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Research Nut: Walnuts

Diet-induced fasting ghrelin elevation reflects the recovery of insulin sensitivity and visceral adiposity regression.

Tsaban, G., A. Yaskolka Meir, H. Zelicha, E. Rinott, A. Kaplan, A. Shalev, A. Katz, D. Brikner, M. Blüher, U. Ceglarek, M. Stumvoll, M.J. Stampfer, I. Shai, 2022. Diet-induced fasting ghrelin elevation reflects the recovery of insulin sensitivity and visceral adiposity regression. JCEM. 107(2):336–345. https://doi.org/10.1210/clinem/dgab681

Aims: Lower fasting-ghrelin-levels (FGL) are associated with obesity and metabolic syndrome. We aimed to explore the dynamics of FGL during weight-loss and its metabolic and adiposity-related manifestations beyond weight-loss. Methods: A secondary analysis of a clinical trial where we randomized participants with abdominal-obesity/dyslipidemia to one of three diets: healthy-dietary-guidelines (HDG), Mediterranean diet (MED), or green-MED diet, all combined with physical activity (PA). Both MED diets were similarly hypocaloric and included 28g/day walnuts. The green-MED group further consumed green tea (3-4 cups/day) and a Wolffia-globosa (Mankai) plant green-shake. We measured FGL and quantified body fat depots by Magnetic-Resonance-Imaging at baseline and after 18-months. Results: Among 294 participants [body-mass-index=31.3kg/m 2;FGL=504±208pg/mL; retention rate=89.8%], lower FGL were associated with unfavorable cardiometabolic parameters as higher visceral-adipose-tissue (VAT), intra-hepatic fat, leptin, and blood pressure (p<0.05 for all; multivariate models). ΔFGL18-month differed between men (+7.3+26.6%) and women (-9.2+21.3%,p=0.001). After 18-months of moderate and similar weight loss among the MED-groups, FGL increased by 1.3%, 5.4%, and 10.5% in HDG, MED, and green-MED groups, respectively (p=0.03 for green-MED vs. HDG), sex-stratified analysis revealed similar changes in men only. Among men, FGL18-month elevation was associated with favorable changes in insulin resistance profile and VAT regression, after adjusting for relative weight-loss (HbA1c:r=-0.216; homeostatic-model-of insulin-resistance:r=-0.154; HDL-c:r=0.147;VAT:r=-0.221;p<0.05 for all). , Insulin resistance and VAT remained inversely related with FGL elevation, beyond which was explained by weight-loss (residual regression analyses;p<0.05). Conclusions: Diet-induced FGL elevation may reflect insulin sensitivity recovery and VAT regression beyond weight-loss, specifically among men. Green-MED diet is associated with greater FGL elevation.

Nut consumption in association with overall mortality and recurrence/disease-specific mortality among long-term breast cancer survivors.

Cong, W., K. Gu, F. Wang, H. Cai, W. Zheng, P. Bao, X.-O. Shu, 2022. Nut consumption in association with overall mortality and recurrence/disease-specific mortality among long-term breast cancer survivors. International Journal of Cancer.doi.org/10.1002/ijc.33824.

High nut consumption is associated with reduced total and certain cause-specific mortality in general populations. However, its association with cancer outcomes among long-term breast cancer survivors remains unknown. We examined the associations of nut consumption (including peanuts and tree nuts), assessed at 5-year postdiagnosis, with overall survival (OS) and disease-free survival (DFS) among 3449 long-term breast cancer survivors from the Shanghai Breast Cancer Survival Study, applying Cox regression analysis. During a median follow-up of 8.27 years post dietary assessment, there were 374 deaths, including 252 breast cancer deaths. Among 3274 survivors without previous recurrence at the dietary assessment, 209 developed breast cancer-specific events, that is, recurrence, metastasis or breast cancer mortality. At 5-year post dietary assessment (ie, 10-year postdiagnosis), regular nut consumers had higher OS (93.7% vs 89.0%) and DFS (94.1% vs 86.2%) rates. After multivariable adjustment, nut consumption was positively associated with OS (Ptrend = .022) and DFS (Ptrend = .003) following a dose-response pattern, with hazard ratios (95% confidence interval) of 0.72 (0.52-1.05) for OS and 0.48 (0.31-0.73) for DFS, for participants with greater than median nut intake compared with nonconsumers. The associations did not vary by nut type. Stratified analyses showed that the associations were more evident among participants with a higher total energy intake for OS (Pinteraction = .02) and among participants with early stage (I-II) breast cancers for DFS (Pinteraction = .04). The nut-DFS associations were not modified by estrogen receptor/progesterone receptor status or other known prognostic factors. In conclusion, nut consumption was associated with better survival, particularly DFS, among long-term breast cancer survivors.

