Gut microbiome-derived glycine lipids are diet-dependent modulators of hepatic injury and atherosclerosis.

Oral and gut Bacteroidetes produce unique classes of serine-glycine lipodipeptides and glycine aminolipids that signal through host Toll-like receptor 2. These glycine lipids have also been detected in human arteries, but their effects on atherosclerosis are unknown. Here, we sought to investigate the bioactivity of bacterial glycine lipids in mouse models of atherosclerosis. Lipid 654 (L654), a serine-glycine lipodipeptide species, was first tested in a high-fat diet (HFD)-fed Ldlr-/- model of atherosclerosis. Intraperitoneal administration of L654 over 7 weeks to HFD-fed Ldlr-/- mice resulted in hypocholesterolemic effects and significantly attenuated the progression of atherosclerosis. We found that L654 also reduced liver inflammatory and extracellular matrix gene expression, which may be related to inhibition of macrophage activation as demonstrated in vivo by lower major histocompatibility complex class II gene expression and confirmed in cell experiments. In addition, L654 and other bacterial glycine lipids in feces, liver, and serum were markedly reduced alongside changes in Bacteroidetes relative abundance in HFD-fed mice. Finally, we tested the bioactivities of L654 and related lipid 567 in chow-fed Apoe-/- mice, which displayed much higher fecal glycine lipids relative to HFD-fed Ldlr-/- mice. Administration of L654 or lipid 567 for 7 weeks to these mice reduced the liver injury marker alanine aminotransferase, but other effects seen in Ldlr-/- were not observed. Therefore, we conclude that conditions in which gut microbiome-derived glycine lipids are lost, such as HFD, may exacerbate the development of atherosclerosis and liver injury, whereas correction of such depletion may protect from these disorders.

Dairy food intake is not associated with spinal trabecular bone score in men and women: the Framingham Osteoporosis Study.

BACKGROUND: Previous studies reported that dairy foods are associated with higher areal bone mineral density (BMD) in older adults. However, data on bone texture are lacking. We determined the association of dairy food intake (milk, yogurt, cheese, milk + yogurt and milk + yogurt + cheese) with spinal trabecular bone score (TBS). METHODS: In this cross-sectional study, a validated semi-quantitative food frequency questionnaire was used to assess dairy food intake (servings/wk). TBS, an analysis of bone texture, was calculated from dual energy X-ray absorptiometry (DXA) scans. Sex-specific multivariable linear regression was used to estimate the association of dairy food intake (energy adjusted via residual methods) with each bone measure adjusting for covariates. RESULTS: Mean age of 4,740 participants was 49 (SD: 13) years and mean milk + yogurt + cheese intake was 10.1 (SD: 8.4) servings/week in men and 10.9 (SD: 8.0) servings/week in women. There were no associations between dairy food intake and spinal TBS in adjusted models. CONCLUSIONS: In this cohort of primarily healthy adults, dairy intake was not associated with bone texture.

Intake of up to 3 Eggs per Day Is Associated with Changes in HDL Function and Increased Plasma Antioxidants in Healthy, Young Adults.

Background: HDL function may be more important than HDL concentration in determining risk for cardiovascular disease. In addition, HDL is a carrier of carotenoids and antioxidant enzymes, which protect HDL and LDL particles against oxidation.Objective: The goal of this study was to determine the impact of consuming 0-3 eggs/d on LDL and HDL particle size, HDL function, and plasma antioxidants in a young, healthy population.Methods: Thirty-eight healthy men and women [age 18-30 y, body mass index (in kg/m2) 18.5-29.9] participated in this 14-wk crossover intervention. Subjects underwent a 2-wk washout (0 eggs/d) followed by sequentially increasing intake of 1, 2, and 3 eggs/d for 4 wk each. After each period, fasting blood was collected for analysis of lipoprotein subfractions, plasma apolipoprotein (apo) concentration, lutein and zeaxanthin concentration, and activities of lecithin-cholesterol acyltransferase, cholesteryl ester transfer protein, and paraoxonase-1.Results: Compared with intake of 0 eggs/d, consuming 1-3 eggs/d resulted in increased large-LDL (21-37%) and large-HDL (6-13%) particle concentrations, plasma apoAI (9-15%), and lecithin-cholesterol acyltransferase activity (5-15%) (P < 0.05 for all biomarkers). Intake of 2-3 eggs/d also promoted an 11% increase in apoAII (P < 0.05) and a 20-31% increase in plasma lutein and zeaxanthin (P < 0.05), whereas intake of 3 eggs/d resulted in a 9-16% increase in serum paraoxonase-1 activity compared with intake of 1-2 eggs/d (P < 0.05). Egg intake did not affect cholesteryl ester transfer protein activity.Conclusions: Intake of 1 egg/d was sufficient to increase HDL function and large-LDL particle concentration; however, intake of 2-3 eggs/d supported greater improvements in HDL function as well as increased plasma carotenoids. Overall, intake of ≤3 eggs/d favored a less atherogenic LDL particle profile, improved HDL function, and increased plasma antioxidants in young, healthy adults. This trial was registered at clinicaltrials.gov as NCT02531958.

