Polyphenols and metabolism: from present knowledge to future challenges.

A diet rich in polyphenols and other types of phytonutrients can reduce the occurrence of chronic diseases. However, a well-established cause-and-effect association has not been clearly demonstrated and several other issues will need to be fully understood before general recommendations will be carried out In the present review, some of the future challenges that the research on phenolic compounds will have to face in the next years are discussed: toxicological aspects of polyphenols and safety risk assessment; synergistic effects between different polyphenols; metabotype-based nutritional advice based on a differential gut microbial metabolism of polyphenols (precision nutrition); combination of polyphenols with other bioactive compounds; innovative formulations to improve the bioavailability of phenolic compounds; and polyphenols in sports nutrition and recovery.Other aspects related to polyphenol research that will have a boost in the next years are: polyphenol and gut microbiota crosstalk, including prebiotic effects and biotransformation of phenolic compounds into bioactive metabolites by gut microorganisms; molecular docking, molecular dynamics simulation, and quantum and molecular mechanics studies on the protein-polyphenol complexes; and polyphenol-based coating films, nanoparticles, and hydrogels to facilitate the delivery of drugs, nucleic acids and proteins.In summary, this article provides some constructive inspirations for advancing in the research of the applications, risk assessment and metabolic effects of dietary polyphenols in humans.

Anti-Obesity Effects of a Collagen with Low Digestibility and High Swelling Capacity: A Human Randomized Control Trial.

BACKGROUND/OBJECTIVES: Collagen is a protein formed by very long amino acid chains. When conveniently treated, it can incorporate water into the net, thus increasing its volume and mass. The present work aimed to evaluate the potential anti-obesity effects of bovine collagen that has been technologically treated to increase its water retention capacity in an acid pH medium, with the objective of inducing satiation. METHODS: Collagen's digestibility was tested with a pepsin digestion test. Its swelling capacity was tested in an acid pH medium simulating gastric conditions. Postprandial levels of ghrelin in response to collagen supplementation were tested in rats. In a randomized control trial, 64 subjects with overweight/obesity were allocated in two groups: supplemented daily with two protein bars enriched with collagen (20 g per day) for 12 weeks, or control group. Anthropometric and biochemical measurements were assessed in all the participants. RESULTS: This collagen showed a low digestibility (<60%) and high swelling capacity (>1900%) in vitro. In humans with overweight and obesity, this collagen significantly reduced body weight, body mass index (BMI), systolic blood pressure (SBP), and fatty liver index (FLI) and increased fat-free mass when compared with the control group. A significant reduction in the sarcopenic index; total, troncular, and visceral fat (measured by DEXA); and serum leptin levels were observed in the collagen group at the end of the intervention, with no differences with respect to controls. Collagen reduced the sensation of hunger and increased fullness and satisfaction. In male Wistar rats, collagen decreased postprandial blood ghrelin levels. CONCLUSIONS: Collagen supplementation (20 g per day for 12 weeks) reduced body weight, BMI, waist circumference, fat mass, FLI, and SBP in humans with overweight and obesity, which might be related to the increased sensation of fullness and satisfaction reported by the volunteers after the intake.

Health Effects and Mechanisms of Inulin Action in Human Metabolism.

Inulin is a plant polysaccharide which, due to its chemical structure, is not digestible by human gut enzymes but by some bacteria of the human microbiota, acting as a prebiotic. Consequently, inulin consumption has been associated with changes in the composition of the intestinal microbiota related to an improvement of the metabolic state, counteracting different obesity-related disturbances. However, the specific mechanisms of action, including bacterial changes, are not exactly known. Here, a bibliographic review was carried out to study the main effects of inulin on human metabolic health, with a special focus on the mechanisms of action of this prebiotic. Inulin supplementation contributes to body weight and BMI control, reduces blood glucose levels, improves insulin sensitivity, and reduces inflammation markers, mainly through the selective favoring of short-chain fatty acid (SCFA)-producer species from the genera Bifidobacterium and Anaerostipes. These SCFAs have been shown to ameliorate glucose metabolism and decrease hepatic lipogenesis, reduce inflammation, modulate immune activity, and improve anthropometric parameters such as body weight or BMI. In conclusion, the studies collected suggest that inulin intake produces positive metabolic effects through the improvement of the intestinal microbiota and through the metabolites produced by its fermentation.

