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Home , Polyphenol, Secoisolariciresinol, Small molecule, Stilbenoid

Determination of the Total Dietary Load of a Population of Healthy Adults in

Appalachia, Ohio

A thesis for oral defense presented to

the faculty of

the College of Health Sciences and Professions of Ohio University

In partial fulfillment

of the requirements for the degree

Master of Science

Mary J. Connell

April 2021

© 2021 Mary J. Connell. All Rights Reserved. 2

This thesis titled

Determination of the Total Dietary Polyphenol Load of a Population of Healthy Adults in

Appalachia, Ohio

by

MARY J. CONNELL

has been approved for

the School of Applied Health Sciences and Wellness

and the College of Health Sciences and Professions by

Robert Brannan

Professor of Applied Health Sciences and Wellness

John McCarthy

Interim Dean, College of Health Sciences and Professions 3

Abstract

CONNELL, MARY, M.S., April 2021, Food and Sciences

Determination of the Total Dietary Polyphenol Load of a Population of Healthy Adults in

Appalachia, Ohio

Director of Research: Angela Hillman

Director of Thesis: Robert Brannan

Interest in dietary has dramatically increased in recent years. This is because these secondary plant metabolites have been shown to have anti-oxidant and pre- biotic qualities (Marchesi et al., 2016). A polyphenol is classified as a compound that contains an aromatic ring and hydroxyl group, and nearly all polyphenols have been implicated with positive health benefits such as disease prevention and treatment (Pandey

& Rizvi, 2009). This may be largely due to the impact of polyphenols on the gut microbiome. Certain strands of bacteria are thought to feed off these colorful compounds.

Researchers have suggested that individuals who frequently consume large amounts of polyphenols are more likely to have a diverse array of healthy bacteria present in their gut microbiomes. Many commonly consumed health products such as , berries, cocoa, and red wine are high in polyphenols. The current research in polyphenols has led to a rise in popularity of certain polyphenol food supplements. Tart cherry and powder have become particularly widespread dietary enhancers. Although these products have some potent potential health benefits, consuming polyphenols through natural food sources is thought to be a more effective way to consume a large and diverse quantity of these -like . However, literature that quantifies total dietary polyphenol 4 load of diets is limited. The goal of this project is to analyze 3-day diet logs to calculate the total polyphenol load of participants from the Athens, Ohio area. Logs will be analyzed to determine if there is a significant difference in total polyphenol load between participants supplementing with tart cherry juice, participants supplementing with tart cherry powder, and participants who are not supplementing with a tart cherry product.

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Dedication

Dedicated to the memory of my Grandpa Robarge, who was a great example of how to

use knowledge and wisdom to care for others.

And to my family, who have supported and encouraged me in my pursuits and made this

thesis possible.

6

Acknowledgments

I would like to thank everyone who has provided me with the resources and guidance to complete this project. Thank you to Dr. Angela Hillman, for providing me with insight and direction as I have worked through the research and writing process.

Thank you to Dr. Brannan, for directing me to this project and helping me navigate deadlines and formatting. Thank you to Dr. Deborah Murray for her support and suggestions as she served on my committee.

Thank you to the teachers, students, and members of the Food and Nutrition

Sciences community at Ohio University. I am so grateful to have had the opportunity to complete this program and learn from such exceptional and experienced people.

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Table of Contents

Page

Abstract ...... 3 Dedication ...... 5 Acknowledgments...... 6 List of Tables ...... 9 List of Figures ...... 10 Chapter 1: Introduction ...... 11 Background ...... 11 Statement of the Problem ...... 13 Research Questions ...... 13 Hypothesis...... 14 Purpose and Significance ...... 14 Delimitations ...... 15 Limitations ...... 15 Definitions...... 16 Abbreviations ...... 17 Chapter 2 ...... 18 Polyphenol Classification ...... 18 ...... 18 Non-flavonoids ...... 22 Factors that Influence Polyphenol Content of Foods ...... 23 Common Polyphenol Sources ...... 25 The Biology of Polyphenols ...... 28 Previous Research ...... 34 Chapter 3: Methodology ...... 39 Recruitment ...... 39 Supplementation Protocol ...... 39 Diet Tracking ...... 41 Analysis...... 41 Chapter 4: Results ...... 43 Chapter 5: Discussion ...... 46 8

