutrition in metabolic diseases since it contributes to the understanding of the role of the gut microbiota in obesity onset and progression, facilitates the identification of potential microorganism targets, and allows the personalization of tailored weight loss diets as well as the prediction of adiposity outcomes based on the gut bacterial profiling of each individual. Integrating microbiota information with other omics knowledge (genetics, epigenetics, transcriptomics, proteomics, and metabolomics) may provide a more comprehensive understanding of the molecular and physiological events underlying obesity and adiposity outcomes for precision nutrition.

Crosstalk between Gut Microbiota and Epigenetic Markers in Obesity Development: Relationship between Ruminococcus, BMI, and MACROD2/SEL1L2 Methylation.

Changes in gut microbiota composition and in epigenetic mechanisms have been proposed to play important roles in energy homeostasis, and the onset and development of obesity. However, the crosstalk between epigenetic markers and the gut microbiome in obesity remains unclear. The main objective of this study was to establish a link between the gut microbiota and DNA methylation patterns in subjects with obesity by identifying differentially methylated DNA regions (DMRs) that could be potentially regulated by the gut microbiota. DNA methylation and bacterial DNA sequencing analysis were performed on 342 subjects with a BMI between 18 and 40 kg/m2. DNA methylation analyses identified a total of 2648 DMRs associated with BMI, while ten bacterial genera were associated with BMI. Interestingly, only the abundance of Ruminococcus was associated with one BMI-related DMR, which is located between the MACROD2/SEL1L2 genes. The Ruminococcus abundance negatively correlated with BMI, while the hypermethylated DMR was associated with reduced MACROD2 protein levels in serum. Additionally, the mediation test showed that 19% of the effect of Ruminococcus abundance on BMI is mediated by the methylation of the MACROD2/SEL1L2 DMR. These findings support the hypothesis that a crosstalk between gut microbiota and epigenetic markers may be contributing to obesity development.

Holistic Integration of Omics Tools for Precision Nutrition in Health and Disease.

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.

Genetic and epigenetic nutritional interactions influencing obesity risk and adiposity outcomes.

PURPOSE OF REVIEW: This article aims to critically overview the current interplay of genetic/epigenetic factors and several nutritional aspects influencing obesity susceptibility and adiposity outcomes for obesity management and weight status monitoring. RECENT FINDINGS: Single nucleotide polymorphisms located in or near genes participating in energy homeostasis, fatty acid metabolism, appetite control, brain regulation, and thermogenesis have been associated with body composition measures (body weight, body mass index, waist circumference, body fat percentage, and visceral adipose tissue) depending on nutrient intakes, dietary patterns, and eating behaviors. Moreover, studies analyzing interactions between the epigenome and dietary intakes in relation to adiposity outcomes are reported. The main epigenetic mechanisms include methylation levels of promoter sequences, telomere length, and micro-ribonucleic acid expression profiles, whereas covalent histone modifications remain less studied. SUMMARY: Exploring potential interactions between the genetic/epigenetic background and nutritional features is improving the current understanding of the obesity physiopathogenesis and the usefulness of translating this precision information in the clinical setting for weight gain prediction, the design of personalized nutrition therapies as well as individual responsiveness estimation to dietary advice. The analysis of further relationships between the genotype, the epigenotype and other precision markers including the gut microbiota and the metabolome is warranted.

Kefir and Intestinal Microbiota Modulation: Implications in Human Health.

