Replacing Saturated Fats with Unsaturated Fats from Walnuts or Vegetable Oils Lowers Atherogenic Lipoprotein Classes Without Increasing Lipoprotein(a).

BACKGROUND: Walnuts have established lipid-/lipoprotein-lowering properties; however, their effect on lipoprotein subclasses has not been investigated. Furthermore, the mechanisms by which walnuts improve lipid/lipoprotein concentrations are incompletely understood. OBJECTIVES: We aimed to examine, as exploratory outcomes of this trial, the effect of replacing SFAs with unsaturated fats from walnuts or vegetable oils on lipoprotein subclasses, cholesterol efflux, and proprotein convertase subtilisin/kexin type 9 (PCSK9). METHODS: A randomized, crossover, controlled-feeding study was conducted in individuals at risk of cardiovascular disease (CVD) (n = 34; 62% men; mean ± SD age 44 ± 10 y; BMI: 30.1 ± 4.9 kg/m2). After a 2-wk run-in diet (12% SFAs, 7% PUFAs, 12% MUFAs), subjects consumed the following diets, in randomized order, for 6 wk: 1) walnut diet (WD) [57-99 g/d walnuts, 7% SFAs, 16% PUFAs [2.7% α-linolenic acid (ALA)], 9% MUFAs]; 2) walnut fatty acid-matched diet [7% SFAs, 16% PUFAs (2.6% ALA), 9% MUFAs]; and 3) oleic acid replaces ALA diet (ORAD) [7% SFAs, 14% PUFAs (0.4% ALA); 12% MUFAs] (all percentages listed are of total kilocalories ). Serum collected after the run-in (baseline) and each diet period was analyzed for lipoprotein classes and subclasses (vertical auto profile), cholesterol efflux, and PCSK9. Linear mixed models were used for data analysis. RESULTS: Compared with the ORAD, total cholesterol (mean ± SEM -8.9± 2.3 mg/dL; -5.1%; P < 0.001), non-HDL cholesterol (-7.4 ± 2.0 mg/dL; -5.4%; P = 0.001), and LDL cholesterol (-6.9 ± 1.9 mg/dL; -6.5%; P = 0.001) were lower after the WD; no other pairwise differences existed. There were no between-diet differences for HDL-cholesterol or LDL-cholesterol subclasses. Lipoprotein(a) [Lp(a)], cholesterol efflux, and PCSK9 were unchanged after the diets. CONCLUSIONS: In individuals at risk of CVD, replacement of SFAs with unsaturated fats from walnuts or vegetable oils improved lipid/lipoprotein classes, including LDL-cholesterol, non-HDL cholesterol, and total cholesterol, without an increase in Lp(a). These improvements were not explained by changes in cholesterol efflux capacity or PCSK9. This trial was registered at clinicaltrials.gov as NCT01235832.

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.

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.

Dietary Patterns Affect the Gut Microbiome-The Link to Risk of Cardiometabolic Diseases.

Clusters of bacterial species within the gut microenvironment, or gut enterotype, have been correlated with cardiometabolic disease risk. The metabolic products and metabolites that bacteria produce, such as short-chain fatty acids, secondary bile acids, and trimethylamine, may also affect the microbial community and disease risk. Diet has a direct impact on the gut microenvironment by providing substrates to and promoting the colonization of resident bacteria. To date, few dietary patterns have been evaluated for their effect on the gut microbiome, but the Mediterranean diet and Vegetarian diets have shown favorable effects for both the gut microbiome and cardiometabolic disease risk. This review examines the gut microbiome as a mediator between these dietary patterns and cardiometabolic disease risk.

Correction: Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

[This corrects the article DOI: 10.1371/journal.pone.0232685.].

Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

BACKGROUND: In the primary analysis of a 12-month double-blind randomized active placebo-controlled trial, treatment of children with cystic fibrosis (CF) and pancreatic insufficiency (PI) with a readily absorbable structured lipid (Encala™, Envara Health, Wayne, PA) was safe, well-tolerated and improved dietary fat absorption (stool coefficient of fat absorption [CFA]), growth, and plasma fatty acids (FA). OBJECTIVE: To determine if the Encala™ treatment effect varied by severity of baseline fat malabsorption. METHODS: Subjects (n = 66, 10.5±3.0 yrs, 39% female) with baseline CFA who completed a three-month treatment with Encala™ or a calorie and macronutrient-matched placebo were included in this subgroup analysis. Subjects were categorized by median baseline CFA: low CFA (<88%) and high CFA (≥88%). At baseline and 3-month evaluations, CFA (72-hour stool, weighed food record) and height (HAZ), weight (WAZ) and BMI (BMIZ) Z-scores were calculated. Fasting plasma fatty acid (FA) concentrations were also measured. RESULTS: Subjects in the low CFA subgroup had significantly improved CFA (+7.5±7.2%, mean 86.3±6.7, p = 0.002), and reduced stool fat loss (-5.7±7.2 g/24 hours) following three months of EncalaTM treatment. These subjects also had increased plasma linoleic acid (+20%), α-linolenic acid (+56%), and total FA (+20%) (p≤0.005 for all) concentrations and improvements in HAZ (0.06±0.08), WAZ (0.17±0.16), and BMIZ (0.20±0.25) (p≤0.002 for all). CFA and FA were unchanged with placebo in the low CFA group, with some WAZ increases (0.14±0.24, p = 0.02). High CFA subjects (both placebo and Encala™ groups) had improvements in WAZ and some FA. CONCLUSIONS: Subjects with CF, PI and more severe fat malabsorption experienced greater improvements in CFA, FA and growth after three months of Encala™ treatment. Encala™ was safe, well-tolerated and efficacious in patients with CF and PI with residual fat malabsorption and improved dietary energy absorption, weight gain and FA status in this at-risk group.

The Weight Optimization Revamping Lifestyle using the Dietary Guidelines (WORLD) Study: Sustained Weight Loss Over 12 Months.

OBJECTIVE: This study aimed to compare two energy-restricted, nutrient-dense diets at the upper or lower ends of the dietary fat recommendation range (lower fat [20% energy from fat] versus moderate fat [35%]) on weight loss using behavioral theory-based nutrition education. METHODS: A total of 101 premenopausal women with overweight or obesity were randomized to an energy-restricted lower-fat or moderate-fat diet for 1 year. Interventions included 28 behavioral theory-based nutrition education sessions plus weekly exercise sessions. RESULTS: Both treatment groups experienced weight loss (-5.0 kg for lower fat and -4.3 kg for moderate fat; P < 0.0001), but there was no difference in weight loss or fat intake between groups. Total and low-density lipoprotein cholesterol decreased (-3. 4 mg/dL and -3.8 mg/dL; P < 0.05), and high-density lipoprotein cholesterol increased (1.9 mg/dL; P < 0.05) in both groups at 12 months. Diet quality, assessed by the Healthy Eating Index, increased significantly at 4 months versus baseline (70.8 [0.9] vs. 77.8 [1.0]) and was maintained through 12 months. Higher Healthy Eating Index scores were associated with greater weight loss at 4 months (r = -0.2; P < 0.05). CONCLUSIONS: In the context of a well-resourced, free-living weight-loss intervention, total fat intake did not change; however, theory-based nutrition education underpinned by food-based recommendations resulted in caloric deficits, improvements in diet quality, and weight loss that was sustained for 1 year.

Vitamin D status, nutrition and growth in HIV-infected mothers and HIV-exposed infants and children in Botswana.

BACKGROUND: Poor vitamin D status is a global health problem and common in patients with human immunodeficiency virus (HIV) in high-income countries. There is less evidence on prevalence of vitamin D deficiency and nutrition and growth in HIV-infected and -exposed children in low- and middle-income countries. OBJECTIVES: To determine the vitamin D status in Batswana HIV-infected mothers and their children, differences among HIV-infected mothers and between HIV-exposed and -infected infants and children, and associations between vitamin D and disease-related outcomes, nutrition, and growth. METHODS: This was a cross-sectional study of HIV+ mothers and HIV-exposed infants and unrelated children (1-7.9 years). Serum 25-hydroxyvitamin D (25(OH)D) was measured, among other nutritional indicators, for mothers, infants and children. Vitamin D status for HIV-infected mothers and children, and an immune panel was assessed. History of HIV anti-retroviral medications and breastfeeding were obtained. Data were collected prior to universal combination antiretroviral therapy in pregnancy. RESULTS: Mothers (n = 36) had a mean serum 25(OH)D of 37.2±12.4ng/mL; 11% had insufficient (<20ng/mL), 17% moderately low (20.0-29.9ng/mL) and 72% sufficient (≥30ng/mL) concentrations. No infants (n = 36) or children (n = 48) were vitamin D insufficient; 22% of HIV- and no HIV+ infants had moderately low concentrations and 78% of HIV- and 100% of HIV+ infants had sufficient status, 8% of HIV- and no HIV+ children had moderately low concentrations and 92% of HIV- and 100% HIV+ children had sufficient concentrations. HIV+ children had significantly lower length/height Z scores compared to HIV- children. Length/height Z score was positively correlated with serum 25(OH)D in all children (r = 0.33, p = 0.023), with a stronger correlation in the HIV+ children (r = 0.47 p = 0.021). In mothers, serum 25(OH)D was positively associated with CD4% (r = 0.40, p = 0.016). CONCLUSIONS: Results showed a low prevalence of vitamin D insufficiency in Botswana. Growth was positively correlated with vitamin D status in HIV-exposed children, and HIV+ children had poorer linear growth than HIV- children.