Comparison of targeted web-based advertising versus traditional methods for recruiting older adults into clinical trials.

BACKGROUND: Recruiting older adults into clinical trials can be particularly challenging. Our objective was to determine if targeted web-based advertising is an effective recruitment strategy. METHODS: We compared the recruitment rates of traditional and targeted web-based methods for three representative clinical trials involving older adults. All studies utilized traditional recruitment methods initially, but shifted toward primarily targeted web-based advertising after experiencing slow recruitment rates. RESULTS: We found that web-based advertising reached more individuals compared to traditional methods. Compared to traditional methods, web-based methods also had at least twice the rate of expressed interest, completion of telephone and in-person screening, eligibility, and enrollment. Additionally, the proportion of individuals excluded after the telephone screening did not differ according to whether targeted web-based advertising (STAMINA: 51%; Berries and Steps: 62%; ISTIM: 20%) or traditional methods (STAMINA: 48%; Berries and Steps: 69%; ISTIM: 23%) were used within each study. Those recruited using web-based advertisements tended to be younger compared to traditional methods, but were similar in racial distribution and education. CONCLUSION: Targeted web-based advertisements may be more effective in recruiting older adults for clinical trials at a faster rate than traditional recruitment methods, but need further evaluation of compatible study designs, potential population bias, and cost-effectiveness.

Association of Proinflammatory Diet With Frailty Onset Among Adults With and Without Depressive Symptoms: Results From the Framingham Offspring Study.

BACKGROUND: Dietary inflammation is associated with increased risk of frailty. Those with depressive symptoms may be at higher risk of frailty onset because they typically have higher levels of inflammation. The study objective was to determine the association between a proinflammatory diet and frailty onset in those with and without clinically relevant depressive symptoms. METHODS: This prospective study included 1 701 nonfrail individuals with self-reported baseline (1998-2001) data available for the evaluation of energy-adjusted dietary inflammatory index (E-DIITM; calculated from food frequency questionnaires), depressive symptoms (from the Center for Epidemiologic Studies Depression; CES-D), and follow-up frailty measurements (2011-2014). Frailty was defined as fulfilling ≥3 Fried frailty criteria (i.e., slow gait, weak grip strength, unintentional weightloss, low physical activity, and self-reported exhaustion). Results are presented by baseline CES-D scores <16 or ≥16 points, which denotes the absence or presence of clinically relevant depressive symptoms, respectively. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (95% CI) between E-DII and frailty onset, adjusting for confounders. RESULTS: In all study participants, mean (SD) age was 58(8) years and E-DII was -1.95 (2.20; range: -6.71 to +5.40, higher scores denote a more proinflammatory diet), and 45% were male. In those without clinically relevant depressive symptoms, 1-unit higher E-DII score was associated with 14% increased odds (95% CI: 1.05-1.24) of frailty. In those with depressive symptoms, 1-unit higher E-DII score was associated with 55% increased odds of frailty (95% CI: 1.13-2.13). CONCLUSIONS: The association between inflammatory diet and increased odds of frailty appeared somewhat stronger among those with depressive symptoms. This preliminary finding warrants further investigation.

Dairy Food Intake Is Not Associated With Frailty in Adults From the Framingham Heart Study.