In the last decades changes in the pattern of health and disease in Latin America and in the world has been observed, with an increase in cases of chronic non-communicable diseases. Changes in intestinal microbiota composition can contribute to the development of these diseases and be useful in their management. In this context, the consumption of fermented foods with probiotic properties, such as kefir, stands out due to its gut microbiota-modulating capacity. There is an increasing interest in the commercial use of kefir since it can be marketed as a natural beverage containing health-promoting bacteria and has been gaining international popularity in Latin America. Also the consumption of these drinks in Latin America seems to be even more relevant, given the socioeconomic situation of this population, which highlights the need for disease prevention at the expense of its treatment. In this narrative review, we discuss how kefir may work against obesity, diabetes mellitus, liver disease, cardiovascular disorders, immunity, and neurological disorders. Peptides, bioactive compounds and strains occurring in kefir, can modulate gut microbiota composition, low-grade inflammation and intestinal permeability, which consequently may generate health benefits. Kefir can also impact on the regulation of organism homeostasis, with a direct effect on the gut-brain axis, being a possible strategy for the prevention of metabolic diseases. Further studies are needed to standardize these bioactive compounds and better elucidate the mechanisms linking kefir and intestinal microbiota modulation. However, due to the benefits reported, low cost and ease of preparation, kefir seems to be a promising approach to prevent and manage microbiota-related diseases in Latin America and the rest of the world.

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition.

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, n-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.

PPARGC1A Gene Promoter Methylation as a Biomarker of Insulin Secretion and Sensitivity in Response to Glucose Challenges.

Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose.

Epigenetic Modifications as Outcomes of Exercise Interventions Related to Specific Metabolic Alterations: A Systematic Review.

BACKGROUND: Chronic diseases arise as a consequence of an unhealthy lifestyle primarily characterized by physical inactivity and unbalanced diets. Regular physical activity can improve health, and there is consistent evidence that these improvements may be the result of epigenetic modifications. OBJECTIVE: To identify epigenetic modificationsas outcomes of exercise interventions related to specific metabolic alterations. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) methodology for manuscript research and preparation was followed using PubMed and EBSCO databases for literature review. Out of 2,638 articles identified, only 34 articles met the inclusion criteria. RESULTS: The sections of the review were organized by metabolic alterations in which studies were grouped according to healthy, diseased, and trained individuals. Resistance exercise in humans induced epigenetic changes in pathways associated with energy metabolism and insulin sensitivity, contributing to healthy skeletal muscle. Endurance exercise also caused modifications in biomarkers associated to metabolic alterations through changes in DNA methylation and the expression of specific miRNAs. However, both resistance and endurance exercise are necessary to obtain a better physiological adaptation and a combination of both seems to be needed to properly tackle the increasing prevalence of non-communicable pathologies. CONCLUSION: Given the heterogeneity and complexity of the existing literature, it is currently not possible to propose a specific recommendation about the type, intensity, or duration of exercise that could be beneficial for different subsets of the population (healthy, diseased, and/or trained). Nevertheless, this review highlights the importance of exercise for health and shows the need to perform more research in this emerging area to identify epigenetic biomarkers that could serve as indicators of exercise adaptations.

Plasma lactate and leukocyte mitochondrial DNA copy number as biomarkers of insulin sensitivity in non-diabetic women.

High plasma lactate levels have been associated with reduced mitochondrial respiratory capacity and increased type 2 diabetes risk, while mitochondrial DNA (mtDNA) copy number has been proposed as a biomarker of mitochondrial function linked to glucose homeostasis. The aim of this study was to evaluate the association between circulating lactate levels and leukocyte mtDNA copy numbers with insulin secretion/sensitivity indexes in 65 Chilean non-diabetic women. mtDNA copy numbers were measured in leukocytes using qPCR and digital-droplet PCR. A 75-g Oral Glucose Tolerance Test (OGTT) was performed to calculate systemic and tissue-specific insulin sensitivity indexes, as well as insulin secretion surrogates based on plasma c-peptide. An intravenous glucose tolerance test (IVGTT; 0.3 g/kg) was also carried out. Disposition indexes were calculated as the product of insulin secretion × sensitivity. Plasma levels of leptin, adiponectin, TNF-α, MCP-1, and non-esterified fatty acids were also determined. Fasting plasma lactate shows a significant association with a wide range of insulin sensitivity/resistance indexes based on fasting plasma samples (HOMA-S, adipose IR index, Revised-QUICKI, leptin-adiponectin ratio, TyG index, McAuley index and TG-to-HDL-C ratio), as well as OGTT-based measures such as the Matsuda index, the hepatic insulin resistance index, and the disposition index. Fasting plasma lactate was also positively associated with the circulating adipokines TNF-α and MCP-1. We also detected a direct association between fasting plasma lactate with leukocyte mtDNA copy numbers. The above results support the use of fasting plasma lactate, and possibly leukocyte mtDNA copy numbers, as biomarkers of reduced oxidative mitochondrial capacity, decreased hepatic insulin sensitivity, and future diabetes risk.

