Precision Nutrition and Cardiovascular Disease Risk Reduction: the Promise of High-Density Lipoproteins.

PURPOSE OF REVIEW: Emerging evidence supports the promise of precision nutritional approaches for cardiovascular disease (CVD) prevention. Here, we discuss current findings from precision nutrition trials and studies reporting substantial inter-individual variability in responses to diets and dietary components relevant to CVD outcomes. We highlight examples where early precision nutrition research already points to actionable intervention targets tailored to an individual's biology and lifestyle. Finally, we make the case for high-density lipoproteins (HDL) as a compelling next generation target for precision nutrition aimed at CVD prevention. HDL possesses complex structural features including diverse protein components, lipids, size distribution, extensive glycosylation, and interacts with the gut microbiome, all of which influence HDL's anti-inflammatory, antioxidant, and cholesterol efflux properties. Elucidating the nuances of HDL structure and function at an individual level may unlock personalized dietary and lifestyle strategies to optimize HDL-mediated atheroprotection and reduce CVD risk. RECENT FINDINGS: Recent human studies have demonstrated that HDL particles are key players in the reduction of CVD risk. Our review highlights the role of HDL and the importance of personalized therapeutic approaches to improve their potential for reducing CVD risk. Factors such as diet, genetics, glycosylation, and gut microbiome interactions can modulate HDL structure and function at the individual level. We emphasize that fractionating HDL into size-based subclasses and measuring particle concentration are necessary to understand HDL biology and for developing the next generation of diagnostics and biomarkers. These discoveries underscore the need to move beyond a one-size-fits-all approach to HDL management. Precision nutrition strategies that account for personalized metabolic, genetic, and lifestyle data hold promise for optimizing HDL therapies and function to mitigate CVD risk more potently. While human studies show HDL play a key role in reducing CVD risk, recent findings indicate that factors such as diet, genetics, glycosylation, and gut microbes modulate HDL function at the individual level, underscoring the need for precision nutrition strategies that account for personalized variability to optimize HDL's potential for mitigating CVD risk.

A single 36-h water-only fast vastly remodels the plasma lipidome.

Background: Prolonged fasting, characterized by restricting caloric intake for 24 h or more, has garnered attention as a nutritional approach to improve lifespan and support healthy aging. Previous research from our group showed that a single bout of 36-h water-only fasting in humans resulted in a distinct metabolomic signature in plasma and increased levels of bioactive metabolites, which improved macrophage function and lifespan in C. elegans. Objective: This secondary outcome analysis aimed to investigate changes in the plasma lipidome associated with prolonged fasting and explore any potential links with markers of cardiometabolic health and aging. Method: We conducted a controlled pilot study with 20 male and female participants (mean age, 27.5 ± 4.4 years; mean BMI, 24.3 ± 3.1 kg/m2) in four metabolic states: (1) overnight fasted (baseline), (2) 2-h postprandial fed state (fed), (3) 36-h fasted state (fasted), and (4) 2-h postprandial refed state 12 h after the 36-h fast (refed). Plasma lipidomic profiles were analyzed using liquid chromatography and electrospray ionization mass spectrometry. Results: Several lipid classes, including lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylethanolamine, and triacylglycerol were significantly reduced in the 36-h fasted state, while free fatty acids, ceramides, and sphingomyelin were significantly increased compared to overnight fast and fed states (P < 0.05). After correction for multiple testing, 245 out of 832 lipid species were significantly altered in the fasted state compared to baseline (P < 0.05). Random forest models revealed that several lipid species, such as LPE(18:1), LPC(18:2), and FFA(20:1) were important features in discriminating the fasted state from both the overnight fasted and postprandial state. Conclusion: Our findings indicate that prolonged fasting vastly remodels the plasma lipidome and markedly alters the concentrations of several lipid species, which may be sensitive biomarkers of prolonged fasting. These changes in lipid metabolism during prolonged fasting have important implications for the management of cardiometabolic health and healthy aging, and warrant further exploration and validation in larger cohorts and different population groups.

Seasonal Factors Are Associated with Activities of Enzymes Involved in High-Density Lipoprotein Metabolism among Pregnant Females in Ghana.

Background: Small-quantity lipid-based nutrient supplements (SQ-LNS) during pregnancy and postnatally were previously shown to improve high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) and length in the children of supplemented mothers at 18 mo of age in the International Lipid-Based Nutrient Supplements (iLiNS) DYAD trial in Ghana. However, the effects of SQ-LNS on maternal HDL functionality during pregnancy are unknown. Objective: The goal of this cross-sectional, secondary outcome analysis was to compare HDL function in mothers supplemented with SQ-LNS vs. iron and folic acid (IFA) during gestation. Methods: HDL CEC and the activities of 3 HDL-associated enzymes were analyzed in archived plasma samples (N = 197) from a subsample of females at 36 weeks of gestation enrolled in the iLiNS-DYAD trial in Ghana. Correlations between HDL function and birth outcomes, inflammatory markers C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP), and the effects of season were explored to determine the influence of these factors on HDL function in this cohort of pregnant females. Results: There were no statistically significant differences in HDL CEC, plasma lecithin-cholesterol acyltransferase (LCAT) activity, cholesteryl ester transfer protein (CETP) activity, or phospholipid transfer protein (PLTP) activity between mothers supplemented with SQ-LNS compared with IFA control, and no statistically significant relationships between maternal HDL function and childbirth outcomes. LCAT activity was negatively correlated with plasma AGP (R = -0.19, P = 0.007) and CRP (R = -0.28, P < 0.001), CETP and LCAT activity were higher during the dry season compared to the wet season, and PLTP activity was higher in the wet season compared to the dry season. Conclusions: Mothers in Ghana supplemented with SQ-LNS compared with IFA during gestation did not have measurable differences in HDL functionality, and maternal HDL function was not associated with childbirth outcomes. However, seasonal factors and markers of inflammation were associated with HDL function, indicating that these factors had a stronger influence on HDL functionality than SQ-LNS supplementation during pregnancy. Clinical Trial Registry number: The study was registered as NCT00970866. https://clinicaltrials.gov/study/NCT00970866.