Plant miR6262 Modulates the Expression of Metabolic and Thermogenic Genes in Human Hepatocytes and Adipocytes.

BACKGROUND: Edible plants have been linked to the mitigation of metabolic disturbances in liver and adipose tissue, including the decrease of lipogenesis and the enhancement of lipolysis and adipocyte browning. In this context, plant microRNAs could be key bioactive molecules underlying the cross-kingdom beneficial effects of plants. This study sought to explore the impact of plant-derived microRNAs on the modulation of adipocyte and hepatocyte genes involved in metabolism and thermogenesis. METHODS: Plant miR6262 was selected as a candidate from miRBase for the predicted effect on the regulation of human metabolic genes. Functional validation was conducted after transfection with plant miRNA mimics in HepG2 hepatocytes exposed to free fatty acids to mimic liver steatosis and hMADs cells differentiated into brown-like adipocytes. RESULTS: miR6262 decreases the expression of the predicted target RXRA in the fatty acids-treated hepatocytes and in brown-like adipocytes and affects the expression profile of critical genes involved in metabolism and thermogenesis, including PPARA, G6PC, SREBF1 (hepatocytes) and CIDEA, CPT1M and PLIN1 (adipocytes). Nevertheless, plant miR6262 mimic transfections did not decrease hepatocyte lipid accumulation or stimulate adipocyte browning. CONCLUSIONS: these findings suggest that plant miR6262 could have a cross-kingdom regulation relevance through the modulation of human genes involved in lipid and glucose metabolism and thermogenesis in adipocytes and hepatocytes.

Editorial Special Issue: 2022 consortium for trans-pyrenean investigations on obesity and diabetes.

This Special Issue of the Journal of Physiology and Biochemistry contains 7 contributions that have been elaborated in the context of the mini-network "Consortium of Trans-Pyrenean Investigations on Obesity and Diabetes" (CTPIOD), which is on its 19th year of existence. This scientific community, mostly involving research groups from France and Spain, but also open to participants coming from other countries, is focused on investigating the molecular and physiological mechanisms implicated in the development of obesity, diabetes, non-alcoholic fatty liver disease, and other noncommunicable diseases, as well as new preventive and therapeutic strategies. This special issue covers novel nutritional, molecular, and physiological aspects related to these metabolic diseases. Some of these papers emerge from the lectures of the 19th Conference on Trans-Pyrenean Investigations in Obesity and Diabetes, organized by the University of Zaragoza and celebrated in the town of Jaca (Spain) on 17-18th October 2022, and have been prepared in collaboration between different groups of the network. Many lectures were focused on the preventive role of specific fatty acids, dietary phenolic compounds and other phytochemicals against metabolic disorders. Consequently, we encouraged submission of original research in this field for this special issue.

Green Tea Kombucha Impacts Inflammation and Salivary Microbiota in Individuals with Excess Body Weight: A Randomized Controlled Trial.

BACKGROUND: Green tea kombucha (GTK) is a fermented beverage with promising health benefits, but few studies proved its impact on human health. Thus, we aimed to investigate the impact of GTK on weight loss, inflammation, and salivary microbiota in individuals with excess body weight. METHODS: This is a randomized controlled clinical trial that lasted 10 weeks with two groups of individuals with excess body weight: control (CG; n = 29; caloric restriction) and kombucha (KG; n = 30; caloric restriction + 200 mL GTK). Body composition, anthropometry, saliva, and blood collection were performed in the beginning and end of the intervention. Plasma interleukins were determined by flow cytometry. Salivary microbiota was analyzed by 16S rRNA sequencing. RESULTS: Both groups decreased weight, BMI, and body fat (p < 0.001) after the intervention, but there were no differences between groups. The KG reduced lipid accumulation product (LAP) (p = 0.029). Both groups decreased IL-1ß and IL-8, but IL-6 increased in the CG (p = 0.023) compared to the kombucha group. Alpha and beta diversity of salivary microbiota increased in the KG. Moreover, the KG presented lower Bacillota/Bacteroidota ratio (p = 0.028), and BMI was positively associated with the Bacillota phylum. CONCLUSIONS: GTK did not enhance weight loss, but it decreased the LAP. GTK helped in the inflammatory profile and induced positive changes in oral microbiota composition.