Conclusion ...... 50 References ...... 51 Appendix A: Example Polyphenol Estimation ...... 84 Appendix B: List of Excluded Foods...... 86 Appendix C: List of Polyphenol Content of Foods from Literature ...... 87

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List of Tables

Page

Table 1 Studies on Polyphenol Intake of Various Populations...... 37 Table 2 Supplemental Nutrition Information ...... 40 Table 3 Descriptives of Groups ...... 44

10

List of Figures

Page

Figure 1 Polyphenol Structures and Examples ...... 11 Figure 2 Polyphenol Absorption and Metabolism ...... 33

11

Chapter 1: Introduction

Background

Polyphenols are a naturally occurring organic that contain at least one aromatic ring and attached hydroxyl group (Rasouli et al., 2017). Polyphenols are divided into categories based on how many aromatic rings they contain and how these rings are structurally connected. Examples are shown in Figure 1.

Figure 1

Polyphenol Structures and Examples

From “Plant Polyphenols as Dietary in Human Health and Disease,” by

K.B. Pandey & S.I. Rizvi, 2009, Oxidative and Cellular Longevity, 2(5), 270–

278. doi: 10.4161/oxim.2.5.9498. CC by 3.0.

12

These secondary metabolites are present in plants and consumption of these diverse compounds has been implicated in the prevention of various diseases (Durazzo et al., 2019). These qualities have attracted the attention of both laymen and researchers in recent years (Adebooye et al., 2018). The ubiquitous nature of these in plant-based foods makes this area of research vast and may explain why this field of study has only recently gained popularity in research and health sectors (Rasouli et al.,

2017). The dietary intake of polyphenols and the subsequent metabolism of the phytochemicals is an incredibly complex mechanism. The benefits of polyphenol consumption depend on the quantity and diversity of polyphenols consumed, as well as the of individual polyphenols (Manach et al., 2004).

The bioavailability of polyphenols is typically low and can vary widely

(D’Archivio et al., 2007). These compounds are eliminated from the body fairly quickly

(1-6 hours) (Hidalgo et al., 2012), and this may imply that frequent consumption of large quantities of polyphenols is necessary to reap their health benefits. This is one reason for the recent surge in popularity of polyphenol-rich products such as pills, tart cherry juice, and tart cherry powder. Tart cherry products in particular have become widely recognized for general health benefits (Kelley et al., 2018). However, studies that examine the effect of tart cherry supplements on the gut microbiota have shown mixed results (Lear et al., 2019; Mayta-Apaza et al., 2018). There is also evidence that the polyphenol content of tart cherry products may vary by supplement type to (Ou et al.,

2012). Previous studies have estimated the average polyphenol consumption of certain populations in Spain (Karam et al., 2018), Poland (Grosso et al., 2014), France (Jara 13

Pérez-Jiménez et al., 2011), Japan (Taguchi et al., 2015), the US (Burkholder-Cooley et al., 2016), and Brazil (Miranda et al., 2016a). The results of these studies vary widely, with the largest reported average polyphenol intake reported as 1756.5 ± 695.8 mg/day in the Polish study (Grosso et al., 2014) and the lowest average polyphenol intake reported as 332.7 mg/day in the Spanish study (Karam et al., 2018). The polyphenol load of a population is highly individualized and may be drastically changed by a single food or beverage item. It is unclear how a supplement such as tart cherry juice or powder may impact the overall dietary polyphenol load.

Statement of the Problem

Because polyphenol intake can vary widely between diets and there is limited research on the dietary polyphenol load of certain populations, the goal of this study is to determine the dietary polyphenol load of a group of a population from Athens, Ohio and determine how tart cherry supplementation impacts this load. It also is unclear how a supplement such as tart cherry juice or powder may impact the overall dietary polyphenol load.

Research Questions

1. What is the total dietary polyphenol consumption of this population based on 3-

day self-reported diet logs?

2. Is the total dietary polyphenol consumption significantly impacted by

supplementation with tart cherry, and is this relationship affected by age or

gender? 14

Hypothesis

1. The total dietary polyphenol load of each participant will be highly

individualized, and the average polyphenol consumption will have a large

standard deviation.

2. Participants receiving a tart cherry supplement will have an average total

polyphenol load that is greater than those of participants in the control group.