BACKGROUND: Nutrients, including protein, calcium, and fat may be associated with risk of frailty, yet specific contributions from whole dairy foods rich in these nutrients remain understudied. OBJECTIVE: To determine associations between dairy intake (milk, yogurt, cheese, total (milk + yogurt + cheese), low-fat and high-fat dairy, and servings per week) and frailty onset and frailty phenotype components. DESIGN: Prospective cohort study. All dairy intake exposures (servings per week) were assessed via a food frequency questionnaire. PARTICIPANTS AND SETTING: Participants (aged 33 to 86 years) from the Framingham Offspring Study who were not frail at baseline (1998-2001) completed a food frequency questionnaire and had 1 or 2 follow-up frailty assessments (2005-2008 and 2011-2014) were included. MAIN OUTCOME MEASURES: Frailty was defined as the presence of ≥3 Fried frailty phenotype components: unintentional weight-loss, exhaustion, slowness (gait speed), weakness (grip strength), and low physical activity. Individuals with zero to two components were considered nonfrail. STATISTICAL ANALYSES PERFORMED: Repeated measures logistic regression estimated odds ratios and 95% CIs for frailty onset. Logistic (exhaustion and weight loss) and linear regression (gait speed, grip strength, and physical activity) estimated the association between baseline dairy intake and each frailty component at follow-up, adjusting for baseline values for age, sex, energy intake (residual analysis), current smoking, and multivitamin use. Models were further adjusted for health status in a secondary analysis. RESULTS: Mean baseline age ± SD was 61 ± 9 years (range = 33 to 87 years), and 54% were women. Of 2,550 nonfrail individuals at baseline, 8.8% (2005-2008) and 13.5% (2011-2014) became frail. Higher yogurt intake was associated with decreased odds of frailty (odds ratio 0.96, 95% CI 0.93 to 0.99; P = 0.02). Each additional serving of yogurt (ß ± SE) .004 ± .001; P < 0.01) and low-fat dairy (ß ± SE) .001 ± .0006; P = 0.04) was associated with significantly faster follow-up gait speed. Dietary intakes of high-fat dairy were associated with increased odds of frailty (odds ratio 1.02, 95% CI 1.00 to 1.04; P = 0.05), but the P value was of borderline significance. No associations were observed for other dairy foods. After adjusting for health status, the associations of high-fat dairy and yogurt with frailty became nonsignificant, although the magnitudes of the associations did not change. The association between yogurt and gait speed decreased in magnitude after adjusting for health status (ß ± SE) .002 ± .001; P = 0.01). CONCLUSIONS: Dietary intakes of yogurt were modestly associated with reduced frailty onset and dietary intakes of high-fat dairy had a borderline association with increased odds of frailty, but other dairy food intakes showed no association in this study of healthy adults. Some dairy food intakes were modestly associated with follow-up gait speed. However, effect sizes were small, and the clinical importance of these associations remains undetermined.

Higher intake of dietary flavonols, specifically dietary quercetin, is associated with lower odds of frailty onset over 12 years of follow-up among adults in the Framingham Heart Study.

BACKGROUND: Polyphenolic antioxidants derived from plant foods may reduce oxidative stress and frailty, but the effect of the polyphenol subclass of dietary flavonoids and their subclasses on frailty is uncertain. OBJECTIVES: To determine the association between dietary flavonoids, their subclasses, quercetin (a specific flavonol), and frailty onset in adults. METHODS: This prospective cohort study included individuals from the Framingham Heart Study with no frailty at baseline. Intake of total flavonoids, subclasses of flavonoids (flavonols, flavan-3-ols, flavonones, flavones, anthocyanins, and polymeric flavonoids), and quercetin were estimated via semi-quantitative FFQ along with frailty (Fried phenotype), and covariates at baseline (1998-2001). Frailty was re-evaluated in 2011-2014. Logistic regression estimated OR and 95% CIs for each flavonoid variable and frailty onset. RESULTS: Mean age was 58.4 y (SD ± 8.3, n = 1701; 55.5% women). The mean total flavonoid intake was 309 mg/d (SD ± 266). After 12.4 (SD ± 0.8) y, 224 (13.2%) individuals developed frailty. Although total flavonoid intake was not statistically associated with frailty onset (adjusted OR: 1.00; 95% CI: 0.99-1.01), each 10 mg/d of higher flavonol intake was linked with 20% lower odds of frailty onset (OR: 0.80; 95% CI: 0.67-0.96). Other subclasses showed no association (P values range: 0.12-0.99), but every 10 mg/d of higher quercetin intake was associated with 35% lower odds of frailty onset (OR: 0.65; 95% CI: 0.48-0.88). CONCLUSIONS: Although no association was observed between total flavonoid intake and frailty onset in adults, a higher intake of flavonols was associated with lower odds of frailty onset, with a particularly strong association for quercetin. This hypothesis-generating study highlights the importance of assessing specific subclasses of flavonoids and the potential of dietary flavonols and quercetin as a strategy to prevent the development of frailty.