Guide for Current Nutrigenetic, Nutrigenomic, and Nutriepigenetic Approaches for Precision Nutrition Involving the Prevention and Management of Chronic Diseases Associated with Obesity.

Chronic diseases, including obesity, are major causes of morbidity and mortality in most countries. The adverse impacts of obesity and associated comorbidities on health remain a major concern due to the lack of effective interventions for prevention and management. Precision nutrition is an emerging therapeutic approach that takes into account an individual's genetic and epigenetic information, as well as age, gender, or particular physiopathological status. Advances in genomic sciences are contributing to a better understanding of the role of genetic variants and epigenetic signatures as well as gene expression patterns in the development of diverse chronic conditions, and how they may modify therapeutic responses. This knowledge has led to the search for genetic and epigenetic biomarkers to predict the risk of developing chronic diseases and personalizing their prevention and treatment. Additionally, original nutritional interventions based on nutrients and bioactive dietary compounds that can modify epigenetic marks and gene expression have been implemented. Although caution must be exercised, these scientific insights are paving the way for the design of innovative strategies for the control of chronic diseases accompanying obesity. This document provides a number of examples of the huge potential of understanding nutrigenetic, nutrigenomic, and nutriepigenetic roles in precision nutrition.

Higher Fruit Intake Is Related to TNF-α Hypomethylation and Better Glucose Tolerance in Healthy Subjects.

BACKGROUND/AIM: This study hypothesized an association between healthy dietary patterns, hypermethylation of the tumor necrosis factor-α (TNF-α) promoter and decreased risk of metabolic changes. METHODS: Forty normal-weight young women were involved in this cross-sectional study. DNA was isolated from white blood cells, and CpG site methylation in TNF-α was analyzed by Sequenom EpiTyper. The quality of the diet was assessed by Healthy Eating Index (HEI-2005). RESULTS: Contradicting our hypothesis, HEI-2005 score was negatively associated with CpG5 (r = -0.460, p = 0.003) and TNF-α total methylation (r = -0.355, p = 0.026). A higher intake of fruits was related to lower insulin, HOMA-IR, and TNF-α methylation. No other dietary pattern was related to TNF-α methylation. TNF-α total methylation correlated positively with systolic blood pressure (r = 0.323; p = 0.042) and CpG5 methylation with body mass index (r = 0.333, p = 0.036). Furthermore, fiber intake was negatively associated with the CpG5 (r = -0.324, p = 0.041) and TNF-α total methylation (r = -0.434, p = 0.005), whereas vitamin C intake was negatively associated with TNF-α total methylation (r = -0.411, p = 0.009). Intakes of apples and citrus fruits were negatively associated with TNF-α total methylation. CONCLUSION: A healthy dietary pattern and higher fruit intake (particularly apples and citrus fruits) were related to better glucose tolerance in healthy subjects, which could be mediated by lower TNF-α methylation.

LINE-1 methylation is positively associated with healthier lifestyle but inversely related to body fat mass in healthy young individuals.

