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    Inflammatory markers as diagnostic and precision nutrition tools for metabolic dysfunction-associated steatotic liver disease: Results from the Fatty Liver in Obesity trial
    (Elsevier, 2024) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Tobaruela-Resola, A.L. (Ana Luz); Benito-Boíllos, A. (Alberto); Zulet, M.A. (María Ángeles); Tur, J.A. (Josep A.); Mogna-Peláez, P. (Paola); Milagro-Yoldi, F.I. (Fermín Ignacio); Herrero, J.I. (José Ignacio); Elorz, M. (Mariana); Abete, I. (Itziar)
    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 sub- jects 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).
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    Dietary Inflammatory Index and liver status in subjects with different adiposity levels within the PREDIMED trial
    (2018) Babio, N. (Nancy); Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Fito, M. (Montserrat); Zulet, M.A. (María Ángeles); Shivappa, N. (Nitin); Tur, J.A. (Josep A.); Gomez-Gracia, E. (Enrique); Ruiz-Canela, M. (Miguel); Portillo, M.P. (María P.); Wärnberg, J. (Julia); Estruch, R. (Ramón); Corella, D. (Dolores); Abete, I. (Itziar); Pinto, X. (Xavier); Cantero-González, I. (Irene); Salas-Salvado, J. (Jordi); Hebert, J.R. (James R.); Aros, F. (Fernando)
    Background & aims: To assess the possible association between a validated Dietary Inflammatory Index (DII) and specific dietary components with suitable non-invasive markers of liver status in overweight and obese subjects within the PREDIMED study. Methods: A cross-sectional study encompassing 794 randomized overweight and obese participants (mean ± SD age: 67.0 ± 5.0 y, 55% females) from the PREDIMED (PREvencion con DIeta MEDiterr anea) trial was conducted. DII is a validated tool evaluating the effect of diet on six inflammatory biomarkers (IL-1b, IL-4, IL-6, IL-10, TNF-a and C-reactive protein). Furthermore, a validated 137-item food-frequencyquestionnaire was used to obtain the information about the food intake. In addition, anthropometric measurements and several non-invasive markers of liver status were assessed and the Fatty Liver Index (FLI) score was calculated. Results: A higher DII and lower adherence to Mediterranean diet (MeDiet) were associated with a higher degree of liver damage (FLI > 60) in obese as compared to overweight participants. Furthermore, the DII score was positively associated with relevant non-invasive liver markers (ALT, AST, GGT and FLI) and directly affected FLI values. Interestingly, a positive correlation was observed between liver damage (>50th percentile FLI) and nutrients and foods linked to a pro-inflammatory dietary pattern. Conclusions: This study reinforced the concept that obesity is associated with liver damage and revealed that the consumption of a pro-inflammatory dietary pattern might contribute to obesity and fatty liver disease features. These data suggest that a well-designed precision diet including putative antiinflammatory components could specifically prevent and ameliorate non-alcoholic fatty liver manifestations in addition to obesity.
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    Interplay of an Obesity-Based Genetic Risk Score with Dietary and Endocrine Factors on Insulin Resistance
    (2020) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Goñi-Mateos, L. (Leticia); Milagro-Yoldi, F.I. (Fermín Ignacio); Cuervo, M. (Marta); Ramos-López, O. (Omar)
    This study aimed to nutrigenetically screen gene-diet and gene-metabolic interactions influencing insulin resistance (IR) phenotypes. A total of 232 obese or overweight adults were categorized by IR status: non-IR (HOMA-IR (homeostatic model assessment - insulin resistance) index 2.5) and IR (HOMA-IR index > 2.5). A weighted genetic risk score (wGRS) was constructed using 95 single nucleotide polymorphisms related to energy homeostasis, which were genotyped by a next generation sequencing system. Body composition, the metabolic profile and lifestyle variables were evaluated, where individuals with IR showed worse metabolic outcomes. Overall, 16 obesity-predisposing genetic variants were associated with IR (p < 0.10 in the multivariate model). The wGRS strongly associated with the HOMA-IR index (adj. R squared = 0.2705, p < 0.0001). Moreover, the wGRS positively interacted with dietary intake of cholesterol (P int. = 0.002), and with serum concentrations of C-reactive protein (P int. = 0.008) regarding IR status, whereas a negative interaction was found regarding adiponectin blood levels (P int. = 0.006). In conclusion, this study suggests that interactions between an adiposity-based wGRS with nutritional and metabolic/endocrine features influence IR phenotypes, which could facilitate the prescription of personalized nutrition recommendations for precision prevention and management of IR and diabetes.