The effects of peanuts and tree nuts on lipid profile in type 2 diabetic patients: A systematic review and meta-analysis of randomized, controlled-feeding clinical studies.

Xia, J.Y., J.H. Yu, D.F. Xu, C. Yang, H. Xia, G.J. Sun, 2021. The effects of peanuts and tree nuts on lipid profile in Type 2 diabetic patients: A systematic review and meta-analysis of randomized, controlled-feeding clinical studies. Front. Nutr. https://doi.org/10.3389/fnut.2021.765571

Background: Type 2 diabetes mellitus was found to be associated with metabolic disorders, particularly abnormal glucose and lipid metabolism. Dietary food choices may have profound effects on blood lipids. The primary objective of this study was to examine the effects of peanuts and tree nuts intake on lipid profile in patients with type 2 diabetes. Methods: According to preferred reporting items for systematic reviews and meta-analysis guidelines, we performed a systematic search of randomized controlled clinical trials and systematic reviews published in PubMed, Web of Science, Embase, Scopus, and Cochrane library, from inception through June 2021. Studies in populations with type 2 diabetes, which compare nuts or peanuts to a controlled-diet group were included. We used the mean difference with 95% CIs to present estimates for continuous outcomes from individual studies. In addition, we used the GRADEpro tool to evaluate the overall quality of evidence. Results: Sixteen studies involving 1,041 participants were eligible for this review. The results showed that peanuts and tree nuts supplementation did not induce significant changes in low-density lipoprotein-cholesterol (LDL-C) (mean difference = −0.11; 95%CI: −0.25 – 0.03, p = 0.117) and high-density lipoprotein-cholesterol (HDL-C) (mean difference = 0.01; 95%CI: −0.01 – 0.04, p = 0.400) in patients with type 2 diabetics. In addition, we found that peanuts and tree nuts intake may cause a significantly reduction in total cholesterol (TC) (mean difference = −0.14; 95%CI: −0.26 – −0.02, p = 0.024) and triglyceride (TG) (mean difference = −0.10; 95%CI: −0.17 – −0.02, p = 0.010). In the subgroup analysis, a significantly greater reduction in TC was observed in studies which duration was <12 weeks (mean difference = −0.22; 95%CI: −0.37 – −0.08, p = 0.002). The quality of the body of evidence was “moderate” for TC and TG, the quality of evidence for LDL-C and HDL-C were “low.” Conclusion: Our findings suggest that consuming peanuts and tree nuts might be beneficial to lower TC concentration and TG concentration in type 2 diabetics subjects. Furthermore, peanuts and tree nuts supplementation could be considered as a part of a healthy lifestyle in the management of blood lipids in patients with type 2 diabetes. Given some limits observed in the current studies, more well-designed trials are still needed.

Quantitative determination of selected urolithin metabolites in human urine by simple sample preparation and UPLC-MS/MS analysis.

Provatas, A.A., S.A. Ayers, A.A. Callas, J.W. Birk, T.A. Lacson, D.W. Rosenberg, 2021. Quantitative determination of selected urolithin metabolites in human urine by simple sample preparation and UPLC-MS/MS analysis. Curr Top Anal Chem.  Vol 13, pg 69-80.

