Absorption, Metabolism and Excretion of Dietary Polyphenolic Bioactives in Humans

Study Overview
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Brief Summary
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The objectives of this study are to i) describe the absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic parameters of selected dietary (poly)phenols in humans; and ii) to compare the ADME and pharmacokinetic parameters of selected dietary (poly)phenols in humans.

Detailed Description
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Dietary (poly)phenols are a large group of bioactive food constituents that can be classified in flavonoids, stilbenes, lignans and phenolic acids. Flavonoids can be subclassified in different subgroups, including but not limited to flavanols (e.g. (-)-epicatechin, (+)-catechin, procyanidins, EGCG, EGC, etc) and flavones (apigenin and luteolin). Examples of flavanol-containing foods and beverages are apples, chocolate, tea, wine, berries, pomegranate and nuts. Examples of flavone-containing foods and beverages are parsley, celery, and chamomile. (Poly)phenolic bioactives are actively investigated for their putative beneficial health effects in humans. In this context, understanding the ADME of dietary (poly)phenols is recognized as a key step to gain insight into the nutritional and biomedical relevance of this group of compounds. Understanding the ADME of polyphenols may aid towards i) the identification of metabolites as potential nutritional biomarkers of (poly)phenol consumption, ii) the identification of potential active metabolites mediating the effects observed after (poly)phenol intake, and iii) the design and execution of dietary intervention studies aiming at assess safety and efficacy of (poly)phenols. Over the last years, significant progress has been made on the description of the ADME of certain (poly)phenols. The investigators recently described the ADME of (-)-epicatechin. However, there is still need to understand the ADME of other polyphenolic bioactives as well as the importance of the role of the gut microbiome in the metabolism of these compounds. In this context, the investigators aim at describing and comparing the ADME of dietary polyphenolic bioactives in humans. To accomplish this, the investigators propose conducting a randomized, double-masked and cross-over dietary intervention study in healthy young adult males. The investigators will evaluate the concentration of polyphenol-derived metabolites in plasma and urine after single acute intakes of polyphenol-containing test materials on 8 different test days.

Official Title
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Absorption, Metabolism and Excretion of Dietary Polyphenolic Bioactives in Humans

Conditions
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Healthy

Intervention / Treatment
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* Other: Thearubigins
* Other: Theaflavins
* Other: Procyanidin Dimer B2 (DB2)
* Other: (-)-Epigallocatechin-3-O-gallate (EGCG)
* Other: (-)-Epicatechin-3-O-gallate (ECG)
* Other: (-)-Epicatechin (EC)
* Other: (-)-Epigallocatechin (EGC)
* Other: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 25-60 years old males No prescription medications BMI 18.5 - 34.9 kg/m2 Weight ≥ 110 pounds previously consumed cocoa, peanut, parsley, celery and chamomile products with no adverse reactions Exclusion Criteria: Adults unable to consent Females Prisoners Non-English speaking* BMI ≥ 35 kg/m2 Performing vigorous physical activity (i.e. more than 6 MET; metabolic equivalence of task as defined by CDC and ACSM guidelines (http://www.cdc.gov/physicalactivity/everyone/glossary/index.html#vig-intensity; and http://www.cdc.gov/nccdphp/dnpa/physical/pdf/PA_Intensity_table_2_1.pdf ) for more than 3 days a week. Dietary allergies including those to nuts, cocoa and chocolate products, parsley, celery and chamomile. Active avoidance of either coffee and caffeinated soft drinks Under current medical supervision A history of cardiovascular disease, stroke, renal, hepatic, or thyroid disease History of clinically significant depression, anxiety or other psychiatric condition History of Raynaud's disease History of difficult blood draws Indications of substance or alcohol abuse within the last 3 years Current use of herbal, plant or botanical supplements (multi-vitamin/mineral supplements are allowed) Blood Pressure > 140/90 mm Hg GI tract disorders, previous GI surgery (except appendectomy) Self-reported malabsorption (e.g. difficulty digesting or absorbing nutrients from food, potentially leading to bloating, cramping or gas) Diarrhea within the last 3 months, or antibiotic intake within the last 3 months Vegetarian, Vegan, food faddists, individuals using non-traditional diets, on a weight loss diet or individuals following diets with significant deviations from the average diet Metabolic panel and cholesterol results or complete blood counts that are outside of the normal reference range and are considered clinically relevant by the study physician Cold, flu, or upper respiratory condition at screening Currently participating in a clinical or dietary intervention study