Circulating miR-122-5p, miR-151a-3p, miR-126-5p and miR-21-5p as potential predictive biomarkers for Metabolic Dysfunction-Associated Steatotic Liver Disease assessment.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a worldwide leading cause of liver-related associated morbidities and mortality. Currently, there is a lack of reliable non-invasive biomarkers for an accurate of MASLD. Hence, this study aimed to evidence the functional role of miRNAs as potential biomarkers for MASLD assessment. Data from 55 participants with steatosis (MASLD group) and 45 without steatosis (control group) from the Fatty Liver in Obesity (FLiO) Study (NCT03183193) were analyzed. Anthropometrics and body composition, biochemical and inflammatory markers, lifestyle factors and liver status were evaluated. Circulating miRNA levels were measured by RT-PCR. Circulating levels of miR-122-5p, miR-151a-3p, miR-126-5p and miR-21-5p were significantly increased in the MASLD group. These miRNAs were significantly associated with steatosis, liver stiffness and hepatic fat content. Logistic regression analyses revealed that miR-151a-3p or miR-21-5p in combination with leptin showed a significant diagnostic accuracy for liver stiffness obtaining an area under the curve (AUC) of 0.76 as well as miR-151a-3p in combination with glucose for hepatic fat content an AUC of 0.81. The best predictor value for steatosis was obtained by combining miR-126-5p with leptin, presenting an AUC of 0.95. Circulating miRNAs could be used as a non-invasive biomarkers for evaluating steatosis, liver stiffness and hepatic fat content, which are crucial in determining MASLD. CLINICAL TRIAL REGISTRATION: • Trial registration number: NCT03183193 ( www.clinicaltrials.gov ). • Date of registration: 12/06/2017.

Inflammatory markers as diagnostic and precision nutrition tools for metabolic dysfunction-associated steatotic liver disease: Results from the Fatty Liver in Obesity trial.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern. The disease is silent, and its diagnosis is often delayed. Inflammatory markers constitute an interesting tool to act as subrogate, non-invasive markers. This study aimed to evaluate the changes of inflammatory markers throughout a two-year dietary intervention in subjects presenting MASLD, to determine which of the markers are suitable to predict the disease, and act as a customizing tool for MASLD's dietary treatment. METHODS: Ninety-eight subjects with MASLD and forty-five controls from the Fatty Liver in Obesity (FLiO) Study were analyzed. MASLD was diagnosed and graded by ultrasound. The MASLD subjects were randomly assigned to two different dietary strategies, the American Heart Association (AHA diet) or a dietary strategy based on the Mediterranean pattern, which was specially designed for the study (FLiO diet), and then followed for two years. Hepatic status was additionally assessed through Magnetic Resonance Imaging (MRI), elastography, and determination of transaminases. RESULTS & DISCUSSION: Inflammatory markers improved throughout the intervention in the MASLD subjects and managed to reach similar levels to controls, especially at 6 and 12 months. Additionally, leptin, adiponectin, M30, and LECT2 managed to significantly diagnose the disease at all time marks of the intervention, making them candidates for subrogate non-invasive markers of the disease. Moreover, baseline chemerin, leptin, LECT2, and M65 were used to build a predictive score to achieve greater weight loss, and therefore, which strategy could be more useful for MASLD 's treatment. The predictive score was significantly able assign a specific diet to 55% of the study participants, meaning that the remaining 45% could achieve the same amount of weight loss following either diet equally. CONCLUSION: Inflammatory markers constitute a potential non-invasive tool to be used in MASLD screening and could also constitute an interesting tool for MASLD's treatment customization, being able to predict the effectiveness of a dietary strategy based on the initial inflammatory state of each subject. TRIAL REGISTRATION: www. CLINICALTRIALS: gov (NCT03183193).