Adherence to the Mediterranean-style diet and high intake of total carotenoids reduces the odds of frailty over 11 years in older adults: Results from the Framingham Offspring Study.

BACKGROUND: The benefit of a Mediterranean-style diet in reducing frailty is not well established in older Americans. OBJECTIVES: We sought to determine associations of a Mediterranean-style dietary pattern and related antioxidants with frailty onset and worsening of the Fried phenotype in adults. METHODS: This prospective study included 2384 nonfrail adults from the Framingham Offspring Study with a Mediterranean-style dietary pattern score (MSDPS) and data on antioxidant intakes (vitamin C, E, and total carotenoids) estimated from an FFQ at the index examination (1998-2001) and 1 prior examination (if available), as well as a frailty assessment at the index examination and at least 1 follow-up. Frailty onset was defined as ≥3 of 5 Fried frailty phenotype criteria at follow-up and the worsening of the Fried frailty phenotype was defined as an increased number of frailty criteria over follow-up (yes or no). Logistic regression with generalized estimating equations estimated ORs and 95% CIs, adjusting for confounders. Analyses were stratified by age (<60 and ≥60 years) for significant interactions. RESULTS: The mean ± SD age was 60 ± 9 years (range, 33-86 years) and 55% were female. In adjusted models, a 1-unit higher MSDPS reduced the odds of frailty by 3% (OR, 0.97; 95% CI: 0.96-0.99). Each 10-mg higher total carotenoid and vitamin E intake reduced the odds of frailty by 16% (OR, 0.84; 95% CI: 0.73-0.98) and 1% (OR, 0.99; 95% CI: 0.98-1.00), respectively. No association with vitamin C (P = 0.36) was observed. The associations among participants aged <60 years of age were stronger for each 1-unit higher MSDPS (OR, 0.93; 95% CI: 0.89-0.96) and total carotenoid intake (OR, 0.59; 95% CI: 0.41-0.82) than those observed in older individuals [ORs, 0.98 (95% CI: 0.97-1.00) and 0.92 (95% CI: 0.79-1.08), respectively]. CONCLUSIONS: Our findings suggest that adherence to a Mediterranean-style diet and higher total carotenoid intake are associated with frailty prevention over time, particularly in adults <60 years.

A proinflammatory diet is associated with increased odds of frailty after 12-year follow-up in a cohort of adults.

BACKGROUND: Frailty occurs in 10-15% of community-living older adults and inflammation is a key determinant of frailty. Though diet is a modulator of inflammation, there are few prospective studies elucidating the role of diet-associated inflammation on frailty onset. OBJECTIVES: We sought to determine whether a proinflammatory diet was associated with increased odds of frailty in adults from the Framingham Heart Study (FHS). DESIGN AND METHODS: This study was nested in a prospective cohort that included individuals without frailty. Diet was assessed in 1998-2001 using a valid FFQ, and frailty was measured in 2011-2014. FFQ-derived energy-adjusted dietary inflammatory index (E-DII®) scores were computed, with higher E-DII scores indicating a more proinflammatory diet. Frailty was defined as fulfilling ≥3 of 5 Fried Phenotype criteria. Information on potential mediators, serum IL-6 and C-reactive protein was obtained in 1998-2001. Logistic regression estimated ORs and 95% CIs for E-DII (as continuous and in quartiles) and frailty onset adjusting for relevant confounders. RESULTS: Of 1701 individuals without frailty at baseline (mean ± SD age: 58 ± 8 y; range: 33-81 y; 55% female), 224 developed frailty (13% incidence) over ∼12 y. The mean ± SD E-DII score was -1.95 ± 2.20; range: -6.71 to +5.40. After adjusting for relevant confounders, a 1-unit higher E-DII score was associated with 16% increased odds of developing frailty (95% CI: 1.07, 1.25). In categorical analyses, participants in the highest (proinflammatory) compared with lowest quartile of E-DII had >2-fold increased odds of frailty (ORquartile4vs.1: 2.22; 95% CI: 1.37, 3.60; P-trend < 0.01). IL-6 and C-reactive protein were not major contributors in the pathway. CONCLUSIONS: In this cohort of middle-aged and older adults, a proinflammatory diet was associated with increased odds of frailty over ∼12 y of follow-up. Trials designed to increase consumption of anti-inflammatory foods for frailty prevention are warranted.