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    Influencia de la dieta sobre marcadores plasmáticos de estrés oxidativo en humanos
    (2008) Martinez, J.A. (José Alfredo); Barbosa, K.B. (K.B.); Zulet, M.A. (María Ángeles); Bressan, J. (J.)
    La instauración del estrés oxidativo se relaciona con la existencia de un desequilibrio entre los sistemas oxidativos y antioxidantes, a favor de los primeros. Tal proceso se ha involucrado en el desarrollo de las enfermedades crónicas no transmisibles, entre ellas: obesidad, aterogénesis, diabetes, transtornos neurodegenerativos y cáncer. El estrés oxidativo se controla a través de sistemas de defensa antioxidantes, incluyendo mecanismos enzimáticos y no enzimáticos. Este último grupo se refiere, sobre todo, a los antioxidantes de origen dietético, especialmente, vitaminas, minerales y fitoquímicos (polifenoles y carotenoides). De ello, deriva la importancia de la dieta como factor involucrado en la modulación del estrés oxidativo. Las implicaciones y efectos de los antioxidantes dietéticos sobre el proceso oxidativo pueden ser evaluados por medio de diversos biomarcadores específicos. Estos indicadores incluyen sobre todo, a los productos derivados de la oxidacion de lípidos, proteínas y ácidos nucleicos por radicales libres y especies reactivas de oxígeno. Por otra parte, los marcadores basados en la valoración de la capacidad antioxidante son también indicadores del estrés oxidativo. Los estudios que abordan la dieta como factor que modula el estrés oxidativo, se basan, preferentemente, en el efecto de las vitaminas y minerales (estudios de suplementación), alimentos y bebidas (fuentes de compuestos antioxidantes) o patrones dietéticos. Algunos estudios han logrado describir efectos beneficiosos sobre los marcadores del estrés oxidativo. No obstante, todavía, los resultados no son del todo concluyentes, presentándose una importante heterogeinidad metodológica en cuanto a las condiciones de los sujetos y de las intervenciones dietéticas evaluadas, así como sobre la interpretación de los resultados y su incidencia sobrre la salud.
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    Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake
    (Wiley Open Access, 2018) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Milagro-Yoldi, F.I. (Fermín Ignacio); Ramos-López, O. (Omar)
    Introduction: Dopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hy-pothesized associations of DNA methylation signatures at genes modulating DA sign -aling with obesity features, metabolic profiles, and dietary intake.Methods: An adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened.Results: After applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p <0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (C ACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the pres -ence or absence of abdominal obesity. Pathway analyses revealed a statistically sig-nificant contribution of the aforementioned genes to dopaminergic synapse transmission (p =4.78E−08). Furthermore,SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p <0.001) and carbohydrate (p <0.001) intakes.Conclusions: The results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition.
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    Interplay of glycemic index, glycemic load, and dietary antioxidant capacity with insulin resistance in subjects with a cardiometabolic risk profile
    (MDPI AG, 2018) Martinez, J.A. (José Alfredo); Benito-Boíllos, A. (Alberto); Zulet, M.A. (María Ángeles); Tur, J.A. (Josep A.); Marin-Alejandre, B.A. (Bertha Araceli); Galarregui-Miquelarena, C. (Cristina); Herrero, J.I. (José Ignacio); Monreal, J.I. (José Ignacio); Elorz, M. (Mariana); Abete, I. (Itziar); Cantero-González, I. (Irene)
    Background: Dietary total antioxidant capacity (TAC), glycemic index (GI), and glycemic load (GL) are accepted indicators of diet quality, which have an effect on diet–disease relationships. The aim of this study was to evaluate potential associations of dietary TAC, GI, and GL with variables related to nutritive status and insulin resistance (IR) risk in cardiometabolic subjects. Methods: A total of 112 overweight or obese adults (age: 50.8 ± 9 years old) were included in the trial. Dietary intake was assessed by a validated 137-item food frequency questionnaire (FFQ), which was also used to calculate the dietary TAC, GI, and GL. Anthropometrics, blood pressure, body composition by dual-energy X-ray absorptiometry (DXA), glycemic and lipid profiles, C-reactive protein (CRP), as well as fatty liver quantification by magnetic resonance imaging (MRI) were assessed. Results: Subjects with higher values of TAC had significantly lower circulating insulin concentration and homeostatic model assessment of insulin resistance (HOMA-IR). Participants with higher values of HOMA-IR showed significantly higher GI and GL. Correlation analyses showed relevant inverse associations of GI and GL with TAC. A regression model evidenced a relationship of HOMA-IR with TAC, GI, and GL. Conclusion: This data reinforces the concept that dietary TAC, GI, and GL are potential markers of diet quality, which have an impact on the susceptible population with a cardiometabolic risk profile.