We report a simple, reliable, and validated method for the rapid screening and quantification of nine urolithin (UL) metabolites in human urine. Ultraperformance liquid chromatograph coupled with a tandem mass spectrometer (UPLC-MS/MS) was utilized for UL analysis following a simple sample preparation. Optimization of chromatographic and mass spectrometric conditions was performed to maximize the sensitivity and selectivity of the targeted analytes. A validation of the methodology was conducted to account for matrix interferences, linearity, method detection limits (MDLs), UL chemical stability, precision and accuracy of the ULs of interest. MDLs were achieved for the selected ULs ranging from 9.2-18.2 ng·mL-1. Excellent linear coefficients of determination were obtained for the range of calibration standards of 5.0-5,000 ng·mL-1, with R2 values between 0.9991 and 0.9998. The surrogate compound, 6,7-dihydroxycoumarin, was used to monitor the extraction efficiency and chrysin as the quantitative internal standard. The recoveries of the analytes were 88-99% with surrogate recoveries greater than 82%. This analytical method was developed and validated for processing samples associated with a human study, where it is hypothesized that walnut supplementation improves colonic health and lowers colorectal cancer risk, in part through enhancing UL formation.

The metabolomic-gut-clinical axis of Mankai plant-derived dietary polyphenols.

Yaskolka, M.A., K. Tuohy K, M. von Bergen, R. Krajmalnik-Brown, U. Heinig, H. Zelicha, G. Tsaban, E. Rinott, A. Kaplan, A. Aharoni, L. Zeibich, D. Chang, B. Dirks, C. Diotallevi, P. Arapitsas, U. Vrhovsek, U. Ceglarek, S.-B. Haange, U. Rolle-Kampczyk, B. Engelmann, M. Lapidot, M. Colt, Q. Sun, I., 2021. The metabolomic-gut-clinical axis of Mankai plant-derived dietary polyphenols. Nutrients. 13(6):1866. https://doi.org/10.3390/nu13061866.

Background: Polyphenols are secondary metabolites produced by plants to defend themselves from environmental stressors. We explored the effect of Wolffia globosa ‘Mankai’, a novel cultivated strain of a polyphenol-rich aquatic plant, on the metabolomic-gut clinical axis in vitro, in-vivo and in a clinical trial. Methods: We used mass-spectrometry-based metabolomics methods from three laboratories to detect Mankai phenolic metabolites and examined predicted functional pathways in a Mankai artificial-gut bioreactor. Plasma and urine polyphenols were assessed among the 294 DIRECT-PLUS 18-month trial participants, comparing the effect of a polyphenol-rich green-Mediterranean diet (+1240 mg/polyphenols/day, provided by Mankai, green tea and walnuts) to a walnuts-enriched (+440 mg/polyphenols/day) Mediterranean diet and a healthy controlled diet. Results: Approximately 200 different phenolic compounds were specifically detected in the Mankai plant. The Mankai-supplemented bioreactor artificial gut displayed a significantly higher relative-abundance of 16S-rRNA bacterial gene sequences encoding for enzymes involved in phenolic compound degradation. In humans, several Mankai-related plasma and urine polyphenols were differentially elevated in the green Mediterranean group compared with the other groups (p < 0.05) after six and 18 months of intervention (e.g., urine hydroxy-phenyl-acetic-acid and urolithin-A; plasma Naringenin and 2,5-diOH-benzoic-acid). Specific polyphenols, such as urolithin-A and 4-ethylphenol, were directly involved with clinical weight-related changes. Conclusions: The Mankai new plant is rich in various unique potent polyphenols, potentially affecting the metabolomic-gut-clinical axis.

Effects of walnut consumption for 2 years on lipoprotein subclasses among healthy elders: findings from the WAHA Randomized Controlled Trial.