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity.

Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance of epithelial barrier and immune function. A number of abundant microbiota-derived tryptophan metabolites exhibit activation potential for the aryl hydrocarbon receptor (AHR). Gene expression facilitated by AHR activation through the presence of dietary or microbiota-generated metabolites can influence gastrointestinal homeostasis and confer protection from intestinal challenges. Utilizing untargeted mass spectrometry-based metabolomics profiling, combined with AHR activity screening assays, we identify four previously unrecognized tryptophan metabolites, present in mouse cecal contents and human stool, with the capacity to activate AHR. Using GC/MS and LC/MS platforms, quantification of these novel AHR activators, along with previously established AHR-activating tryptophan metabolites, was achieved, providing a relative order of abundance. Using physiologically relevant concentrations and quantitative gene expression analyses, the relative efficacy of these tryptophan metabolites with regard to mouse or human AHR activation potential is examined. These data reveal indole, 2-oxindole, indole-3-acetic acid and kynurenic acid as the dominant AHR activators in mouse cecal contents and human stool from participants on a controlled diet. Here we provide the first documentation of the relative abundance and AHR activation potential of a panel of microbiota-derived tryptophan metabolites. Furthermore, these data reveal the human AHR to be more sensitive, at physiologically relevant concentrations, to tryptophan metabolite activation than mouse AHR. Additionally, correlation analyses indicate a relationship linking major tryptophan metabolite abundance with AHR activity, suggesting these cecal/fecal metabolites represent biomarkers of intestinal AHR activity.

The Effect of Inflammation and Insulin Resistance on Lipid and Lipoprotein Responsiveness to Dietary Intervention.

Lipids and lipoproteins are major targets for cardiovascular disease (CVD) prevention. Findings from a limited number of clinical trials suggest diet-induced atherogenic lipoprotein lowering can be altered in the presence of chronic low-grade inflammation or insulin resistance. This review summarizes results from randomized controlled trials that have examined diet-induced changes in lipids/lipoproteins by inflammatory or insulin sensitivity status. In addition, mechanisms to explain these clinical observations are explored. Post hoc analyses of data from a limited number of randomized controlled trials suggest attenuation of diet-induced lipid/lipoprotein lowering in individuals with inflammation and/or insulin resistance. These findings are supported by experimental studies showing that inflammatory stimuli and hyperinsulinemia alter genes involved in endogenous cholesterol synthesis and cholesterol uptake, reduce cholesterol efflux, and increase fatty acid biosynthesis. Further a priori defined research is required to better characterize how chronic low-grade inflammation and insulin resistance modulate lipid and lipoprotein responsiveness to guide CVD risk reduction in individuals presenting with these phenotypes.

The effect of nuts on markers of glycemic control: a systematic review and meta-analysis of randomized controlled trials.

Background: Observational evidence suggests higher nut consumption is associated with better glycemic control; however, it is unclear if this association is causal. Objectives: We aimed to conduct a systematic review and meta-analysis of randomized controlled trials to examine the effect of tree nuts and peanuts on markers of glycemic control in adults. Methods: A systematic review and meta-analysis of randomized controlled trials was conducted. A total of 1063 potentially eligible articles were screened in duplicate. From these articles, 40 were eligible for inclusion and data from these articles were extracted in duplicate. The weighted mean difference (WMD) between the nut intervention and control arms was determined for fasting glucose, fasting insulin, glycated hemoglobin (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR) using the DerSimonian and Laird random-effects method. For outcomes where a limited number of studies were published, a qualitative synthesis was presented. Results: A total of 40 randomized controlled trials including 2832 unique participants, with a median duration of 3 mo (range: 1-12 mo), were included. Overall consumption of tree nuts or peanuts had a favorable effect on HOMA-IR (WMD: -0.23; 95% CI: -0.40, -0.06; I2 = 51.7%) and fasting insulin (WMD: -0.40 µIU/mL; 95% CI: -0.73, -0.07 µIU/mL; I2 = 49.4%). There was no significant effect of nut consumption on fasting blood glucose (WMD: -0.52 mg/dL; 95% CI: -1.43, 0.38 mg/dL; I2 = 53.4%) or HbA1c (WMD: 0.02%; 95% CI: -0.01%, 0.04%; I2 = 51.0%). Conclusions: Consumption of peanuts or tree nuts significantly decreased HOMA-IR and fasting insulin; there was no effect of nut consumption on HbA1c or fasting glucose. The results suggest that nut consumption may improve insulin sensitivity. In the future, well-designed clinical trials are required to elucidate the mechanisms that account for these observed effects.