Sourdough bread enriched with exopolysaccharides and gazpacho by-products modulates in vitro the microbiota dysbiosis.

Sourdough bread enriched with soluble fiber (by in-situ exopolysaccharides production) and insoluble fiber (by gazpacho by-products addition) showed prebiotic effects an in vitro dynamic colonic fermentation performance with obese volunteer's microbiota. Bifidobacterium population was maintained whereas Lactobacillus increased throughout the colonic sections. Conversely, Enterobacteriaceae and Clostridium groups clearly decreased. Specific bacteria associated with beneficial effects increased in the ascending colon (Lactobacillus fermentum, Lactobacillus paracasei, Bifidobacterium longum and Bifidobacterium adolescentis) whereas Eubacterium eligens, Alistipes senegalensis, Prevotella copri and Eubacterium desmolans increased in the transversal and descending colon. Additionally, Blautia faecis and Ruminococcus albus increased in the transversal colon, and Bifidobacterium longum, Roseburia faecis and Victivallis vadensis in the descending colon. Bifidobacterium and Lactobacillus fermented the in-situ exopolysaccharides and released pectins from gazpacho by-products, as well as cellulosic degraded bacteria. This increased the short and medium chain fatty acids. Acetic acid, as well as butyric acid, increased throughout the colonic tract, which showed greater increases only in the transversal and descending colonic segments. Conversely, propionic acid was slightly affected by the colonic fermentation. These results show that sourdough bread is a useful food matrix for the enrichment of vegetable by-products (or other fibers) in order to formulate products with microbiota modulatory capacities.

Multipanel Approach including miRNAs, Inflammatory Markers, and Depressive Symptoms for Metabolic Dysfunction-Associated Steatotic Liver Disease Diagnosis during 2-Year Nutritional Intervention.

Metabolic dysfunction-associated steatotic liver disease (MASLD), with a prevalence of 30% of adults globally, is considered a multifactorial disease. There is a lack of effective non-invasive methods for accurate diagnosis and monitoring. Therefore, this study aimed to explore associations between changes in circulating miRNA levels, inflammatory markers, and depressive symptoms with hepatic variables in MASLD subjects and their combined potential to predict the disease after following a dietary intervention. Biochemical markers, body composition, circulating miRNAs and hepatic and psychological status of 55 subjects with MASLD with obesity and overweight from the FLiO study were evaluated by undergoing a 6-, 12- and 24-month nutritional intervention. The highest accuracy values of combined panels to predict the disease were identified after 24 months. A combination panel that included changes in liver stiffness, high-density lipoprotein cholesterol (HDL-c), body mass index (BMI), depressive symptoms, and triglycerides (TG) yielded an AUC of 0.90. Another panel that included changes in hepatic fat content, total cholesterol (TC), miR15b-3p, TG, and depressive symptoms revealed an AUC of 0.89. These findings identify non-invasive biomarker panels including circulating miRNAs, inflammatory markers, depressive symptoms and other metabolic variables for predicting MASLD presence and emphasize the importance of precision nutrition in MASLD management and the sustained adherence to healthy lifestyle patterns.

Fiber from elicited butternut pumpkin (Cucurbita moschata D. cv. Ariel) modulates the human intestinal microbiota dysbiosis.