Dairy Food Intake Is Not Associated with Measures of Bone Microarchitecture in Men and Women: The Framingham Osteoporosis Study.

Previous studies reported that dairy foods are associated with higher areal bone mineral density (BMD) in older adults. However, data on bone strength and bone microarchitecture are lacking. We determined the association of dairy food intake (milk, yogurt, cheese, milk + yogurt, and milk + yogurt + cheese, servings/week) with high resolution peripheral quantitative computed tomography (HR-pQCT) measures of bone (failure load, cortical BMD, cortical thickness, trabecular BMD, and trabecular number). This cross-sectional study included participants with diet from a food frequency questionnaire (in 2005-2008 and/or 1998-2001) and measurements of cortical and trabecular BMD and microarchitecture at the distal tibia and radius (from HR-pQCT in 2012-2015). Sex-specific multivariable linear regression estimated the association of dairy food intake (energy adjusted) with each bone measure adjusting for covariates. Mean age was 64 (SD 8) years and total milk + yogurt + cheese intake was 10.0 (SD 6.6) and 10.6 (6.4) servings/week in men and women, respectively. No significant associations were observed for any of the dairy foods and bone microarchitecture measures except for cheese intake, which was inversely associated with cortical BMD at the radius (p = 0.001) and tibia (p = 0.002) in women alone. In this cohort of primarily healthy older men and women, dairy intake was not associated with bone microarchitecture. The findings related to cheese intake and bone microarchitecture in women warrant further investigation.

The Feasibility of Using Computrition Software for Nutrition Research-A Pilot Study.

We evaluated the feasibility of using Computrition to design and implement a low vs. typical sodium meal plan intervention for older adults. Dietitians used Computrition to design a 7-day meal plan with three caloric levels (≤1750, 2000, ≥2250 kcals/day) and two sodium densities (low = 0.9 mg/kcal; n = 11 or typical = 2 mg/kcal; n = 9). Feasibility was determined by post-hoc definitions of effectiveness, sodium compliance, palatability of diet, sustainability, and safety. Given the low number of participants in one of the three calorie groups, the higher calorie groups were combined. Thus, comparisons are between low vs. typical meal plans at two calorie levels (≤1750 or ≥2000 kcals/day). Overall, regardless of the calorie group, the meal plans created with Computrition were effective in reaching the targeted sodium density and were safe for participants. Furthermore, individuals appeared to be equally compliant and reported similar palatability across meal plans. However, one of the three criteria for the sustainability definition was not met. In conclusion, we successfully used Computrition to design low and typical sodium meal plans that were effective, compliable, and safe. Future studies of older adults in similar settings should focus on improving the palatability of the meal plans and scaling this protocol to larger studies in older adults.

The Effects of a Low Sodium Meal Plan on Blood Pressure in Older Adults: The SOTRUE Randomized Feasibility Trial.