Replacing Saturated Fat With Walnuts or Vegetable Oils Improves Central Blood Pressure and Serum Lipids in Adults at Risk for Cardiovascular Disease: A Randomized Controlled-Feeding Trial.

Background Walnuts have beneficial effects on cardiovascular risk factors, but it is unclear whether these effects are attributable to the fatty acid ( FA ) content, including α-linolenic acid ( ALA ), and/or bioactives. Methods and Results A randomized, controlled, 3-period, crossover, feeding trial was conducted in individuals at risk for cardiovascular disease (n=45). Following a 2-week standard Western diet run-in (12% saturated FAs [ SFA ], 7% polyunsaturated FAs, 12% monounsaturated FAs), participants consumed 3 isocaloric weight-maintenance diets for 6 weeks each: a walnut diet ( WD ; 7% SFA , 16% polyunsaturated FAs, 3% ALA , 9% monounsaturated FAs); a walnut FA -matched diet; and an oleic acid-replaced- ALA diet (7% SFA , 14% polyunsaturated FAs, 0.5% ALA , 12% monounsaturated FAs), which substituted the amount of ALA from walnuts in the WD with oleic acid. This design enabled evaluation of the effects of whole walnuts versus constituent components. The primary end point, central systolic blood pressure, was unchanged, and there were no significant changes in arterial stiffness. There was a treatment effect ( P=0.04) for central diastolic blood pressure; there was a greater change following the WD versus the oleic acid-replaced-ALA diet (-1.78±1.0 versus 0.15±0.7 mm Hg, P=0.04). There were no differences between the WD and the walnut fatty acid-matched diet (-0.22±0.8 mm Hg, P=0.20) or the walnut FA-matched and oleic acid-replaced-ALA diets ( P=0.74). The WD significantly lowered brachial and central mean arterial pressure. All diets lowered total cholesterol, LDL (low-density lipoprotein) cholesterol, HDL (high-density lipoprotein) cholesterol, and non- HDL cholesterol. Conclusions Cardiovascular benefits occurred with all moderate-fat, high-unsaturated-fat diets. As part of a low- SFA diet, the greater improvement in central diastolic blood pressure following the WD versus the oleic acid-replaced-ALA diet indicates benefits of walnuts as a whole-food replacement for SFA . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT02210767.

Tree Nut Consumption and Adipose Tissue Mass: Mechanisms of Action.

There is concern that tree nuts may cause weight gain due to their energy density, yet evidence shows that tree nuts do not adversely affect weight status. Epidemiologic and experimental studies have shown a reduced risk of chronic diseases with tree nut consumption without an increased risk of weight gain. In fact, tree nuts may protect against weight gain and benefit weight-loss interventions. However, the relation between tree nut consumption and adiposity is not well understood at the mechanistic level. This review summarizes the proposed underlying mechanisms that might account for this relation. Evidence suggests that tree nuts may affect adiposity through appetite control, displacement of unfavorable nutrients, increased diet-induced thermogenesis, availability of metabolizable energy, antiobesity action of bioactive compounds, and improved functionality of the gut microbiome. The gut microbiome is a common factor among these mechanisms and may mediate, in part, the relation between tree nut consumption and reduced adiposity. Further research is needed to understand the impact of tree nuts on the gut microbiome and how the gut microbial environment affects the nutrient absorption and metabolism of tree nuts. The evidence to date suggests that tree nut consumption favorably affects body composition through different mechanisms that involve the gut microbiome. A better understanding of these mechanisms will contribute to the evolving science base that addresses the causes and treatments for overweight and obesity.