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Research Nut: Walnuts

Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

Koh, S.J., Y.I. Choi, Y. Kim, Y.S. Kim, S.W. Choi, J.W. Kim, B.G. Kim, K.L. Lee, 2018. Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice. Eur J Nutr. doi: 10.1007/s00394-018-1704-3.

PURPOSE: Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer. METHODS: COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10-/- mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. RESULTS: WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10-/- mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC). CONCLUSIONS: WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.

Considerations to facilitate a US study that replicates PREDIMED.

Jacobs, D.R. Jr., K.S. Petersen, K. Svendsen, E. Ros, C.B. Sloan, L.M. Steffen, L.C. Tapsell, P.M. Kris-Etherton, 2018. Considerations to facilitate a US study that replicates PREDIMED. Metabolism. pii: S0026-0495(18)30118-5. doi: 10.1016/j.metabol.2018.05.001. [Epub ahead of print]

The PREDIMED clinical trial provided strong evidence that a Mediterranean dietary pattern (MedDiet) could help prevent cardiovascular disease (CVD) events in high risk middle-aged/older people. This report considers the feasibility of replicating PREDIMED in the U.S., including recommendations for dietary and behavioral principles. A 14-point Mediterranean diet Adherence Score (MEDAS) guided the PREDIMED MedDiet recommendations. At baseline MEDAS points were ~8.5. During intervention this score increased to nearly 11 in MedDiet vs. 9 in control. In the MedDiet groups, only about 0.5 points of the net 2 point MEDAS increase was attributable to the gratis supplements of olive oil or nuts. An issue in a U.S. replication is the large difference in typical U.S. versus Spanish diet and lifestyle. A typical U.S. diet would achieve a MEDAS of 1-2. A replication is scientifically feasible with an assumption such as that the MedDiet reflects a continuum of specific food choices and meal patterns. As such, a 2 point change in MEDAS at any point on the continuum would be hypothesized to reduce incident CVD. A conservative approach would aim for a randomized 4 point MEDAS difference, e.g. 5-6 points vs. an average U.S. diet group that achieved only 1-2 points.

Walnut consumption alters the gastrointestinal microbiota, microbially derived secondary bile acids, and health markers in healthy adults: a randomized controlled trial.

Holscher, H.D., H.M. Guetterman, K.S. Swanson, R. An,N.R. Matthan, A.H. Lichtenstein, J.A. Novotny, D.J. Baer, 2018. Walnut consumption alters the gastrointestinal microbiota, microbially derived secondary bile acids, and health markers in healthy adults: a randomized controlled trial. J Nutr. doi: 10.1093/jn/nxy004. [Epub ahead of print]

Background: Epidemiologic data suggest that diets rich in nuts have beneficial health effects, including reducing total and cause-specific mortality from cancer and heart disease. Although there is accumulating preclinical evidence that walnuts beneficially affect the gastrointestinal microbiota and gut and metabolic health, these relations have not been investigated in humans. Objective: We aimed to assess the impact of walnut consumption on the human gastrointestinal microbiota and metabolic markers of health. Methods: A controlled-feeding, randomized crossover study was undertaken in healthy men and women [n = 18; mean age = 53.1 y; body mass index (kg/m2): 28.8]. Study participants received isocaloric diets containing 0 or 42 g walnuts/d for two 3-wk periods, with a 1-wk washout between diet periods. Fecal and blood samples were collected at baseline and at the end of each period to assess secondary outcomes of the study, including effects of walnut consumption on fecal microbiota and bile acids and metabolic markers of health. Results:
Compared with after the control period, walnut consumption resulted in a 49-160% higher relative abundance of Faecalibacterium, Clostridium, Dialister, and Roseburia and 16-38% lower relative abundances of Ruminococcus, Dorea, Oscillospira, and Bifidobacterium (P < 0.05). Fecal secondary bile acids, deoxycholic acid and lithocholic acid, were 25% and 45% lower, respectively, after the walnut treatment compared with the control treatment (P < 0.05). Serum LDL cholesterol and the non-cholesterol sterol campesterol concentrations were 7% and 6% lower, respectively, after walnut consumption compared with after the control treatment (P < 0.01). Conclusions: Walnut consumption affected the composition and function of the human gastrointestinal microbiota, increasing the relative abundances of Firmicutes species in butyrate-producing Clostridium clusters XIVa and IV, including Faecalibacterium and Roseburia, and reducing microbially derived, proinflammatory secondary bile acids and LDL cholesterol. These results suggest that the gastrointestinal microbiota may contribute to the underlying mechanisms of the beneficial health effects of walnut consumption.

