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Walnut Consumption, Plasma Metabolomics, and Risk of Type 2 Diabetes and Cardiovascular Disease.

Guasch-Ferré, M., P. Hernández-Alonso, J.P. Drouin-Chartier, M. Ruiz-Canela, C. Razquin, E. Toledo, J. Li, C. Dennis, C. Wittenbecher, D. Corella, R. Estruch, M. Fitó, E. Ros, N. Babio, S.N. Bhupathiraju, C.B. Clish, L. Liang, M.A. Martínez-González, F.B. Hu, J. Salas-Salvadó, 2020. Walnut consumption, plasma metabolomics, and risk of type 2 diabetes and cardiovascular disease. J Nutr. 00:1–9.

Background: Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also associated with lower risk of cardiometabolic diseases. Objectives: The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD. Methods: The discovery population included 1833 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m2): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training–validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models. Results: A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P < 0.001). Conclusions: A metabolite profile including 19 metabolites was associated with walnut consumption and with a lower risk of incident T2D and CVD in a Mediterranean population at high cardiovascular risk.

Effects of 2-Year walnut-supplemented diet on inflammatory biomarkers.

Cofán, M., S. Rajaram, A. Sala-Vila, C. Valls-Pedret, M. Serra-Mir, I. Roth, T.M. Freitas-Simoes, E. Bitok, J. Sabaté, E. Ros, 2020.  Effects of 2-Year walnut-supplemented diet on inflammatory biomarkers. J Am Coll Cardiol. 76(19):2282–2284

Robust epidemiological evidence suggests that regular nut consumption is associated with lower cardiovascular disease (CVD) risk. As summarized in a recent meta-analysis of 19 prospective studies (1),when  comparing extreme quantiles of total nut consumption (2.5 to 28 g/day), total CVD and CVD mortality were  15% and 23% lower, respectively. Walnut consumption independent from other nutsrevealed similar inverse associations with CVD in 3 studies

Walnuts and vegetable oils containing oleic acid differentially affect the gut microbiota and associations with cardiovascular risk factors: Follow-up of a randomized, controlled, feeding trial in adults at risk for cardiovascular disease.

Tindall, A.M., C.J. McLimans, K.S. Petersen, P.M. Kris-Etherton, R. Lamendella, 2020. Walnuts and vegetable oils containing oleic acid differentially affect the gut microbiota and associations with cardiovascular risk factors: Follow-up of a randomized, controlled, feeding trial in adults at risk for cardiovascular disease. J Nutr. 150:806–817.

Background: It is unclear whether the favorable effects of walnuts on the gut microbiota are attributable to the fatty acids, including α-linolenic acid (ALA), and/or the bioactive compounds and fiber. Objective: This study examined between-diet gut bacterial differences in individuals at increased cardiovascular risk following diets that replace SFAs with walnuts or vegetable oils. Methods: Forty-two adults at cardiovascular risk were included in a randomized, crossover, controlled-feeding trial that provided a 2-wk standard Western diet (SWD) run-in and three 6-wk isocaloric study diets: a diet containing whole walnuts (WD; 57–99 g/d walnuts; 2.7% ALA), a fatty acid–matched diet devoid of walnuts (walnut fatty acid–matched diet; WFMD; 2.6% ALA), and a diet replacing ALA with oleic acid without walnuts (oleic acid replaces ALA diet; ORAD; 0.4% ALA). Fecal samples were collected following the run-in and study diets to assess gut microbiota with 16S rRNA sequencing and Qiime2 for amplicon sequence variant picking. Results: Subjects had elevated BMI (30 ± 1 kg/m2), blood pressure (121 ± 2/77 ± 1 mmHg), and LDL cholesterol (120 ± 5 mg/dL). Following the WD, Roseburia [relative abundance (RA) = 4.2%, linear discriminant analysis (LDA) = 4], Eubacterium eligensgroup (RA = 1.4%, LDA = 4), LachnospiraceaeUCG001 (RA = 1.2%, LDA = 3.2), Lachnospiraceae UCG004 (RA = 1.0%, LDA = 3), and Leuconostocaceae (RA = 0.03%, LDA = 2.8) were most abundant relative to taxa in the SWD (P ≤ 0.05 for all). The WD was also enriched in Gordonibacter relative to the WFMD. Roseburia (3.6%, LDA = 4) and Eubacterium eligensgroup (RA = 1.5%, LDA = 3.4) were abundant following the WFMD, and Clostridialesvadin BB60group (RA = 0.3%, LDA = 2) and gutmetagenome (RA = 0.2%, LDA = 2) were most abundant following the ORAD relative to the SWD (P ≤ 0.05 for all). Lachnospiraceae were inversely correlated with blood pressure and lipid/lipoprotein measurements following the WD. Conclusions: The results indicate similar enrichment of Roseburia following the WD and WFMD, which could be explained by the fatty acid composition. Gordonibacter enrichment and the inverse association between Lachnospiraceae and cardiovascular risk factors following the WD suggest that the gut microbiota may contribute to the health benefits of walnut consumption in adults at cardiovascular risk. This trial was registered at clinicaltrials.gov as NCT02210767.