Elicited pumpkin was evaluated as a potential daily consumption product able to modulate the gut microbiota. An in vitro dynamic colonic fermentation performance with microbiota from obese volunteers was used. Prebiotic effects were observed after the pumpkin treatment. Bifidobacterium abundance was maintained during the treatment period whereas Lactobacillus increased in the transversal and descending colon. Conversely, Enterobacteriaceae and Clostridium groups were more stable, although scarce decreasing trends were observed for same species. Increments of Lactobacillus acidophilus and Limosilactobacillus fermentum (old Lactobacillus fermentum) were observed in the whole colonic tract after the treatment period. However, modulatory effects were mainly observed in the transversal and descending colon. Diverse bacteria species were increased, such as Akkermansia muciniphila, Bacteroides dorei, Cloacibacillus porcorum, Clostridium lactatifermentans, Ruminococcus albus, Ruminococcus lactaris, Coprococcus catus, Alistipes shahii or Bacteroides vulgatus. The prebiotic effect of the elicited pumpkin was provided by the fiber of the pumpkin, suggesting a release of pectin molecules in the transversal and distal colonic tract through low cellulosic fiber degradation, explaining the increases in the total propionic and butyric acid in these colonic sections. Also, a possible modulatory role of carotenoids from the sample was suggested since carotenes were found in the descending colon. Hence, the results of this research highlighted pumpkin as a natural product able to modulate the microbiota towards a healthier profile.

MicroRNAs from edible plants reach the human gastrointestinal tract and may act as potential regulators of gene expression.

MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that regulate gene expression at the post-transcriptional level. A cross-kingdom regulatory function has been unveiled for plant miRNAs (xenomiRs), which could shape inter-species interactions of plants with other organisms (bacteria and humans) and thus, be key functional molecules of plant-based food in mammals. However, discrepancies regarding the stability and bioavailability of dietary plant miRNAs on the host cast in doubt whether these molecules could have a significant impact on human physiology. The aim of the present study was to identify miRNAs in edible plants and determine their bioavailability on humans after an acute intake of plant-based products. It was found that plant food, including fruits, vegetables and greens, nuts, legumes, and cereals, contains a wide range of miRNAs. XenomiRs miR156e, miR159 and miR162 were detected in great abundance in edible plants and were present among many plant foods, and thus, they were selected as candidates to analyse their bioavailability in humans. These plant miRNAs resisted cooking processes (heat-treatments) and their relative presence increased in faeces after and acute intake of plant-based foods, although they were not detected in serum. Bioinformatic analysis revealed that these miRNAs could potentially target human and bacterial genes involved in processes such as cell signalling and metabolism. In conclusion, edible plants contain miRNAs, such as miR156e, miR159 and miR162, that could resist degradation during cooking and digestion and reach the distal segments of the gastrointestinal tract. Nevertheless, strategies should be developed to improve their absorption to potentially reach host tissues and organs and modulate human physiology.

Plant miR8126-3p and miR8126-5p Decrease Lipid Accumulation through Modulation of Metabolic Genes in a Human Hepatocyte Model That Mimics Steatosis.

Plant-based food interventions are promising therapeutic approaches for non-alcoholic fatty liver disease (NAFLD) treatment, and microRNAs (miRNAs) have emerged as functional bioactive components of dietary plants involved in cross-kingdom communication. Deeper investigations are needed to determine the potential impact of plant miRNAs in NAFLD. This study aimed to identify plant miRNAs that could eventually modulate the expression of human metabolic genes and protect against the progression of hepatic steatosis. Plant miRNAs from the miRBase were used to predict human target genes, and miR8126-3p and miR8126-5p were selected as candidates for their potential role in inhibiting glucose and lipid metabolism-related genes. Human HepG2 cells were transfected with plant miRNA mimics and then exposed to a mixture of oleic and palmitic acids to mimic steatosis. miR8126-3p and miR8126-5p transfections inhibited the expression of the putative target genes QKI and MAPKAPK2, respectively, and had an impact on the expression profile of key metabolic genes, including PPARA and SREBF1. Quantification of intrahepatic triglycerides revealed that miR8126-3p and miR8126-5p attenuated lipid accumulation. These findings suggest that plant miR8126-3p and miR8126-5p would induce metabolic changes in human hepatocytes eventually protecting against lipid accumulation, and thus, they could be potential therapeutic tools for preventing and alleviating lipid accumulation.

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.

Caenorhabditis elegans as a Screening Model for Probiotics with Properties against Metabolic Syndrome.