Effects of walnut consumption on blood lipids and other cardiovascular risk factors: an updated meta-analysis and systematic review of controlled trials.

Guasch-Ferré, M., J. Li, F.B. Hu, J. Salas-Salvadó, D.K. Tobias, 2018. Effects of walnut consumption on blood lipids and other cardiovascular risk factors: an updated meta-analysis and systematic review of controlled trials. Am J Clin Nutr. doi: 10.1093/ajcn/nqy091. [Epub ahead of print]

BACKGROUND: Intervention studies suggest that incorporating walnuts into the diet may improve blood lipids without promoting weight gain. OBJECTIVE: We conducted a systematic review and meta-analysis of controlled trials evaluating the effects of walnut consumption on blood lipids and other cardiovascular risk factors. Design: We conducted a comprehensive search of PubMed and EMBASE databases (from database inception to January 2018) of clinical trials comparing walnut-enriched diets with control diets. We performed random-effects meta-analyses comparing walnut-enriched and control diets for changes in pre-post intervention in blood lipids (mmol/L), apolipoproteins (mg/dL), body weight (kg), and blood pressure (mm Hg). RESULTS: Twenty-six clinical trials with a total of 1059 participants were included. The following weighted mean differences (WMDs) in reductions were obtained for walnut-enriched diets compared with control groups: -6.99 mg/dL (95% CI: -9.39, -4.58 mg/dL; P < 0.001) (3.25% greater reduction) for total blood cholesterol (TC) and -5.51 mg/dL (95% CI: -7.72, -3.29 mg/dL; P < 0.001) (3.73% greater reduction) for low-density lipoprotein (LDL) cholesterol. Triglyceride concentrations were also reduced in walnut-enriched diets compared with control [WMD = -4.69 (95% CI: -8.93, -0.45); P = 0.03; 5.52% greater reduction]. More pronounced reductions in blood lipids were observed when walnut interventions were compared with American and Western diets [WMD for TC = -12.30 (95% CI: -23.17, -1.43) and for LDL = -8.28 (95% CI: -13.04, -3.51); P < 0.001]. Apolipoprotein B (mg/dL) was also reduced significantly more on walnut-enriched diets compared with control groups [WMD = -3.74 (95% CI: -6.51, -0.97); P = 0.008] and a trend towards a reduction was observed for apolipoprotein A [WMD = -2.91 (95% CI: -5.98, 0.08); P = 0.057]. Walnut-enriched diets did not lead to significant differences in weight change (kg) compared with control diets [WMD = -0.12 (95% CI: -2.12, 1.88); P = 0.90], systolic blood pressure (mm Hg) [WMD = -0.72 (95% CI: -2.75, 1.30); P = 0.48], or diastolic blood pressure (mm Hg) [WMD = -0.10 (95% CI: -1.49, 1.30); P = 0.88]. Conclusions: Incorporating walnuts into the diet improved blood lipid profile without adversely affecting body weight or blood pressure.

Identifying usual food choices at meals in overweight and obese study volunteers: implications for dietary advice.

Guan, V.X., Y.C. Probst, E.P. Neale, M.J. Batterham, L.C. Tapsell, 2018. Identifying usual food choices at meals in overweight and obese study volunteers: implications for dietary advice. Br J Nutr. 120(4):472-480. doi: 10.1017/S0007114518001587.

Understanding food choices made for meals in overweight and obese individuals may aid strategies for weight loss tailored to their eating habits. However, limited studies have explored food choices at meal occasions. The aim of this study was to identify the usual food choices for meals of overweight and obese volunteers for a weight-loss trial. A cross-sectional analysis was performed using screening diet history data from a 12-month weight-loss trial (the HealthTrack study). A descriptive data mining tool, the Apriori algorithm of association rules, was applied to identify food choices at meal occasions using a nested hierarchical food group classification system. Overall, 432 breakfasts, 428 lunches, 432 dinners and 433 others (meals) were identified from the intake data (n 433 participants). A total of 142 items of closely related food clusters were identified at three food group levels. At the first sub-food group level, bread emerged as central to food combinations at lunch, but unprocessed meat appeared for this at dinner. The dinner meal was characterised by more varieties of vegetables and of foods in general. The definitions of food groups played a pivotal role in identifying food choice patterns at main meals. Given the large number of foods available, having an understanding of eating patterns in which key foods drive overall meal content can help translate and develop novel dietary strategies for weight loss at the individual level.