Health benefits of pistachios consumption.

Terzo, S., S. Baldassano, G.F. Caldara, V. Ferrantelli, G. Lo Dico, F. Mulè, A. Amato, 2019. Health benefits of pistachios consumption. Nat Prod Res. 33(5):715-726.

The health benefits of nuts, mainly in relation to the improvement of dysmetabolic conditions such as obesity, type 2 diabetes mellitus and the related cardiovascular diseases, have been widely demonstrated. Compared to other nuts, pistachios have a lower fat and caloric content, and contain the highest levels of unsaturated fatty acids, potassium, γ-tocopherol, phytosterols and xanthophyll carotenoids, all substances that are well known for their antioxidant and anti-inflammatory actions. This variety of nutrients contributes to the growing body of evidence that the consumption of pistachios improves health, leading to a greater potential of healthy antioxidant and anti-inflammatory activity, glycemic control, and endothelial function. The present review examines the nutrients and phytochemicals present in pistachios as well as the potential health benefits of including pistachios in a diet.

Identification of plasma lipid metabolites associated with nut consumption in US men and women.

Malik, V.S., M. Guasch-Ferre, F.B. Hu, M.K. Townsend, O.A. Zeleznik, A.H. Eliassen, S.S. Tworoger, E.W. Karlson, K.H. Costenbader, A. Ascherio, K.M. Wilson, L.A. Mucci, E.L. Giovannucci, C.S. Fuchs, Y. Bao, 2019. Identification of plasma lipid metabolites associated with nut consumption in US men and women. J Nutr 149:1215–1221.

BACKGROUND: Intake of nuts has been inversely associated with risk of type 2 diabetes and cardiovascular disease, partly through inducing a healthy lipid profile. How nut intake may affect lipid metabolites remains unclear. OBJECTIVE: The aim of this study was to identify the plasma lipid metabolites associated with habitual nut consumption in US men and women. METHODS: We analyzed cross-sectional data from 1099 participants in the Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study. Metabolic profiling was conducted on plasma by LC-mass spectrometry. Nut intake was estimated from food-frequency questionnaires. We included 144 known lipid metabolites that had CVs ≤25%. Multivariate linear regression was used to assess the associations of nut consumption with individual plasma lipid metabolites. RESULTS: We identified 17 lipid metabolites that were significantly associated with nut intake, based on a 1 serving (28 g)/d increment in multivariate models [false discovery rate (FDR) P value <0.05]. Among these species, 8 were positively associated with nut intake [C24:0 sphingomyelin (SM), C36:3 phosphatidylcholine (PC) plasmalogen-A, C36:2 PC plasmalogen, C24:0 ceramide, C36:1 PC plasmalogen, C22:0 SM, C34:1 PC plasmalogen, and C36:2 phosphatidylethanolamine plasmalogen], with changes in relative metabolite level (expressed in number of SDs on the log scale) ranging from 0.36 to 0.46 for 1 serving/d of nuts. The other 9 metabolites were inversely associated with nut intake with changes in relative metabolite level ranging from -0.34 to -0.44. In stratified analysis, 3 metabolites were positively associated with both peanuts and peanut butter (C24:0 SM, C24:0 ceramide, and C22:0 SM), whereas 6 metabolites were inversely associated with other nuts (FDR P value <0.05). CONCLUSIONS: A panel of lipid metabolites was associated with intake of nuts, which may provide insight into biological mechanisms underlying associations between nuts and cardiometabolic health. Metabolites that were positively associated with intake of nuts may be helpful in identifying potential biomarkers of nut intake.

Effect of pistachio on brachial artery diameter and flow-mediated dilatation: A systematic review and meta-analysis of randomized, controlled-feeding clinical studies.

