Metabolic enzymes and pathways that confer the structural diversity of pomegranate phytochemicals also warrant further investigation. For example, the production of diverse HT monomers and polymers has been suggested to involve the activity of multiple laccase enzymes. However, the HT-forming laccases have not been cloned and characterized from pomegranate or any other plant species. Elucidation of the laccase family enzymes in pomegranate that bring about the great diversity of HT structures will have broad implications in dissecting the biological functions of HTs. In vitro assays and animal model studies have demonstrated various health benefits of urolithins, the ET derivatives. It is critical to obtain clinically relevant data on their efficacies prior to widespread applications in human disease interventions. Overall, exploration of the diversity and interactions of pomegranate phytochemicals, as well as preclinical and clinical investigations of their bioactivities, holds great promise of fully realizing the potential of this ancient fruit and modern functional food. Since a majority of the phytochemicals identified in pomegranate have also been found in other plants, examining the interactions and health-promoting functions of pomegranate phytochemicals will also have a far-reaching impact on exploiting the bio-active components of various edible medicinal plants and functional plant food. Cardiovascular diseases are the leading cause of death globally .
Major risk factors for developing CVDs include age, biological sex , high blood pressure, smoking,plastic planters dyslipidemia, and impaired fasting glucose among others . Because these risk factors cluster and interact multi-plicatively, the term cardiometabolic disease is often used to describe a grouping of disorders including hypertension, dyslipidemia, impaired glucose and insulin dynamics, and abdominal adiposity that together increase the risk for CVDs as well as type 2 diabetes . Acknowledging that diet quality plays a major role in cardiometabolic disease-free life expectancy , the American Heart Association published Strategic Impact Goals designed to improve cardiometabolic health and reduce related deaths through promotion of healthy behaviors including improvements in diet quality . Whereas exclusive adherence to a healthy diet is ideal for optimizing disease risk and reducing disability-adjusted life years, the potential impact of migrating dietary patterns toward inclusion of key foods containing bio-active compounds should not be underestimated. A large and constantly evolving body of research suggests that dietary bio-actives play a key role in human health maintenance as well as disease prevention and mitigation, particularly during the aging process. As such, the US NIH Office of Dietary Supplements has proposed the term bio-actives or bio-active food compounds for use in referring to constituents in foods or dietary supplements other than those needed to meet basic human nutritional needs yet responsible for changes in health status. Among the more commonly studied bio-actives is the family of secondary plant metabolites known as flavonoids. In recent years, the nutrition science community has provided evidence elucidating the effects of flavonoids on cardiometabolic health . Such research reports that the health-promoting properties of flavonoids are likely due to a synergistic combination of their antioxidant, anti-inflammatory, antimutagenic, and anticarcinogenic properties along with their modulating effects on cellular enzyme functionality .
Although there are many subclasses of flavonoids grouped according to chemical structure, flavan- 3-ols—abundantly present in tea, apples, pears, berries, and chocolate/cocoa products—are the most highly consumed flavonoid subclass according to data from the NHANES . As such, the objective of this Expert Panel was to review the available evidence assessing flavan-3-ol intake and cardiometabolic health for development of an intake guideline.The Academy of Nutrition and Dietetics , who were consulted to lead this project, led the process of Expert Panel recruitment. An independent Work Group Selection Subcommittee from the Council of Research led the selection process to ensure appropriate expertise and limit selection bias. An open recruitment message with a link to online application was circulated via stakeholders for experts in the topic area via the Academy and related scientific societies in the field of nutrition . Interested candidates provided conflict-of-interest forms, curriculum vitae, and personal statements indicating interest and qualifications related to the topic. Each candidate was evaluated based on a set of standard predetermined criteria , and candidates with the highest scores were selected for the Expert Panel, with the highest scoring candidate selected for the chair position. A total of 6 members were appointed to develop the guideline. The Expert Panel participated in all steps of the guideline development process, which included reviewing and evaluating the evidence, developing a recommendation statement based on the EtD framework, and writing a manuscript. The Expert Panel and members of the guideline development team met via web meetings for the duration of the project. In the interest of full disclosure, the Expert Panel was required to disclose potential conflicts of interest by completing the Academy of Nutrition and Dietetics Conflict of Interest Form. COIs were updated at the beginning of every meeting.The Expert Panel defined the scope of the guideline to focus on flavan-3-ol intake and risk of cardiometabolic disease in the general adult population. This recommendation is written from the perspective of individual decision-making rather than a public health perspective. As such, the target audience for this guideline was the general adult population including healthy individuals as well as those with overweight or obesity and those who are at risk of chronic disease.