Multi-Omic Analyses Reveal Bifidogenic Effect and Metabolomic Shifts in Healthy Human Cohort Supplemented With a Prebiotic Dietary Fiber Blend.

Dietary fiber, a nutrient derived mainly from whole grains, vegetables, fruits, and legumes, is known to confer a number of health benefits, yet most Americans consume less than half of the daily recommended amount. Convenience and affordability are key factors determining the ability of individuals to incorporate fiber-rich foods into their diet, and many Americans struggle to access, afford, and prepare foods rich in fiber. The objective of this clinical study was to test the changes in microbial community composition, human metabolomics, and general health markers of a convenient, easy to use prebiotic supplement in generally healthy young participants consuming a diet low in fiber. Twenty healthy adults participated in this randomized, placebo-controlled, double-blind, crossover study which was registered at clinicaltrials.gov as NCT03785860. During the study participants consumed 12 g of a prebiotic fiber supplement and 12 g of placebo daily as a powder mixed with water as part of their habitual diet in randomized order for 4 weeks, with a 4-week washout between treatment arms. Fecal microbial DNA was extracted and sequenced by shallow shotgun sequencing on an Illumina NovaSeq. Plasma metabolites were detected using liquid chromatography-mass spectrometry with untargeted analysis. The phylum Actinobacteria, genus Bifidobacterium, and several Bifidobacterium species (B. bifidum, B. adolescentis, B. breve, B. catenulatum, and B. longum) significantly increased after prebiotic supplementation when compared to the placebo. The abundance of genes associated with the utilization of the prebiotic fiber ingredients (sacA, xfp, xpk) and the production of acetate (poxB, ackA) significantly changed with prebiotic supplementation. Additionally, the abundance of genes associated with the prebiotic utilization (xfp, xpk), acetate production (ackA), and choline to betaine oxidation (gbsB) were significantly correlated with changes in the abundance of the genus Bifidobacterium in the prebiotic group. Plasma concentrations of the bacterially produced metabolite indolepropionate significantly increased. The results of this study demonstrate that an easy to consume, low dose (12 g) of a prebiotic powder taken daily increases the abundance of beneficial bifidobacteria and the production of health-promoting bacteria-derived metabolites in healthy individuals with a habitual low-fiber diet. Clinical Trial Registration: www.clinicaltrials.gov/, identifier: NCT03785860.

Isolation of HDL by sequential flotation ultracentrifugation followed by size exclusion chromatography reveals size-based enrichment of HDL-associated proteins.

High-density lipoprotein (HDL) particles have multiple beneficial and cardioprotective roles, yet our understanding of their full structural and functional repertoire is limited due to challenges in separating HDL particles from contaminating plasma proteins and other lipid-carrying particles that overlap HDL in size and/or density. Here we describe a method for isolating HDL particles using a combination of sequential flotation density ultracentrifugation and fast protein liquid chromatography with a size exclusion column. Purity was visualized by polyacrylamide gel electrophoresis and verified by proteomics, while size and structural integrity were confirmed by transmission electron microscopy. This HDL isolation method can be used to isolate a high yield of purified HDL from a low starting plasma volume for functional analyses. This method also enables investigators to select their specific HDL fraction of interest: from the least inclusive but highest purity HDL fraction eluting in the middle of the HDL peak, to pooling all of the fractions to capture the breadth of HDL particles in the original plasma sample. We show that certain proteins such as lecithin cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), and clusterin (CLUS) are enriched in large HDL particles whereas proteins such as alpha-2HS-glycoprotein (A2HSG), alpha-1 antitrypsin (A1AT), and vitamin D binding protein (VDBP) are enriched or found exclusively in small HDL particles.

A Guide to Diet-Microbiome Study Design.

Intense recent interest in understanding how the human gut microbiome influences health has kindled a concomitant interest in linking dietary choices to microbiome variation. Diet is known to be a driver of microbiome variation, and yet the precise mechanisms by which certain dietary components modulate the microbiome, and by which the microbiome produces byproducts and secondary metabolites from dietary components, are not well-understood. Interestingly, despite the influence of diet on the gut microbiome, the majority of microbiome studies published to date contain little or no analysis of dietary intake. Although an increasing number of microbiome studies are now collecting some form of dietary data or even performing diet interventions, there are no clear standards in the microbiome field for how to collect diet data or how to design a diet-microbiome study. In this article, we review the current practices in diet-microbiome analysis and study design and make several recommendations for best practices to provoke broader discussion in the field. We recommend that microbiome studies include multiple consecutive microbiome samples per study timepoint or phase and multiple days of dietary history prior to each microbiome sample whenever feasible. We find evidence that direct effects of diet on the microbiome are likely to be observable within days, while the length of an intervention required for observing microbiome-mediated effects on the host phenotype or host biomarkers, depending on the outcome, may be much longer, on the order of weeks or months. Finally, recent studies demonstrating that diet-microbiome interactions are personalized suggest that diet-microbiome studies should either include longitudinal sampling within individuals to identify personalized responses, or should include an adequate number of participants spanning a range of microbiome types to identify generalized responses.