Fogacci, F., A.F.G. Cicero, G. Derosa, M. Rizzo, M. Veronesi, C. Borghi, 2019. Effect of pistachio on brachial artery diameter and flow-mediated dilatation: A systematic review and meta-analysis of randomized, controlled-feeding clinical studies. Crit Rev Food Sci Nutr. 59(2):328-335.

BACKGROUND: Results of previous clinical trials evaluating the effect of pistachio supplementation on endothelial reactivity (ER) are controversial. AIMS: We aimed to assess the impact of pistachio on ER through systematic review of literature and meta-analysis of available randomized, controlled-feeding clinical studies (RCTs). METHODS: The literature search included SCOPUS, PubMed-Medline, ISI Web of Science and Google Scholar databases up to 1st August 2017 to identify RCTs investigating the impact of pistachio on ER. Two independent reviewers extracted data on study characteristics, methods and outcomes. Overall, the impact of pistachio on ER was reported in 4 trials. RESULTS: The meta-analysis did not suggest a significant change in brachial artery flow-mediated dilatation (FMD) (WMD: +0.28%; 95% CI: -0.58, 1.13; p = 0.525) while brachial artery diameter (BAD) improved (WMD: +0.04%; 95% CI: 0.03, 0.06; p<0.001) following pistachios consumption. CONCLUSION: The present meta-analysis suggests a significant effect of pistachios on ER, affecting BAD but not FMD.

Health benefits of nut consumption in middle‐aged and elderly population.

Rusu, M.E., A. Mocan, I.C.F.R. Ferreira, D.-S. Popa, 2019. Health benefits of nut consumption in middle‐aged and elderly population. Antioxidants. 8, 302; doi:10.3390/antiox8080302.

Aging is considered the major risk factor for most chronic disorders. Oxidative stress and chronic inflammation are two major contributors for cellular senescence, downregulation of stress response pathways with a decrease of protective cellular activity and accumulation of cellular damage, leading in time to age‐related diseases. This review investigated the most recent clinical trials and cohort studies published in the last ten years, which presented the influence of tree nut and peanut antioxidant diets in preventing or delaying age‐related diseases in middle‐aged and elderly subjects (≥55 years old). Tree nut and peanut ingestion has the possibility to influence blood lipid count, biochemical and anthropometric parameters, endothelial function and inflammatory biomarkers, thereby positively affecting cardiometabolic morbidity and mortality, cancers, and cognitive disorders, mainly through the nuts’ healthy lipid profile and antioxidant and anti-inflammatory mechanisms of actions. Clinical evidence and scientific findings demonstrate the importance of diets characterized by a high intake of nuts and emphasize their potential in preventing age‐related diseases, validating the addition of tree nuts and peanuts in the diet of older adults. Therefore, increased consumption of bioactive antioxidant compounds from nuts clearly impacts many risk factors related to aging and can extend health span and lifespan.

Does nut consumption reduce mortality and/or risk of cardiometabolic disease? An updated review based on meta-analyses.

Kim, Y., J.B. Keogh, P.M. Clifton, 2019. Does nut consumption reduce mortality and/or risk of cardiometabolic disease? An updated review based on meta-analyses. Int. J. Environ. Res. Public Health. 16, 4957; doi:10.3390/ijerph16244957.

Aim. We aimed to determine if nut consumption decreases mortality and/or the risk of cardiometabolic diseases based on updated meta-analyses of epidemiological and intervention studies. Methods. An updated electronic search was conducted in PubMed/MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Library databases for original meta-analyses to investigate the effects of nut consumption on cardiometabolic disease in humans. Results. Seven new meta-analyses were included in this updated review. Findings similar to our previous review were observed, showing that nut consumption significantly decreased cardiovascular disease (CVD) mortality (-19% to -25%; n = 4), coronary heart disease (CHD) mortality (-24% to -30%; n = 3), stroke mortality (-17% to -18%; n = 3), CVD incidence (-15% to -19 %; n = 4), CHD [or coronary artery disease (CAD)] incidence (-17% to -34%; n = 8), and stroke incidence (-10% to -11%; n = 6) comparing high with low categories of nut consumption. Fasting glucose levels (0.08 to 0.15 mmol/L; n = 6), total cholesterol (TC; 0.021 to 0.30 mmol/L; n = 10), and low-density lipoprotein cholesterol (LDL-C; 0.017 to 0.26 mmol/L; n = 10) were significantly decreased with nut consumption compared with control diets. Body weight and blood pressure were not significantly affected by nut consumption. Conclusion. Nut consumption appears to exert a protective effect on cardiometabolic disease, possibly through improved concentrations of fasting glucose, total cholesterol, and LDL-C.