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, double-masked and cross-over dietary intervention study in healthy young adult males
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Single oral intake of flavanol-free fruit-flavored non-dairy drink | Other: Control<br>* Single oral intake of a flavanol-free, fruit flavored, non-dairy drink.<br>|
| Experimental: Theaflavins<br>Single oral intake of a fruit-flavored non-dairy drink containing a mixture of theaflavins | Other: Theaflavins<br>* Single oral intake of 120 µmol of an equimolar mixture of theaflavins (isolated from black tea) in a flavanol-free, fruit flavored, non-dairy drink. The theaflavin mix includes theaflavin, theaflavin-3-gallate and theaflavin-3,3'-gallate<br>|
| Experimental: Procyanidin Dimer B2 (DB2)<br>Single oral intake of a fruit-flavored non-dairy drink containing Procyanidin Dimer B2 (DB2) | Other: Procyanidin Dimer B2 (DB2)<br>* Single oral intake of 120 µmol of Procyanidin Dimer B2 (DB2) (isolated from Theobroma cacao) in a flavanol-free, fruit flavored, non-dairy drink.<br>|
| Experimental: (-)-Epigallocatechin-3-O-gallate (EGCG)<br>Single oral intake of a fruit-flavored non-dairy drink containing (-)-Epigallocatechin-3-O-gallate (EGCG) | Other: (-)-Epigallocatechin-3-O-gallate (EGCG)<br>* Single oral intake of 120 µmol of (-)-Epigallocatechin-3-O-gallate (EGCG)(isolated from green tea) in a flavanol-free, fruit flavored, non-dairy drink.<br>|
| Experimental: (-)-Epicatechin-3-O-gallate (ECG)<br>Single oral intake of a fruit-flavored non-dairy drink containing (-)-Epicatechin-3-O-gallate (ECG) | Other: (-)-Epicatechin-3-O-gallate (ECG)<br>* Single oral intake of 120 µmol of (-)-Epicatechin-3-O-gallate (ECG) (isolated from green tea) in a flavanol-free, fruit flavored, non-dairy drink.<br>|
| Active Comparator: (-)-Epicatechin (EC)<br>Single oral intake of a fruit-flavored non-dairy drink containing (-)-Epicatechin (EC) | Other: (-)-Epicatechin (EC)<br>* Single oral intake of 120 µmol of (-)-Epicatechin (EC) (isolated from green tea) in a flavanol-free, fruit flavored, non-dairy drink.<br>|
| Experimental: (-)-Epigallocatechin (EGC)<br>Single oral intake of a fruit-flavored non-dairy drink containing (-)-Epigallocatechin (EGC) | Other: (-)-Epigallocatechin (EGC)<br>* Single oral intake of 120 µmol of (-)-Epigallocatechin (EGC) (isolated from green tea) in a flavanol-free, fruit flavored, non-dairy drink.<br>|
| Experimental: Thearubigins<br>Single oral intake of a fruit-flavored non-dairy drink containing thearubigins | Other: Thearubigins<br>* Single oral intake of 94.9 mg of therubigins (isolated from black tea) in a flavanol-free, fruit flavored, non-dairy drink<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the concentration of flavanol metabolites in urine. | Flavanol metabolites include gut microbiome derived metabolites include conjugates of 5-(3',4'-dihydroxyphenyl)-g-valerolactone metabolites and structurally related flavanol conjugated metabolites. | Urine collected 12h previous to intervention and up to 24 h after intervention | 
| Changes in the concentration of flavanol metabolites in plasma | Flavanol metabolites include gut microbiome-derived metabolites like 5-(3',4'-dihydroxyphenyl)-g-valerolactone and structurally related flavanol conjugated metabolites. | Plasma collected before (0h) and up to 6h post intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Flavanols, Cocoa Flavanols, Epicatechins, Polyphenols, Procyanidins, EGCG, EGC, ECG, Theaflavins, Thearubigins