The systematic review/meta-analysis informing this guideline development was based on the published manuscript by Raman et al. . This review systematically examined available evidence from both randomized controlled trials and prospective cohort studies in adults to evaluate the potential effects of flavan-3-ol intake on cardiometabolic health. Included studies should have quantified the amount of flavan-3-ol consumed per day or per week, and comparators included studies with low flavan-3-ol content,no flavan-3-ol intake, or placebo. The systematic review was conducted using GRADE methodology. From 1946 to March 2019, a systematic search of multiple databases was conducted , and studies were screened for inclusion or exclusion [Figure 1 in Raman et al. ]. A total of 157 randomized controlled trials and 15 cohort studies met the eligibility criteria. All included studies were critically appraised for risk of bias, with relevant data extracted from included studies. Descriptive synthesis of evidence was conducted for all identified outcomes, and when possible, meta-analysis was conducted. For continuous data, results were summarized as mean difference between treatment groups with 95% CI, and dichotomous outcomes were reported as ORs or RRs with 95% CIs. The published systematic review/meta-analysis by Raman et al. was reviewed in depth by the Expert Panel and vetted critically on the strength of systematic review methods employed, synthesis of evidence, and strength of evidence rating/quality or grading using the AMSTAR 2 tool .The Expert Panel and the guideline development team used GRADE’s EtD framework to help translate available evidence into a recommendation statement. The purpose of the EtD framework is to use evidence in a structured and transparent manner to help develop recommendation statements. Along with the EtD framework,plastic nursery plant pot the framework for developing recommended intakes of bio-active dietary substances by Yates et al. was also used to guide the development of this recommendation statement. The Expert Panel individually and blindly completed GRADE’s EtD framework, used evidence summaries on effects of flavan-3- ol intakes on health outcomes, reviewed benefits and harms, certainty of evidence, outcome importance, resource use and equity, patient values, and acceptability and feasibility of a recommendation to increase flavan-3-ol intake. The results of the EtD survey and implications of those judgments for the recommendation were reviewed by the Expert Panel members. Each Expert Panel member completed the EtD framework to provide a justification for having a recommendation for this topic. There was a consensus to write a recommendation based on the results of the EtD framework. Multiple web calls were conducted to identify core concepts/ideas that needed to be included, with the wording of the recommendation discussed at length. After much discussion and multiple rounds of editing to reach consensus, a recommendation statement was developed and accepted unanimously by the Expert Panel. The guidelines underwent an external peer review evaluation by recruited subject matter experts using the AGREE II tool . Comments from external reviewers were collated by the guideline development team and sent to the Expert Panel for discussion and editorial consideration. The Expert Panel Chair coordinated the final revision of the guideline document based on review comments.Among the general adult population, we suggest increasing consumption of nutrient-dense foods rich in flavan-3-ols and low in added sugars, including but not limited to tea, apples, berries, and cocoa. Based on moderate quality research, consumption of 400–600 mg/d flavan-3- ols can reduce risk associated with cardiovascular disease and diabetes. Increasing consumption of dietary flavan-3-ols may help improve blood pressure, cholesterol concentrations, and blood sugar.
A continually growing body of research demonstrates higher consumption may reduce the risk of certain cardiometabolic disease and related mortality. This is a food-based guideline and not a recommendation for flavan- 3-ol supplements because these may cause gastrointestinal irritation and/or liver injury, particularly when taken in excess or on an empty stomach.The Academy of Nutrition and Dietetics, National Academies of Science, Engineering, and Mathematics, and most experts agree that clinical practice guidelines should be based on high-quality systematic reviews of evidence . Our recommendation reflects careful consideration of the systematic review/meta-analysis by Raman et al. along with other scientific evidence reporting on flavan-3-ols and cardiometabolic health outcomes with much supporting data reported herein . Not only was the strength of evidence considered, but the Expert Panel also considered the magnitude of benefits and harms, costs, barriers and facilitators, resource and feasibility issues, and implementation factors. Strength of recommendation was assigned based on the Expert Panel’s evaluation of the totality of evidence, benefits and harms, consistency, clinical effect, and both generalizability and applicability. The influence of flavan-3-ols on cardiometabolic risk factors served as the basis for the recommendation statement, although again, strength of evidence was stronger for some biomarkers . Dose consistency among various meta-analyses including data from randomized clinical trials and observational studies supports the 400–600 mg/d recommendation for cardiometabolic health. The Expert Panel also considered the European Food Safety Authority Panel on Dietetic Products, Nutrition, and Allergies’ Scientific Opinions authorizing the health claim on consumption of cocoa flavanols and maintenance of normal endothelium-dependent vasodilation, and the specific proposed concentrations for proanthocyanidins and catechins by the Chinese Nutrition Society . Although the small effects exerted by flavan-3-ols on individual biomarkers might seem clinically insignificant in isolation, it has been noted that each 2-mmHg increase in systolic blood pressure increases mortality due to ischemic heart disease and stroke by 7% and 10%, respectively . As another example, a 0.026-mmol/L increase in HDL cholesterol concentrations has been reported to reduce CVD risk by 2–3% . Similarly, a 1% reduction in CVD risk has been reported with either a 1% reduction in LDL cholesterol or 1% increment in HDL cholesterol concentrations . Taken collectively, the cumulative improvements, albeit modest, in multiple biomarkers shown across the current scientific literature could have substantial benefits to overall risk reduction at both the individual and public health level. To better understand the protective effects of flavan-3- ols, it is important to first consider their bio-accessibility and bioavailability. Due to extensive metabolism by both human and microbial systems, metabolites are the main forms present in circulation and available for tissue uptake, metabolism, and biological activity . During absorption in the small intestine, flavan- 3-ols can be subjected to metabolic activities in enterocytes . Next, hepatic phase II conjugation with methyl, sulfate, and glucuronide conjugation alters their polarity, after which metabolites can be recycled back into the small intestine by biliary excretion . The human micro-biota is capable of efficiently metabolizing flavan-3-ols and their conjugated metabolites into smaller molecular weight compounds that are efficiently absorbed into the bloodstream and detected in human urine. A variety of flavan-3-ol metabolites have been detected in human plasma postingestion, which can be freely circulating or bound to proteins in the bloodstream. It has been suggested that after entering the bloodstream, flavan-3-ols interact with a series of complex molecular mechanisms that mediate CVD . Furthermore, direct interactions between flavan-3-ols and the gut micro-biome are likely to alter host immune and inflammatory status as well as micro-biome diversity. For example, the activity of absorbed parent compounds and of microbial metabolites appears to involve action on key cell receptors or crosstalk between cell signaling pathways, ultimately differentially affecting various cells and tissues, depending on the cell phenotype and metabolic environment .