Rajaram, S., M. Cofán, A. Sala-Vila, E. Haddad, M. Serra-Mir, E. Bitok, I. Roth, T.M. Freitas-Simoes, A. Kaur, C. Valls-Pedret, M. Doménech, K. Oda, D. Corella, J. Sabaté, E. Ros, 2021. Effects of walnut consumption for 2 years on lipoprotein subclasses among healthy elders: findings from the WAHA Randomized Controlled Trial. Circulation. 144(13):1083–1085.

Background: Frequent consumption of nuts, an important component of plant-based diets, is associated with 15% lower total cardiovascular disease (CVD) and 23% lower CVD mortality rates. Small, short-term randomized controlled trials (RCTs) indicate that diets supplemented with nuts have a consistent cholesterol-lowering effect; however, no trials of nut-enriched diets for lipid changes focused on elderly individuals, recruited participants from diverse geographical locations, or lasted 2 years. Also, there is little information concerning effects of nuts on lipoprotein subclasses. Objective: We hypothesized that incorporating walnuts into the usual diet would improve the lipid profile irrespective of differences in geographical and dietary background. Methods: The Walnuts and Healthy Aging (WAHA) study is a two-center (Barcelona, Spain and California, USA), 2-year, parallel-group RCT testing the effects of walnut supplemented diets in healthy elders. Lipoprotein changes were a pre-specified secondary outcome. Eligible candidates were cognitively healthy elders (63-79 years-old) without major comorbidities. Participants (n=708) were allocated to either a walnut-free (control) or walnut-supplemented diet (≈15% of energy, 30-60g/day). In 2-monthly visits, compliance, tolerance, medication changes, and body weight were recorded. At each visit, 8–week allotments of raw, pieced walnuts were delivered to the corresponding group. Results: 636 participants completed the study (90% retention rate) and 628 had full data for lipoprotein analyses (mean age 69 years, 67% women, 32% treated with statins). Mean baseline LDL-C and triglycerides were 117 and 105 mg/dL, respectively. The walnut diet significantly decreased (mg/dL) total cholesterol (mean -8.5 [95% CI, -11.2, -5.4]), LDL-C (mean -4.3 [-6.6, -1.6]), and intermediate-density lipoprotein (IDL)-C (-1.3 [-1.5, -1.0]), corresponding to reductions of 4.4%, 3.6%, and 16.8%, respectively, while triglycerides and HDL-C were unaffected (Figures-B, C). Total LDL particles and small LDL particle number decreased by 4.3% and 6.1%, respectively (Figure-D). Results were not different by study site. Lipid responses to the walnut diet differed by sex: LDL-C was reduced by 7.9% in men and by 2.6% in women (P-interaction=0.007). Conclusions: The results demonstrate that incorporating daily doses of walnuts (≈15% of energy) to the habitual diet of free-living elders with an essentially normal lipid profile resulted in a mean 4.3 mg/dL LDL-C reduction, which is modest, although greater responses have been observed among individuals with hypercholesterolemia. Our data also support a beneficial effect of the walnut diet on NMR-assessed lipoprotein subfractions, with reductions of IDL-C (a sizable contributor to remnant-C) and total LDL particles. Prospective studies have reported that LDL particle number consistently outperforms LDL-C in CVD risk prediction and that remnant-C causally relates to CVD independent of LDL-C. That lipid responses were not different in two cohorts consuming diverse diets strengthens the generalization of our results. WAHA is the largest and longest nut trial to date, overcoming the limitations of prior smaller and shorter nut studies. The novel finding of sexual dimorphism in LDL-C response to walnut supplementation needs confirmation. WAHA was conducted in free-living individuals, who chose their daily foods, which may be viewed as desirable since it is closer to real life than the situation in controlled feeding studies. On the basis of associations ascertained in cohort studies, the observed shift of the lipoprotein subclass phenotype suggests a reduction of lipoprotein-related CVD risk by long-term consumption of walnuts, which provides novel mechanistic insight for their potential cardiovascular benefit beyond effects on the standard lipid panel. Our data reinforce the notion that regular walnut consumption may be a useful part of a multi-component dietary intervention or dietary pattern to lower atherogenic lipids and improve CVD risk.