Reduced sodium meal plans are recommended by the Centers of Disease Control to lower blood pressure in older adults; however, this strategy has not been tested in a clinical trial. The Satter House Trial of Reduced Sodium Meals (SOTRUE) was an individual-level, double-blind, randomized controlled pilot study of adults living in a congregate living facility subsidized by the Federal Department of Housing and Urban Development (HUD). Adults over age 60 years ate 3 isocaloric meals with two snacks daily for 14 days. The meal plans differed in sodium density (<0.95 vs. >2 mg/kcal), but were equivalent in potassium and macronutrients. Seated systolic BP (SBP) was the primary outcome, while urine sodium-creatinine ratio was used to measure compliance. Twenty participants were randomized (95% women; 95% white; mean age 78 ± 8 years), beginning in 7 October 2019. Retention was 100% with the last participant ending 4 November 2019. Mean baseline SBP changed from 121 to 116 mmHg with the typical sodium diet (-5 mmHg; 95% CI: -18, 8) and from 123 to 112 mmHg with the low sodium diet (-11 mmHg; 95% CI: -15.2, -7.7). Compared to the typical sodium meal plan, the low sodium meal plan lowered SBP by 4.8 mmHg (95% CI: -14.4, 4.9; p = 0.31) and urine sodium-creatinine ratio by 36% (-36.0; 95% CI: -60.3, 3.4; p = 0.07), both non-significant. SOTRUE demonstrates the feasibility of sodium reduction in federally mandated meal plans. A longer and larger study is needed to establish the efficacy and safety of low sodium meals in older adults.

Dietary Sodium Intake and Sodium Density in the United States: Estimates From NHANES 2005-2006 and 2015-2016.

BACKGROUND: In the United States, current guidelines recommend a total sodium intake <2,300 mg/day, a guideline which does not consider kilocalorie intake. However, kilocalorie intake varies substantially by age and sex. We hypothesized that compared with sodium density, total sodium intake overestimates adherence to sodium recommendations, especially in adults consuming fewer kilocalories. METHODS: In the National Health and Nutrition Examination Survey (NHANES), we estimated the prevalence of adherence to sodium intake recommendations (<2,300 mg/day) and corresponding sodium density intake (<1.1 mg/kcal = 2,300 mg at 2,100 kcal) by sex, age, race/ethnicity, and kilocalorie level. Adherence estimates were compared between the 2005-2006 (n = 5,060) and 2015-2016 (n = 5,266) survey periods. RESULTS: In 2005-2006, 23.1% (95% confidence interval [CI]: 21.5, 24.9) of the US population consumed <2,300 mg of sodium/day, but only 8.5% (CI: 7.6, 9.4) consumed <1.1 mg/kcal in sodium density. In 2015-2016, these figures were 20.9% (CI: 18.8, 23.2) and 5.1% (CI: 4.4, 6.0), respectively. In 2015-2016, compared with 2005-2006, adherence by sodium density decreased more substantially (odds ratio = 0.59; CI: 0.48, 0.72; P < 0.001) than adherence by total sodium consumption (odds ratio = 0.85; CI: 0.73, 0.98; P = 0.03). The difference in adherence between total sodium and sodium density goals was greater among those with lower kilocalorie intake, namely, older adults, women, and Hispanic adults. CONCLUSIONS: Adherence estimated by sodium density is substantially less than adherence estimated by total sodium intake, especially among persons with lower kilocalorie intake. Further efforts to achieve population-wide reduction in sodium density intake are urgently needed.

Cow's milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.

Milk sphingomyelin (SM), a polar lipid (PL) component of milk fat globule membranes, is protective against dyslipidemia. However, it is unclear whether ingestion of milk PLs protect against atherosclerosis. To determine this, male LDLr-/- mice (age 6 weeks) were fed ad libitum either a high-fat, added-cholesterol diet (CTL; 45% kcal from fat, 0.2% cholesterol by weight; n=15) or the same diet supplemented with 1% milk PL (1% MPL; n=15) or 2% milk PL (2% MPL; n=15) added by weight from butter serum. After 14 weeks on diets, mice fed 2% MPL had significantly lower serum cholesterol (-51%) compared to CTL (P<.01), with dose-dependent effects in lowering VLDL- and LDL-cholesterol. Mice fed 2% MPL displayed lower inflammatory markers in the serum, liver, adipose and aorta. Notably, milk PLs reduced atherosclerosis development in both the thoracic aorta and the aortic root, with 2% MPL-fed mice having significantly lower neutral lipid plaque size by 59% (P<.01) and 71% (P<.02) compared to CTL, respectively. Additionally, the 2% MPL-fed mice had greater relative abundance of Bacteroidetes, Actinobacteria and Bifidobacterium, and lower Firmicutes in cecal feces compared to CTL. Milk PL feeding resulted in significantly different microbial communities as demonstrated by altered beta diversity indices. In summary, 2% MPL strongly reduced atherogenic lipoprotein cholesterol, modulated gut microbiota, lowered inflammation and attenuated atherosclerosis development. Thus, milk PL content may be important to consider when choosing dairy products as foods for cardiovascular disease prevention.