3. Gender will significantly impact total polyphenol dietary load, but age will not.

Purpose and Significance

The purpose of this study is to contribute to a growing body of literature on total dietary polyphenol intake of specific populations. To date, no previous studies have evaluated the total dietary polyphenol load of a population from Appalachia, Ohio. The second purpose of this study is to assess how tart cherry supplements impact the total dietary polyphenol load. Tart cherry products have become recognized for a wide variety of health benefits in recent years and, as a result, have gained commercial popularity

(Alba et al., 2019). Various tart cherry products have unique profiles, and, therefore, different products may affect the total polyphenol load in different ways (Ou et al., 2012). Although it is known generally that tart cherry products contain high levels of polyphenols, it is unclear if tart cherry products have the potential to serve as the primary or secondary source of polyphenols in the diet. Knowing how tart cherry products impact dietary polyphenol load may help consumers and researchers better understand the potency of these products. 15

Delimitations

The participants selected were 18-50 years old. They were not be pregnant or diabetic. They had no unresolved infections or diseases such as diabetes, cardiovascular disease, inflammatory diseases, or autoimmune diseases. They were non-smokers and were free from anti-inflammatory or corticosteroid use for at least 2 months. They had not taken in the last year. The subjects completed 3-day diet logs. Analysis of the diet logs excluded highly processed foods, animal-based foods, and foods that contained high amounts of refined sugar, as previous research indicated that these foods did not significantly contribute to the total polyphenol load of the diet (Karam et al.,

2018). The polyphenol content of certain foods was estimated in cases of limited data or conflicting resources. (For example, the polyphenol content of two tablespoons of guacamole was calculated using the polyphenol value for two tablespoons of avocado.) It was assumed that different cooking methods did not significantly impact the polyphenol content of foods. (For instance, kidney beans appeared in the database in their raw form.

The polyphenol content of raw beans was assumed to be equal to the polyphenol content of kidney beans that were boiled, canned, baked, etc.)

Limitations

The logs were self-reported and may be subject to error. The logs only accounted for 3 days of each participant’s diet and may not have given a complete picture of each individual’s normal diet. There may also have been some error associated with determining the polyphenol content of certain foods. The polyphenol databases did not include certain items and other literature was not available on these foods. There may 16 also have been some inaccuracy associated with the reported values of polyphenol content. The polyphenol content of certain foods varies with season, ripeness, and environment. There may have been some slight variation between databases (

Explorer and USDA Polyphenol database) and the Phenol Explorer data was used when those discrepancies occurred. There may also have been some variation between the polyphenol values of logged foods and the polyphenol values of foods in the database due to differences in cooking and processing.

Definitions

Antioxidants – Prevent oxidation/degradation of certain compounds; in the body they are usually are in the form of free radical scavengers

Food frequency questionnaire (FFQ) – A form designed to provide information about the micro and macronutrients consumed by the subject in the past 12-months

Gut microbiome – The community of microbes that populate the digestive tract

Inflammatory – Relating to the body’s immune response, which is often upregulated in the state of disease

Micronutrients- Elements or compounds present in small amounts in the diet which are necessary for various biological functions

Polyphenols - naturally occurring organic molecules that contain at least one aromatic ring and attached hydroxyl group; classes include flavonoids and non-flavonoids, phenolic acids, stilbenes, , , , , , flavanols ( and ), and

Polyphenol database – A collection of data on the polyphenol content of certain foods 17

Polyphenol load – The average total amount of polyphenols consumed by an individual in a given amount of time (usually reported in mg/day)

Prebiotic – Components of food that enhance the growth of the living organisms such as bacteria in the digestive tract

Phytochemicals – Nonessential nutrients that are present in plants and usually provide various health benefits

Abbreviations

USDA – United States Department of Agriculture

EGCG -

FFQ – Food Frequency Questionnaire

DHQ – Dietary History Questionnaire

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Chapter 2

Polyphenol Classification

Not only has polyphenol research expanded in recent years, but the extraction and production of commercial polyphenol-rich foods has also expanded. Polyphenols are an incredibly diverse set of micronutrients. These chemical compounds are generally split into the two major categories of flavonoids and non-flavonoids (Singla et al., 2019) which can be further classified as phenolic acids, stilbenes, lignans, flavones, isoflavones, flavanones, anthocyanidins, and flavanols (catechins and proanthocyanidins) (Manach et al., 2004). Some researchers also include chalcones as another subgroup of flavonoids

(Panche et al., 2016). Each type of is present in a vast array of plant compounds and performs numerous functions in the body. New polyphenols are constantly being characterized and each sub-class of polyphenol has its own diversity. Over 8000 phenolic structures have been characterized (Harborne & Williams, 2000). In fact, the USDA has developed an extensive database that contains only information on flavonoids, the most abundant polyphenols (Holden et al., 2005).