Brief research report: estimation of the protein digestibility-corrected amino acid score of defatted walnuts.

Lackey, K.A., S.A. Fleming, 2021. Brief research report: estimation of the protein digestibility-corrected amino acid score of defatted walnuts. Frontiers in Nutrition. 8, 702857. https://doi.org/10.3389/fnut.2021.702857

Introduction: Walnuts are considered a good source of essential fatty acids, which is unique among tree nuts. Walnuts are also composed of about 10–15% protein, but the quality of this protein has not been evaluated. Pistachios and almonds have been evaluated for their protein content using a protein digestibility-corrected amino acid score (PDCAAS), but it is unclear how the quality of protein in walnuts relates to that in other commonly consumed tree nuts. The objective of this study was to substantiate the protein quality of walnuts by determining their PDCAAS. Methods: A small, 10-day dietary intervention trial was conducted using male Sprague-Dawley rats (n = 8, 4 per group) with two diets: a nitrogen-free diet and a diet containing protein exclusively from defatted walnuts. Feed intake and fecal output of nitrogen were measured to estimate the true protein digestibility, and the amino acid compositions of walnuts compared to child and adult populations were used to calculate amino acid scores (AAS) and PDCAAS. Results: The true protein digestibility score of raw walnuts was calculated to be 86.22%. Raw walnuts contained 15.6 g protein/g walnut with AAS of 0.45 and 0.63 for children aged 6 months to 3 years and 3–10 years, respectively. For each population, a PDCAAS of 39 and 46% was calculated, respectively, using a protein conversion constant of 5.30. Using a protein constant of 6.25, a PDCAAS of 39% (6 months – 3 years) or 46% (3-10 years) was calculated. Conclusions: This is the first known assessment of the PDCAAS of walnuts. Like almonds, appear to have a low-to-moderate score, indicating they are not a quality source of protein.

Association of nut consumption with risk of total cancer and 5 specific cancers: evidence from 3 large prospective cohort studies.

Fang, Z., Y. Wu, Y. Li, X. Zhang, W.C. Willett, A.H. Eliassen, B. Rosner, M. Song, L.A. Mucci, E.L. Giovannucci, 2021. Association of nut consumption with risk of total cancer and 5 specific cancers: evidence from 3 large prospective cohort studies. Amer J Clin Nutr. 114(6):1925–1935. https://doi.org/10.1093/ajcn/nqab295

Background: The associations between nut consumption and cancer risk have not been extensively investigated. Objectives: We aimed to examine the associations between nut consumption, especially specific types of nuts (peanut, tree nut, walnut, and tree nut other than walnut), and cancer risk. Methods: Nut consumption was assessed by FFQ at baseline and updated every 2–4 y in the Nurses’ Health Study (1980– 2014), the Nurses’ Health Study II (1991–2015), and the Health Professionals Follow-up Study (1986–2018). We examined the associations between the intake of total and specific types of nuts and risk of total cancer and common cancers, including lung, colorectal, breast, bladder, and aggressive prostate cancer. Cox proportional hazards models were used to obtain the HRs and 95% CIs in each cohort as well as pooled. Results: During 5,873,671 person-years of follow-up in 180,832 women and 45,560 men, we documented 44,561 incident cancer cases. As compared with nonconsumers, the pooled multivariable HRs of total nut consumption for ≥5 times/wk were 0.99 (95% CI: 0.94, 1.04; P-trend = 0.54) for total cancer, 0.88 (95% CI: 0.74, 1.04; P-trend = 0.18) for lung cancer, 1.07 (95% CI: 0.92, 1.26; P-trend = 0.89) for colorectal cancer, 0.90 (95% CI: 0.71, 1.14; P-trend = 0.65) for bladder cancer, 0.96 (95% CI: 0.85, 1.08; Ptrend = 0.36) for breast cancer, and 1.18 (95% CI: 0.92, 1.51; Ptrend = 0.52) for aggressive prostate cancer Conclusions: In 3 large prospective cohorts, frequent nut consumption was not associated with risk of total cancer and common individual cancers.