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    Estrategias de guía e ingredientes dietéticos de precisión para enfermedades crónicas en población pre-sénior y sénior
    (NCBI, 2018) Martinez, J.A. (José Alfredo); Loria-Kohen, V. (Viviana); Zulet, M.A. (María Ángeles); Ramirez-de-Molina, A. (Ana); Galarregui-Miquelarena, C. (Cristina); Navas-Carretero, S. (Santiago); Reglero, G. (Guillermo); Abete, I. (Itziar)
    El envejecimiento de la población supone un importante reto, económico y cualitativo, para el sistema de salud orientándolo hacia una atención de tipo preventivo, en la que la nutrición de precisión (NP) y la prescripción de hábitos saludables adquieren relevancia capital. El fin de la NP es procurar una nutrición adaptada a cada individuo, entendiendo que la prevención o el tratamiento de trastornos crónicos (obesidad, diabetes, enfermedad cardiovascular, etc.) deben abordarse de un modo integral, considerando información personal y clínica relevante, edad y características feno- y genotípicas. La elaboración de la presente guía surge de la necesidad de desarrollar modelos nutricionales de precisión que permitan la individualización del tratamiento nutricional, con énfasis en el adulto mayor. Las necesidades nutricionales, las recomendaciones dietéticas y los ingredientes para una NP en las personas pre-sénior y sénior quedan resumidas en realizar al menos 3 comidas diarias, reducir las calorías totales, optar por una alimentación variada y equilibrada con alimentos frescos y de alta densidad nutricional, incorporar verduras, legumbres y pescado, consumir productos lácteos y fibra, preferir carnes blancas en lugar de rojas, evitar frituras, embutidos y alimentos procesados, moderar el consumo de sal, café y alcohol, e hidratarse adecuadamente.
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    Associations between olfactory pathway gene methylation marks, obesity features and dietary intakes
    (Springer Science and Business Media LLC, 2019) Santos, J.L. (José Luis); Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Zulet, M.A. (María Ángeles); Milagro-Yoldi, F.I. (Fermín Ignacio); Ramos-López, O. (Omar)
    Background: Olfaction is an important sense influencing food preferences, appetite, and eating behaviors. This hypothesis-driven study aimed to assess associations between olfactory pathway gene methylation signatures, obesity features, and dietary intakes. Methods: A nutriepigenomic analysis was conducted in 474 adults from the Methyl Epigenome Network Association (MENA) project. Anthropometric measurements, clinical data, and serum metabolic profiles of the study population were obtained from structured databases of the MENA cohorts. Habitual dietary intake was assessed using a validated semiquantitative food frequency questionnaire. DNA methylation was measured in circulating white blood cells by microarray (Infinium Human Methylation 450 K BeadChips). FDR values (p < 0.0001) were used to select those CpGs that showed the best correlation with body mass index (BMI) and waist circumference (WC). Pathway analyses involving the characterization of genes involved in the olfactory transduction system were performed using KEGG and pathDIP reference databases. Results: Overall, 15 CpG sites at olfactory pathway genes were associated with BMI (p < 0.0001) and WC (p < 0.0001) after adjustments for potential confounding factors. Together, methylation levels at the15 CpG sites accounted for 22% and 20% of the variability in BMI and WC (r 2 = 0.219, p < 0.001, and r 2 = 0.204, p < 0.001, respectively). These genes encompassed olfactory receptors (OR4D2, OR51A7, OR2T34, and OR2Y1) and several downstream signaling molecules (SLC8A1, ANO2, PDE2A, CALML3, GNG7, CALML6, PRKG1, and CAMK2D), which significantly regulated odor detection and signal transduction processes within the complete olfactory cascade, as revealed by pathway enrichment analyses (p = 1.94 × 10–10). Moreover, OR4D2 and OR2Y1 gene methylation patterns strongly correlated with daily intakes of total energy (p < 0.0001), carbohydrates (p < 0.0001), protein (p < 0.0001), and fat (p < 0.0001). Conclusions: The results of this study suggest novel relationships between olfactory pathway gene methylation signatures, obesity indices, and dietary intakes.