With the goal of investigating if epigenetic biomarkers from white blood cells (WBC) are associated with dietary, anthropometric, metabolic, inflammatory and oxidative stress parameters in young and apparently healthy individuals. We evaluated 156 individuals (91 women, 65 men; age: 23.1±3.5 years; body mass index: 22.0±2.9 kg/m(2)) for anthropometric, biochemical and clinical markers, including some components of the antioxidant defense system and inflammatory response. DNA methylation of LINE-1, TNF-α and IL-6 and the expression of some genes related to the inflammatory process were analyzed in WBC. Adiposity was lower among individuals with higher LINE-1 methylation. On the contrary, body fat-free mass was higher among those with higher LINE-1 methylation. Individuals with higher LINE-1 methylation had higher daily intakes of calories, iron and riboflavin. However, those individuals who presented lower percentages of LINE-1 methylation reported higher intakes of copper, niacin and thiamin. Interestingly, the group with higher LINE-1 methylation had a lower percentage of current smokers and more individuals practicing sports. On the other hand, TNF-α methylation percentage was negatively associated with waist girth, waist-to-hip ratio and waist-to-stature ratio. Plasma TNF-α levels were lower in those individuals with higher TNF-α methylation. This study suggests that higher levels of LINE-1 and TNF-α methylation are associated with better indicators of adiposity status in healthy young individuals. In addition, energy and micronutrient intake, as well as a healthy lifestyle, may have a role in the regulation of DNA methylation in WBC and the subsequent metabolic changes may affect epigenetic biomarkers.

DNA methylation pattern in overweight women under an energy-restricted diet supplemented with fish oil.

Dietary factors modulate gene expression and are able to alter epigenetic signatures in peripheral blood mononuclear cells (PBMC). However, there are limited studies about the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) on the epigenetic mechanisms that regulate gene expression. This research investigates the effects of n-3-rich fish oil supplementation on DNA methylation profile of several genes whose expression has been reported to be downregulated by n-3 PUFA in PBMC: CD36, FFAR3, CD14, PDK4, and FADS1. Young overweight women were supplemented with fish oil or control in a randomized 8-week intervention trial following a balanced diet with 30% energy restriction. Fatty acid receptor CD36 decreased DNA methylation at CpG +477 due to energy restriction. Hypocaloric diet-induced weight loss also reduced the methylation percentages of CpG sites located in CD14, PDK4, and FADS1. The methylation patterns of these genes were only slightly affected by the fish oil supplementation, being the most relevant to the attenuation of the weight loss-induced decrease in CD36 methylation after adjusting by baseline body weight. These results suggest that the n-3 PUFA-induced changes in the expression of these genes in PBMC are not mediated by DNA methylation, although other epigenetic mechanisms cannot be discarded.

The rs9939609 polymorphism in the FTO gene is associated with fat and fiber intakes in patients with type 2 diabetes.

BACKGROUND/AIMS: The common polymorphism in the FTO gene (rs9939609) has been associated with obesity, type 2 diabetes, and appetite regulation. The aim of this study was to evaluate possible associations of FTO rs9939609 with dietary factors in patients with type 2 diabetes. METHODS: This was a cross-sectional study of 236 patients with type 2 diabetes (age 60.0 ± 10.3 years; diabetes duration 12.7 ± 8.2 years; 53.4% females) who were genotyped for FTO rs9939609. Patients underwent clinical and laboratory evaluations and 3-day weighed diet records. Data on dietary intake were categorized as high or low, based on median values. RESULTS: The AA genotype in the FTO gene was positively associated with high fat (>34% energy; OR = 2.17; 95% CI 1.02-4.63) and low fiber intakes (<16 g/day; OR = 2.42; 95% CI 1.05-5.57), adjusted for gender, BMI, total energy intake, systolic blood pressure, and HbA1c. When gender was taken into account, AA females had higher fat (37.4 ± 5.3 vs. 32.6 ± 7.5 and 32.2 ± 6.2% energy; p = 0.005) and lower fiber intakes (12.4 ± 4.4 vs. 15.1 ± 6.3 and 16.7 ± 5.6 g/day; p = 0.023) than patients with TT and AT genotypes. Multiple logistic regression models confirmed female associations for high fat (OR = 9.73; 95% CI 2.12-44.66) and low fiber intakes (OR = 4.28; 95% CI 1.14-16.06; p < 0.05 for all models). CONCLUSIONS: Patients with type 2 diabetes, who were carriers of the AA genotype of the FTO rs9939609, had increased fat and decreased fiber consumption, independently of BMI.