Effects of consuming almonds on insulin sensitivity and other cardiometabolic health markers in adults with prediabetes.

Palacios, O.M., K.C. Maki, D. Xiao, M.L. Wilcox, M.R. Dicklin, M. Kramer, R. Trivedi, B. Burton-Freeman, I. Edirisinghe, 2019. Effects of consuming almonds on insulin sensitivity and other cardiometabolic health markers in adults with prediabetes. Journal of the American College of Nutrition. doi:10.1080/07315724.2019.1660929.

Objective: This study was designed to assess the effects of replacing high-carbohydrate (CHO) foods with raw almonds on insulin sensitivity and cardiometabolic health markers in overweight or obese adults with prediabetes. Method: This randomized crossover study consisted of two 6-week dietary intervention periods, separated by a ≥ 4-week washout. Subjects incorporated 1.5oz of raw almonds twice daily or isocaloric CHO-based foods into their diets, with instructions to maintain body weight. Dietary intakes as well as insulin sensitivity, CHO metabolism indices, lipoprotein lipids and particles, and inflammatory markers were assessed. Results: Thirty-three subjects (17 male, 16 female), mean age 48.3±2.2years and body mass index 30.5±0.7kg/m2, provided evaluable data. Compared to CHO, almonds resulted in significantly (p<0.01) higher intakes of protein, fat (unsaturated fatty acids), fiber, and magnesium and significantly (p<0.001) lower intakes of CHO and sugars. No differences were observed between diet conditions for changes from baseline in the insulin sensitivity index from a short intravenous glucose tolerance test or other indices of glucose homeostasis. No significant differences were observed in biomarkers of cardiovascular risk except that the CHO intervention led to a shift toward a higher concentration of cholesterol in small, dense low-density lipoprotein subfraction 3+4 (LDL3+4) particles (p = 0.024 vs almonds). Conclusions: Intake of 3.0 oz/d raw almonds, vs energy-matched CHO foods, improved the dietary nutrient profile, but did not significantly affect insulin sensitivity and most markers of cardiometabolic health in overweight and obese men and women with prediabetes.

Mechanisms underlying the cardiometabolic protective effect of walnut consumption in obese subjects: a cross‐over, randomized, double‐blinded, controlled inpatient physiology study.

Tuccinardi, D., O.M. Farr, J. Upadhyay, S.M. Oussaada, M.I. Klapa, M. Candela, S. Rampelli, S. Lehoux, I. Lázaro, A. Sala‐Vila, P. Brigidi, R.D. Cummings, C.S. Mantzoros, 2019. Mechanisms underlying the cardiometabolic protective effect of walnut consumption in obese subjects: a cross‐over, randomized, double‐blinded, controlled inpatient physiology study. Diabetes Obes Metab. 21(9):2086-2095.

Aims: To assess the effects of walnuts on cardiometabolic outcomes in obese subjects and to explore underlying mechanisms using novel methods including metabolomic, lipidomic, glycomic, and microbiome analysis integrated with lipid particle fractionation, appetite-regulating hormones and hemodynamic measurements. Materials and Methods: 10 obese subjects were enrolled in this cross-over, randomized, double-blind, placebo-controlled clinical trial. Patients participated in two 5-day inpatient stays during which they consumed a smoothie containing 48g walnuts or a macronutrient-matched placebo smoothie without nuts, with a one-month washout period between the two visits. Results: Walnut consumption improved aspects of the lipid profile, i.e. reduced fasting small and dense LDL particles (p<.02) and increased postprandial large HDL particles (p<.01). Lipoprotein Insulin Resistance Score, glucose and insulin AUC decreased significantly after walnut consumption (p<.01, p<.02, p<.04, respectively). Consuming walnuts significantly increased 10 N-glycans, with 8 of them carrying a fucose core. Lipidomic analysis showed a robust reduction in harmful ceramides, hexosylceramides and sphingomyelins, which have been shown to mediate effects on cardiometabolic risk. Peptide YY AUC significantly increased after walnut consumption (p<.03). No major significant changes in hemodynamic, metabolomic analysis or in host health-promoting bacteria such as Faecalibacterium were found. Conclusions: These data provide a more comprehensive mechanistic perspective of the effect of dietary walnut consumption on cardiometabolic parameters. Lipidomic and lipid nuclear magnetic resonance spectroscopy analysis showed an early but significant reduction in ceramides and other atherogenic lipids with walnut consumption that may explain the longer-term benefits of walnuts on insulin resistance, cardiovascular risk and mortality.