Flavonoids

The flavonoids present in plants dictate many of the plants’ characteristics such as color, odor, and hardiness (Samanta et al., 2011). The biological benefits of these compounds can be reaped by humans through the regular ingestion of plant compounds.

In humans, flavonoids can regulate the functions of numerous cellular enzymes and therefore modulate many metabolic processes (Panche et al., 2016). Flavonoids also act as free radical scavengers in the body (Rice-Evans et al., 1996). , flavanols, 19 flavones, flavanones, isoflavones anthocyanidins, and have each been studied for distinct health benefits.

Flavonols

The most studied flavonols are , , and fisetin which are present in red wine and and are thought to have cardiovascular benefits (Panche et al., 2016). Flavonols found in tea are the most powerful natural antioxidants (Vinson et al., 1995). Quercetin and kaempferol are two of the most common flavonoids found in edible plants (Adebamowo et al., 2005). It is thought that the most bioavailable form of quercetin is present in large quantities in (Dabeek & Marra, 2019). Kaempferol is present in many leafy green vegetables and seems to be absorbed more readily than quercetin (DuPont et al., 2004).

Flavanols

Flavanols such as epicatechin and are common to wine, tea, and chocolate (Schroeter et al., 2006). Tea is known for its anti-inflammatory qualities, and this property is likely due to the presence of high amounts of catechins in these leaves

(Ohishi et al., 2016). Of the four kinds of tea, white, green, Oolong, and black, is the most widely consumed and has been studied in the treatment and prevention of cancer, cardiovascular diseases, neurodegenerative diseases, and other inflammatory diseases (Reygaert, 2018). The high flavanol content of cocoa and cocoa products is likely the reason that chocolate products have been suggested to improved neuromodulation in patients at risk for cognitive decline (Socci et al., 2017). Cocoa is 20 especially high in (–)-epicatechin, a flavanol that has been shown to improve the flow of blood through blood vessels (Schroeter et al., 2006).

Flavones

Flavones are especially high in herbs like parsley and tea such as

(Hostetler et al., 2017). As with most polyphenols, chemical modification and absorption happens in the small intestine, colon, and liver, although some rapid absorption may occur in the stomach (Hostetler et al., 2017). is a flavone that has been widely studied for its potential in treating cancer, diabetes, and Alzheimer’s and has been considered a potential additive for pharmaceutical (Salehi et al., 2019).

The most common flavanones are , , , and isosakuranetin which are found in the sweet , tangelo, , grapefruit, and sour orange (Khan et al., 2014). Flavonones are a unique polyphenol in that they are found almost exclusively in citrus fruits, although some are present in and herbs (Manach et al., 2003).

Flavanones give citrus peel its bitter flavor and have free radical scavenging capabilities

(Panche et al., 2016). Citrus flavonoids have been most extensively studied for their anti- inflammatory, anticancer, and cardiovascular affects (Benavente-García & Castillo,

2008).

Isoflavones

Isoflavone content is especially high in and (Panche et al.,

2016). Some of the most common compounds in these legumes are and which chemically resemble and can have estrogenic or antiestrogenic effects (Křížová et al., 2019). Because of their ability to modulate estrogen 21 activity, isoflavones are thought to have the potential to have both positive and negative influence on endocrine . Both isoflavones and lignans are considered .

Anthocyanins

Anthocyanins are commonly found in dark reddish-purple plants like berries, , and plums (Manach et al., 2004). Anthocyanins are probably the second most visible form of plant pigmentation after (Kong et al., 2003). Their vibrant colors have made them a subject of interest in the food industry. Researchers are currently attempting to extract these colorful compounds and use them in place of artificial colorings (Santos-Buelga et al., 2014) There are many anthocyanins found in fruits and vegetables, but the most common anthocyanin is the -3-

(Khoo et al., 2017). This compound has been observed to have a wide range of health benefits, but the mechanisms behind these benefits can be difficult to elucidate. This is because anthocyanins often work in synergy with other compounds, they are easily subject to chemical degradation, their bioactivity depends highly on environmental stimuli, and their metabolism by humans includes a high degree of chemical modification which can make metabolites difficult to track and identify (Lila, 2004). Despite the low bioavailability of these colorful compounds, anthocyanins have still been associated with a decreased risk for cancer, cardiovascular disease, obesity, and neuronal degradation

(Khoo et al., 2017). 22

Non-flavonoids

Although less extensively studied than flavonoids, the non-flavonoids lignans, phenolic acids, and stilbenes also confer a range of health benefits when consumed regularly.