There is a growing need to develop new approaches to prevent and treat diseases related to metabolic syndromes, including obesity or type 2 diabetes, that focus on the different factors involved in the pathogenesis of these diseases. Due to the role of gut microbiota in the regulation of glucose and insulin homeostasis, probiotics with beneficial properties have emerged as an alternative therapeutic tool to ameliorate metabolic diseases-related disturbances, including fat excess or inflammation. In the last few years, different strains of bacteria, mainly lactic acid bacteria (LAB) and species from the genus Bifidobacterium, have emerged as potential probiotics due to their anti-obesogenic and/or anti-diabetic properties. However, in vivo studies are needed to demonstrate the mechanisms involved in these probiotic features. In this context, Caenorhabditis elegans has emerged as a very powerful simple in vivo model to study the physiological and molecular effects of probiotics with potential applications regarding the different pathologies of metabolic syndrome. This review aims to summarize the main studies describing anti-obesogenic, anti-diabetic, or anti-inflammatory properties of probiotics using C. elegans as an in vivo research model, as well as providing a description of the molecular mechanisms involved in these activities.

Effect of low-and non-calorie sweeteners on the gut microbiota: A review of clinical trials and cross-sectional studies.

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.

A Predictive Tool Based on DNA Methylation Data for Personalized Weight Loss through Different Dietary Strategies: A Pilot Study.

BACKGROUND AND AIMS: Obesity is a public health problem. The usual treatment is a reduction in calorie intake and an increase in energy expenditure, but not all individuals respond equally to these treatments. Epigenetics could be a factor that contributes to this heterogeneity. The aim of this research was to determine the association between DNA methylation at baseline and the percentage of BMI loss (%BMIL) after two dietary interventions, in order to design a prediction model to evaluate %BMIL based on methylation data. METHODS AND RESULTS: Spanish participants with overweight or obesity (n = 306) were randomly assigned to two lifestyle interventions with hypocaloric diets: one moderately high in protein (MHP) and the other low in fat (LF) for 4 months (Obekit study; ClinicalTrials.gov ID: NCT02737267). Basal DNA methylation was analyzed in white blood cells using the Infinium MethylationEPIC array. After identifying those methylation sites associated with %BMIL (p < 0.05 and SD > 0.1), two weighted methylation sub-scores were constructed for each diet: 15 CpGs were used for the MHP diet and 11 CpGs for the LF diet. Afterwards, a total methylation score was made by subtracting the previous sub-scores. These data were used to design a prediction model for %BMIL through a linear mixed effect model with the interaction between diet and total score. CONCLUSION: Overall, DNA methylation predicts the %BMIL of two 4-month hypocaloric diets and was able to determine which type of diet is the most appropriate for each individual. The results of this pioneer study confirm that epigenetic biomarkers may be further used for precision nutrition and the design of personalized dietary strategies against obesity.

miR482f and miR482c-5p from edible plant-derived foods inhibit the expression of pro-inflammatory genes in human THP-1 macrophages.

Background: Edible plants can exert anti-inflammatory activities in humans, being potentially useful in the treatment of inflammatory diseases. Plant-derived microRNAs have emerged as cross-kingdom gene expression regulators and could act as bioactive molecules involved in the beneficial effects of some edible plants. We investigated the role of edible plant-derived microRNAs in the modulation of pro-inflammatory human genes. Methods: MicroRNAs from plant-derived foods were identified by next-generation sequencing. MicroRNAs with inflammatory putative targets were selected, after performing in silico analyses. The expression of candidate plant-derived miRNAs was analyzed by qPCR in edible plant-derived foods and their effects were evaluated in THP-1 monocytes differentiated to macrophages. The bioavailability of candidate plant miRNAs in humans was evaluated in feces and serum samples by qPCR. Results: miR482f and miR482c-5p are present in several edible plant-derived foods, such as fruits, vegetables, and cooked legumes and cereals, and fats and oils. Transfections with miR482f and miR482c-5p mimics decreased the gene expression of CLEC7A and NFAM1, and TRL6, respectively, in human THP-1 monocytes differentiated to macrophages, which had an impact on gene expression profile of inflammatory biomarkers. Both microRNAs (miR482f and miR482c-5p) resisted degradation during digestion and were detected in human feces, although not in serum. Conclusion: Our findings suggest that miR482f and miR482c-5p can promote an anti-inflammatory gene expression profile in human macrophages in vitro and their bioavailability in humans can be achieved through diet, but eventually restricted at the gut level.