Branched-chain amino acids in relation to food preferences and insulin resistance in obese subjects consuming walnuts: A cross-over, randomized, double-blind, placebo-controlled inpatient physiology study.

Tuccinardi, D., N. Perakakis, O.M. Farr, J. Upadhyay, C.S. Mantzoros, 2021. Branched-chain amino acids in relation to food preferences and insulin resistance in obese subjects consuming walnuts: A cross-over, randomized, double-blind, placebo-controlled inpatient physiology study. Clin Nutr. 40(5):3032-3036.

Background & aims: To assess whether the concentrations of circulating Branched-Chain Amino Acids (BCAAs) change after walnut consumption and, whether these changes are associated with alterations in markers of insulin resistance and food preferences. Methods: In a crossover, randomized, double-blind, placebo-controlled study, ten subjects participated in two 5-day inpatient study admissions, during which they had a smoothie containing 48 g walnuts or a macronutrient-matched placebo smoothie without nuts every morning. Between the two phases there was a 1-month washout period. Results: Fasting valine and isoleucine levels were reduced (p = .047 and p < .001) and beta-hydroxybutyrate levels were increased after 5-days of walnut consumption compared to placebo (p = .023). Fasting valine and isoleucine correlated with HOMA-IR while on walnut (r = 0.709, p = .032 and r = 0.679, p = .044). The postprandial area under the curve (AUC) of leucine in response to the smoothie consumption on day 5 was higher after walnut vs placebo (p = .023) and correlated negatively with the percentage of Kcal from carbohydrate and protein consumed during an ad libitum buffet meal consumed the same day for lunch (r = −0.661, p = .037; r = −0.628, p = .05, respectively). Conclusion: The fasting and post-absorptive profiles of BCAAs are differentially affected by walnut consumption. The reduction in fasting valine and isoleucine may contribute to the longer-term benefits of walnuts on insulin resistance, cardiovascular risk and mortality, whereas the increase in post-absorptive profiles with walnuts may influence food preference.

Dietary intake of walnut prevented Helicobacter pylori-associated gastric cancer through rejuvenation of chronic atrophic gastritis.

Park, J.M., Y.M. Han, Y.J. Park, K.B. Hahm, 2021. Dietary intake of walnut prevented Helicobacter pylori-associated gastric cancer through rejuvenation of chronic atrophic gastritis. J Clin Biochem Nutr. 68(1): 37–50.

The fact that Fat-1 transgenic mice producing n-3 polyunsaturated fatty acids via overexpressed 3-desaturase significantly mitigated Helicobacter pylori (H. pylori)-associated gastric tumorigenesis through rejuvenation of chronic atrophic gastritis (CAG) led us to study whether dietary intake of walnut plentiful of n-3 PUFAs can be nutritional intervention to prevent H. pylori-associated gastric cancer. In our model that H. pylori-initiated, high salt diet-promoted gastric carcinogenesis, pellet diet containing 100 mg/kg and 200 mg/kg walnut was administered up to 36 weeks. As results, control mice (24 weeks) developed significant chronic CAG, in which dietary walnuts significantly ameliorated chronic atrophic gastritis. Expressions of COX-2/PGE2/NF-κB/c-Jun, elevated in 24 weeks control group, were all significantly decreased with walnut (p<0.01). Tumor suppressive enzyme, 15-PGDH, was significantly preserved with walnut. Control mice (36 weeks) all developed significant tumors accompanied with severe CAG. However, significantly decreased tumorigenesis was noted in group treated with walnuts, in which expressions of COX-2/PGE2/NF-κB/IL-6/STAT3, all elevated in 36 weeks control group, were significantly decreased with walnut. Defensive proteins including HO-1, Nrf2, and SOCS-1 were significantly increased in walnut group. Proliferative index as marked with Ki-67 and PCNA was significantly regulated with walnut relevant to 15-PGDH preservation. Conclusively, walnut can be an anticipating nutritional intervention against H. pylori.