Dietary walnuts protect against obesity-driven intestinal stem cell decline and tumorigenesis.

Guan, F., T. Tabrizian, A. Novaj, M. Nakanishi, D.W. Rosenberg, D. Huffman, 2018. Dietary walnuts protect against obesity-driven intestinal stem cell decline and tumorigenesis. Front. Nutr. doi.org/10.3389/fnut.2018.00037

Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and related mortality. Thus, given the alarmingly high rates of obesity in the US and globally, it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts have been increasingly recognized to mitigate cancer risk, and contain many bioactive constituents with antioxidant and anti-inflammatory properties that could potentially counteract pathways thought to be initiators of obesity-related cancer. Therefore, the purpose of this study was to determine if walnuts could preserve intestinal homeostasis, and attenuate tumorigenesis and growth in the context of obesity and a high calorie diet. To this end, we studied effects of walnuts on these parameters under different dietary conditions in wildtype mice, two independent Apc models (Apc1638N/+ and ApcΔ14), and in MC38 colon cancer cells in vivo, respectively. Walnuts did not alter the metabolic phenotype or intestinal morphology in normal mice fed either a low-fat diet (LFD), LFD with 6% walnuts (LFD+W), high-fat diet (HFD), or HFD with 7.6% walnuts (HFD+W). However, walnuts did lead to a significant reduction in circulating CCL5 and preserved intestinal stem cell (ISC) function under HFD-fed conditions. Furthermore, walnuts reduced tumor multiplicity in Apc1638N/+ male HFD+W animals, as compared to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; P = 0.015), tended to reduce the number of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; P = 0.07), and preferentially limited tumor growth in ApcΔ14 male mice (P = 0.019) fed a high-calorie western-style diet. In summary, these data demonstrate that walnuts confer significant protection against intestinal tumorigenesis and growth and preserve ISC function in the context of a high-calorie diet and obesity. Thus, these data add to the accumulating evidence connecting walnuts as a potentially effective dietary strategy to break the obesity-colon cancer link.

Effect of distinct lifestyle interventions on mobilization of fat storage pools: The CENTRAL MRI randomized controlled trial.

Gepner, Y., I. Shelef, D. Schwarzfuchs, H. Zelicha, L. Tene, A. Yaskolka Meir, G. Tsaban, N. Cohen, N. Bril, M. Rein, D. Serfaty, S. Kenigsbuch, O. Komy, A. Wolak, Y. Chassidim, R. Golan, H. Avni-Hassid, A. Bilitzky, B. Sarusi, E. Goshen, E. Shemesh, Y. Henkin, M. Stumvoll, M. Blüher, J. Thiery, U. Ceglarek, A. Rudich, M.J. Stampfer, I. Shai, 2018. Effect of distinct lifestyle interventions on mobilization of fat storage pools: The CENTRAL MRI randomized controlled trial. Circulation. 137(11):1143-1157. doi: 10.1161/CirculationAHA.117.030501.