Pediococcus acidilactici (pA1c®) alleviates obesity-related dyslipidemia and inflammation in Wistar rats by activating beta-oxidation and modulating the gut microbiota.

Due to the importance of the gut microbiota in the regulation of energy homeostasis, probiotics have emerged as an alternative therapy to ameliorate obesity-related disturbances, including cholesterol metabolism dysregulation, dyslipidemia and inflammation. Therefore, the objectives of this study were to evaluate the effect of the probiotic strain Pediococcus acidilactici (pA1c®) on the regulation of adiposity, cholesterol and lipid metabolism, inflammatory markers and gut microbiota composition in diet-induced obese rats. Twenty-nine four-week-old male Wistar rats were divided into three groups: rats fed a control diet (CNT group, n = 8), rats fed a high fat/high sucrose diet (HFS group, n = 11), and rats fed a HFS diet supplemented with pA1c® (pA1c®group, n = 10). Organs and fat depots were weighed, and different biochemical parameters were analysed in serum. Gene expression analyses in the adipose tissue were conducted using real-time quantitative-PCR. Faecal microbiota composition was evaluated using 16S metagenomics. Animals supplemented with pA1c® exhibited a lower proportion of visceral adiposity, a higher proportion of muscle, an improvement in the total-cholesterol/HDL-cholesterol ratio and a decrease in the total cholesterol, triglyceride and aspartate aminotransaminase (AST) serum levels, together with a decrease in several inflammation-related molecules. The expression of key genes related to adipose (Adipoq, Cebpa and Pparg) and glucose (Slc2a1 and Slc2a4) metabolism in the adipose tissue was normalized by pA1c®. Moreover, it was demonstrated that pA1c® supplementation activated fatty acid ß-oxidation in the adipose tissue and the liver. Metagenomics demonstrated the presence of pA1c® in the faecal samples, an increase in alpha diversity, an increase in the abundance of beneficial bacteria, and a decrease in the abundance of harmful micro-organisms, including the Streptococcus genus. Thus, our data suggest the potential of pA1c® in the prevention of obesity-related disturbances including hypercholesterolemia, hypertriglyceridemia, inflammation and gut microbiota dysbiosis.

Isoliquiritigenin in combination with visceral adipose tissue and related markers as a predictive tool for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world. New non-invasive diagnostic tools are needed to promptly treat this disease and avoid its complications. This study aimed to find key metabolites and related variables that could be used to predict and diagnose NAFLD. Ninety-eight subjects with NAFLD and 45 controls from the Fatty Liver in Obesity (FLiO) Study (NCT03183193) were analyzed. NAFLD was diagnosed and graded by ultrasound and classified into two groups: 0 (controls) and ≥ 1 (NAFLD). Hepatic status was additionally assessed through magnetic resonance imaging (MRI), elastography, and determination of transaminases. Anthropometry, body composition (DXA), biochemical parameters, and lifestyle factors were evaluated as well. Non-targeted metabolomics of serum was performed with high-performance liquid chromatography coupled to time-of-flight mass spectrometry (HPLC-TOF-MS). Isoliquiritigenin (ISO) had the strongest association with NAFLD out of the determinant metabolites. Individuals with higher concentrations of ISO had healthier metabolic and hepatic status and were less likely to have NAFLD (OR 0.13). Receiver operating characteristic (ROC) curves demonstrated the predictive power of ISO in panel combination with other NAFLD and IR-related variables, such as visceral adipose tissue (VAT) (AUROC 0.972), adiponectin (AUROC 0.917), plasmatic glucose (AUROC 0.817), and CK18-M30 (AUROC 0.810). Individuals with lower levels of ISO have from 71 to 82% more risk of presenting NAFLD compared to individuals with higher levels. Metabolites such as ISO, in combination with visceral adipose tissue, IR, and related markers, constitute a potential non-invasive tool to predict and diagnose NAFLD.