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    Associations between dietary polyphenols and type 2 diabetes in a cross-sectional analysis of the PREDIMED-plus trial: Role of body mass index and sex
    (MDPI AG, 2019) Babio, N. (Nancy); Hernáez, Á. (Álvaro); Fernandez-Garcia, J.C. (José C.); Castañer, O. (Olga); Martinez, J.A. (José Alfredo); Fito, M. (Montserrat); Tojal-Sierra, L. (Lucas); Álvarez-Pérez, J. (Jacqueline); Konieczna, J. (Jadwiga); Daimiel, L. (Lidia); Tinahones, F.J. (Francisco J.); Vioque, J. (Jesús); Becerra-Tomas, N. (Nerea); Tur, J.A. (Josep A.); Martinez-Lacruz, R. (Raul); Galera-Cusí, A. (Ana); Romaguera, D. (Dora); Tresserra-Rimbau, A. (Anna); Lapetra, J. (José); Pastor-Polo, C. (Concepción); Matía-Martín, P. (Pilar); Rubín-García, M. (María); Delgado-Rodriguez, M. (Miguel); López-Miranda, J. (José); Galdon, A. (Alba); Galmes-Panades, A.M. (Aina M.); Castro-Barquero, S. (Sara); Ros, E. (Emilio); Ruiz-Canela, M. (Miguel); Notario-Barandiaran, L. (Leyre); Perez-Vega, K.A. (Karla Alejandra); Julibert, A. (Alicia); Vitelli-Storelli, F. (Facundo); Alonso-Gomez, A. (Ángel); Wärnberg, J. (Julia); García-Molina, L. (Laura); Estruch, R. (Ramón); Vazquez-Ruiz, Z. (Zenaida); Diaz-Lopez, A. (Andres); Santos-Lozano, J.M. (José M.); Lamuela-Raventos, R.M. (Rosa Maria); Pérez-Lopez, J. (Jessica); Gea, A. (Alfredo); Serra-Majem, L. (Luis); Corella, D. (Dolores); Basterra-Gortari, F.J. (Francisco Javier); Abete, I. (Itziar); Vidal, J. (Josep); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Sorli, J.V. (Jose V.); Moreno-Rodríguez, A. (Anai)
    Overweight and obesity are important risk factors for type 2 diabetes (T2D). Moving towards healthier diets, namely, diets rich in bioactive compounds, could decrease the odds of suffering T2D. However, those individuals with high body mass index (BMI) may have altered absorption or metabolism of some nutrients and dietary components, including polyphenols. Therefore, we aimed to assess whether high intakes of some classes of polyphenols are associated with T2D in a population with metabolic syndrome and how these associations depend on BMI and sex. This baseline cross-sectional analysis includes 6633 participants from the PREDIMED-Plus trial. Polyphenol intakes were calculated from food frequency questionnaires (FFQ). Cox regression models with constant time at risk and robust variance estimators were used to estimate the prevalence ratios (PRs) for polyphenol intake and T2D prevalence using the lowest quartile as the reference group. Analyses were stratified by sex and BMI groups (overweight and obese) to evaluate potential effect modification. Catechins, proanthocyanidins, hydroxybenzoic acids, and lignans were inversely associated with T2D. Hydroxycinnamic acids were directly related in men. These associations were different depending on sex and BMI, that is, women and overweight obtained stronger inverse associations
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    Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells
    (Springer, 2017-02-08) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Martinez-Gonzalez, M.A. (Miguel Ángel); Fito, M. (Montserrat); Milagro-Yoldi, F.I. (Fermín Ignacio); Arpon, A. (Ana); Razquin, C. (Cristina); Ros, E. (Emilio); Casas, R. (Rosa); Estruch, R. (Ramón); Corella, D. (Dolores); Salas-Salvado, J. (Jordi)
    Epigenetic processes, including DNA methylation, might be modulated by environmental factors such as the diet, which in turn have been associated with the onset of several diseases such as obesity or cardiovascular events. Meanwhile, Mediterranean diet (MedDiet) has demonstrated favourable effects on cardiovascular risk, blood pressure, inflammation and other complications related to excessive adiposity. Some of these effects could be mediated by epigenetic modifications. Therefore, the objective of this study was to investigate whether the adherence to MedDiet is associated with changes in the methylation status from peripheral blood cells. A subset of 36 individuals was selected within the Prevención con Dieta Mediterránea (PREDIMED)-Navarra study, a randomised, controlled, parallel trial with three groups of intervention in high cardiovascular risk volunteers, two with a MedDiet and one low-fat control group. Changes in methylation between baseline and 5 years were studied. DNA methylation arrays were analysed by several robust statistical tests and functional classifications. Eight genes related to inflammation and immunocompetence (EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2, PPARGC1B) were finally selected as changes in their methylation levels correlated with adherence to MedDiet and because they presented sensitivity related to a high variability in methylation changes. Additionally, EEF2 methylation levels positively correlated with concentrations of TNF-α and CRP. This report is apparently the first showing that adherence to MedDiet is associated with the methylation of the reported genes related to inflammation with a potential regulatory impact.