Background: We aimed to assess whether distinct lifestyle strategies can differentially affect specific body adipose depots. Methods: We performed an eighteen-month randomized controlled trial among 278 sedentary adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored provided lunch. Participants were randomized to iso-caloric low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC) diet+28g walnuts/day with/without added moderate physical activity (PA;80% aerobic; supervised/free gym membership). Overall primary outcome was body fat re-distribution, and the main specific endpoint was visceral adipose tissue (VAT). We further followed the dynamics of different fat depots [deep/superficial subcutaneous (D/SSAT), liver, pericardial, muscle, pancreas and renal-sinus] by magnetic-resonance-imaging. Results: Of 278 participants (age=48y; 89%men, body-mass-index=30.8kg/m2), 86% completed the trial, with good adherence. The LF group preferentially decreased reported fat intake (-21.0% vs. -11.5% for the MED/LC; P<0.001), and the MED/LC group decreased reported carbohydrates intake (-39.5%vs. -21.3% for the LF;P<0.001). The PA+ groups significantly increased the metabolic-equivalents (METs)/week vs. the PA- groups (19.0 vs. 2.1;P=0.009). Whereas final moderate weight loss was indifferent, exercise attenuated the waist circumference rebound with the greatest effect in MED/LCPA+ group (P<0.05). VAT (-22%), intra-hepatic (-29%), and Intra-pericardial (-11%) fats declines were higher than pancreatic and femur intermuscular fats (1-2%) loss. Independent of weight loss, PA+ with either diet had a significantly greater effect on decreasing VAT [mean-of-difference=-6.67cm2;95%CI:(-14.8 to -0.45) compared with PA-]. The MED/LC diet was superior to LF in decreasing intra-hepatic, intra-pericardial and pancreatic fats (P<0.05 for all). In contrast, renal-sinus and femoral-intermuscular fats were not differentially altered by lifestyle interventions, but by weight loss per-se. In multivariate models, further adjusted for weight loss, losing VAT or intra-hepatic fat were independently associated with improved lipid profile, losing deep-SAT with improved insulin sensitivity and losing superficial-SAT remained neutral except of association with decreased leptin. Conclusions: Moderate weight loss alone inadequately reflects the significant lifestyle effects on atherogenic and diabetogenic fat depots. The MED/LC diet mobilizes specific ectopic fat depots, and exercise has an independent contribution to VAT loss. Fat depots exhibit diverse responsiveness and are differentially related to cardiometabolic markers. Distinct lifestyle protocols may uniquely induce fat mobilization from specific anatomical sites.

The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial.

Freitas-Simoes, T.M., M. Cofán, M.A. Blasco, N. Soberón, M. Foronda, D. Corella, E.M. Asensio, M. Serra-Mir, I. Roth, C. Calvo, C. Valls-Pedret, R.P. Casaroli-Marano, M. Doménech, S. Rajaram, J. Sabaté, E. Ros, A. Sala-Vila, 2018. The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial. Clin Nutr. pii: S0261-5614(18)30074-8. doi: 10.1016/j.clnu.2018.02.011. [Epub ahead of print]

BACKGROUND & AIMS: Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes. DESIGN: Cross-sectional study in 344 subjects (mean age 68.8 y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases (https://clinicaltrials.gov/ct2/show/NCT01634841). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography. RESULTS: In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval], -0.10 (-0.19 to -0.01), P = 0.023). CONCLUSION: An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process.

Walnut consumption for two years and leukocyte telomere attrition in Mediterranean elders: results of a randomized controlled trial.

Freitas-Simoes, T.M., M. Cofán, M.A. Blasco, N. Soberón, M. Foronda, M. Serra-Mir, I. Roth, C. Valls-Pedret, M. Doménech, E. Ponferrada-Ariza, C. Calvo, S. Rajaram, J. Sabaté, E. Ros, A. Sala-Vila, 2018. Walnut consumption for two years and leukocyte telomere attrition in Mediterranean elders: results of a randomized controlled trial. Nutrients. 10(12). pii: E1907. doi: 10.3390/nu10121907.

Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63–79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years; corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time × intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power.

Walnut consumption increases activation of the insula to highly desirable food cues: A randomized, double-blind, placebo-controlled, cross-over fMRI study.

Farr, O.M., D. Tuccinardi, J. Upadhyay, S.M. Oussaada, C.S. Mantzoros, 2018. Walnut consumption increases activation of the insula to highly desirable food cues: A randomized, double-blind, placebo-controlled, cross-over fMRI study. Diabetes Obes Metab. 20(1):173-177. doi: 10.1111/dom.13060.

AIMS: The use of walnuts is recommended for obesity and type 2 diabetes, although the mechanisms through which walnuts may improve appetite and/or glycemic control remain largely unknown. MATERIALS AND METHODS: To determine whether short-term walnut consumption could alter the neural control of appetite using functional magnetic resonance imaging, we performed a randomized, placebo-controlled, double-blind, cross-over trial of 10 patients who received, while living in the controlled environment of a clinical research center, either walnuts or placebo (using a validated smoothie delivery system) for 5 days each, separated by a wash-out period of one month. RESULTS: Walnut consumption decreased feelings of hunger and appetite assessed using visual analog scales and increased the activation of the right insula to highly desirable food cues. CONCLUSIONS: These findings suggest that walnut consumption may increase salience and cognitive control processing of highly desirable food cues, leading to the beneficial metabolic effects observed.