Dietary Egg Sphingomyelin Prevents Aortic Root Plaque Accumulation in Apolipoprotein-E Knockout Mice.

Western-style diets have been linked with dyslipidemia and inflammation, two well-known risk factors associated with cardiovascular disease (CVD). Dietary sphingomyelin (SM) has been reported to modulate gut microbiota, and lower serum lipids and inflammation in mice on Western-style diets. However, few studies have examined if nutritionally-relevant intake of dietary SM can impact atherosclerosis progression. Thus, the aim of this study was to determine if incorporating 0.1% (w/w) egg SM (ESM) (equivalent to ~750 mg/day in humans) into a high-fat (45% kcal), cholesterol-enriched diet (HFD) could prevent atheroprogression in apoE-/- mice (n = 15/group). We found that mice fed with the ESM-rich diet had significantly lower epididymal fat mass (-46%) and tended to have higher spleen weights (+15%). There were no significant differences in serum lipids between groups. However, ESM-fed mice had significantly lower alanine aminotransferase (ALT) activity. Additionally, ESM-fed mice displayed significantly less aortic root lipid accumulation (-31%) compared to controls. This improvement in atherosclerosis was paired with over a two-fold reduction in circulating serum amyloid A (SAA) in ESM-fed mice. Finally, there was also a modulation of the gut microbiota with ESM supplementation. ESM may have the potential to prevent atherosclerosis, however further research in the clinical setting is warranted.

Effects of Freeze-Dried Grape Powder on High-Density Lipoprotein Function in Adults with Metabolic Syndrome: A Randomized Controlled Pilot Study.

BACKGROUND: High-density lipoprotein (HDL) particles are protective against atherosclerosis. However, HDL function is impaired in metabolic syndrome (MetS) due to low-grade inflammation and dyslipidemia. Foods containing polyphenols, such as grapes, may prevent HDL dysfunction via antioxidant or anti-inflammatory effects. We evaluated the effects of grape powder ingestion on measures of HDL function in adults with MetS. METHODS: Twenty adults (age: 32-70 years; body mass index: 25.3-45.4 kg/m2) consumed either 60 grams/day of freeze-dried grape powder (GRAPE) or a placebo for 4 weeks, separated by a 3-week washout period, in a randomized, double-blind crossover study. The primary outcome was serum paraoxonase-1 (PON1) arylesterase activity, a measure of HDL antioxidant function. Secondary outcomes included PON1 lactonase activity, plasma lipids, metabolic markers, cholesterol efflux capacity, and other HDL functional markers. RESULTS: After 4 weeks, GRAPE did not alter the serum PON1 activity or other markers of HDL function compared with placebo. Measures of HDL function were positively correlated with each other and inversely with measures of insulin resistance and inflammation. GRAPE intake led to a significant reduction in fasting plasma triglycerides compared with placebo (P = 0.032). No other significant effects of GRAPE were observed for other plasma lipids, anthropometrics, or metabolic measures. CONCLUSIONS: Grape powder consumption did not impact HDL function in this cohort of adults with MetS. However, it was shown to improve fasting triglycerides, a risk factor for cardiovascular disease.

Long-Term Supplementation of Black Elderberries Promotes Hyperlipidemia, but Reduces Liver Inflammation and Improves HDL Function and Atherosclerotic Plaque Stability in Apolipoprotein E-Knockout Mice.

SCOPE: HDL particles are protective against atherosclerosis, but may become dysfunctional during inflammation and chronic disease progression. Anthocyanin-rich foods, such as the black elderberry, may improve HDL function and prevent disease development via antioxidant and/or anti-inflammatory effects. This study investigates the long-term consumption of black elderberry extract (BEE) on HDL function and atherosclerosis in apolipoprotein (apo) E-/- mice. METHODS AND RESULTS: ApoE-/- mice (n = 12/group) are fed a low-fat diet, supplemented with 0, 0.25%, or 1% (by weight) BEE (≈37.5-150 mg anthocyanins per kg body weight) for 24 weeks. Feeding 1% BEE increases total serum cholesterol (+31%) and non-HDL cholesterol (+32%) compared with the control diet. PON1 arylesterase (+32%) and lactonase (+45%) activities also increase with the 1% BEE diet. Both 0.25% BEE and 1% BEE diets strongly increase HDL cholesterol efflux capacity (CEC) by 64% and 85%, respectively. Further, BEE dose-dependently lowers serum liver enzymes and hepatic inflammatory gene expression. Although there is no change in neutral lipid accumulation in atherosclerotic lesions, BEE promotes connective tissue deposition in the aortic root. CONCLUSIONS: Chronic BEE supplementation in apoE-/- mice dose-dependently improves HDL function. Despite BEE promoting hyperlipidemia, which likely offsets HDL effects, BEE increases connective tissue content, suggesting improved atherosclerotic plaque stability.

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL Function.

Strong experimental evidence confirms that HDL directly alleviates atherosclerosis. HDL particles display diverse atheroprotective functions in reverse cholesterol transport (RCT), antioxidant, anti-inflammatory, and antiapoptotic processes. In certain inflammatory disease states, however, HDL particles may become dysfunctional and proatherogenic. Flavonoids show the potential to improve HDL function through their well-documented effects on cellular antioxidant status and inflammation. The aim of this review is to summarize the basic science and clinical research examining the effects of dietary flavonoids on RCT and HDL function. Based on preclinical studies that used cell culture and rodent models, it appears that many flavonoids (e.g., anthocyanidins, flavonols, and flavone subclasses) influence RCT and HDL function beyond simple HDL cholesterol concentration by regulating cellular cholesterol efflux from macrophages and hepatic paraoxonase 1 expression and activity. In clinical studies, dietary anthocyanin intake is associated with beneficial changes in serum biomarkers related to HDL function in a variety of human populations (e.g., in those who are hyperlipidemic, hypertensive, or diabetic), including increased HDL cholesterol concentration, as well as HDL antioxidant and cholesterol efflux capacities. However, clinical research on HDL functionality is lacking for some flavonoid subclasses (e.g., flavanols, flavones, flavanones, and isoflavones). Although there has been a tremendous effort to develop HDL-targeted drug therapies, more research is warranted on how the intake of foods or specific nutrients affects HDL function.

Dietary sphingomyelin attenuates hepatic steatosis and adipose tissue inflammation in high-fat-diet-induced obese mice.

Western-type diets can induce obesity and related conditions such as dyslipidemia, insulin resistance and hepatic steatosis. We evaluated the effects of milk sphingomyelin (SM) and egg SM on diet-induced obesity, the development of hepatic steatosis and adipose inflammation in C57BL/6J mice fed a high-fat, cholesterol-enriched diet for 10 weeks. Mice were fed a low-fat diet (10% kcal from fat) (n=10), a high-fat diet (60% kcal from fat) (HFD, n=14) or a high-fat diet modified to contain either 0.1% (w/w) milk SM (n=14) or 0.1% (w/w) egg SM (n=14). After 10 weeks, egg SM ameliorated weight gain, hypercholesterolemia and hyperglycemia induced by HFD. Both egg SM and milk SM attenuated hepatic steatosis development, with significantly lower hepatic triglycerides (TGs) and cholesterol relative to HFD. This reduction in hepatic steatosis was stronger with egg SM supplementation relative to milk SM. Reductions in hepatic TGs observed with dietary SM were associated with lower hepatic mRNA expression of PPARγ-related genes: Scd1 and Pparg2 in both SM groups, and Cd36 and Fabp4 with egg SM. Egg SM and, to a lesser extent, milk SM reduced inflammation and markers of macrophage infiltration in adipose tissue. Egg SM also reduced skeletal muscle TG content compared to HFD. Overall, the current study provides evidence of dietary SM improving metabolic complications associated with diet-induced obesity in mice. Further research is warranted to understand the differences in bioactivity observed between egg and milk SM.