Lignans

Lignans can interfere with estrogen metabolism and -rich compounds have therefore been studied for their ability to treat breast cancer (Ezzat et al., 2018). and sesame seeds are especially high in lignans. The most common lignan occurring in food is diglucoside, which is metabolized in the gut to secoisolariciresinol and may have a favorable effect on some cardiovascular (Peterson et al.,

2010).

Phenolic Acids

Phenolic acids are present in nearly all plants. Caffeic, p-coumaric, vanillic, ferulic, and protocatechuic acids are ubiquitous to most plant compounds, while other phenolic acids are more specific to certain plants (Shahidi & Wanasundara, 1992). Leafy greens, berries, and dark stone fruits have all been cited as excellent sources of phenolic acids (Khanam et al., 2012; Mattila et al., 2006). Phenolic acids are categorized into two groups: hydroxybenzoic and hydroxycinnamic acids. These compounds have many of the anti-inflammatory and antioxidant properties of other polyphenols. Although, as with the other compounds, this class of substances offers a unique set of biological functions as well. is thought to increase the strength of the mucosal lining and protect against the development of ulcers (Asokkumar et al., 2014). has been studied 23 for its antioxidant properties and its ability to lower blood glucose levels and prevent diabetes (Jung et al., 2006).

Stilbenes

Plants synthesize stilbenes in order to fight infections (Pandey & Rizvi, 2009).

Resveratrol is probably the most extensively characterized stilbene and has been used in treatment of neurological disorders, cardiovascular diseases, and diabetes (Berman et al.,

2017). Although is most famously present in red wine, it is also present in foods like grapes, mulberries, and (Jang et al., 1997). Resveratrol is the main stilbene present in grapes, however, other stilbene types and resveratrol derivatives such as , pallidol, parthenocissin, and have been identified in grapes (Flamini et al., 2013). The type and quantity of stilbene compound present in grapes can depend heavily on the species of grape (Pawlus et al., 2013).

Factors that Influence Polyphenol Content of Foods

Cultivation factors

Many factors impact the quantity of polyphenols present in various foods. One study noted that variations in sunlight exposure, methods of cultivation, and fertilizers used, and other factors resulted in inconsistent polyphenol measurements across different studies (Faller & Fialho, 2009). For instance, one study found that the anthocyanin content of grapevine leaves varies depending on the geographical location in which they are grown in France (Martín-Tornero et al., 2020). 24

Cooking

Cooking method also impacts the polyphenol content of foods. The impact depends on the produce being prepared and the cooking method. Certain cooking methods, such as steaming, can actually increase the polyphenol content of foods

(Dolinsky et al., 2016). All processing methods can affect the polyphenol content of certain substances, although some have less impact on polyphenol content than others.

Studies have shown that frozen and juiced tart cherries have a comparable polyphenol profile to fresh ones (Ou et al., 2012). Certain processing methods may lead to better preservation of polyphenols. One study demonstrated that drying beans in an oven as opposed to in the open air leads to a significantly greater amount of phenolic acids and flavonoids in the final coffee product (Alkaltham et al., 2020). The impact of cooking on polyphenol content of a food seems to vary from compound to compound. One study found that freezing, thawing, and microwaving a soup high in kaempferol did not change the amount of compound present in the soup (DuPont et al., 2004).

Plant Constituents

It is important to note that different portions of plants may have different polyphenol profiles. The outer layer of grapes contains especially high concentrations of anthocyanins. Not only are there more anthocyanins present in the skin, these polyphenols seem to have greater bioactivity than the anthocyanins present in other portions of the fruit. The chemical acylation of these anthocyanins gives them especially powerful antioxidant properties (Tamura & Yamagami, 1994). This suggests that some of the benefits associated with eating whole fruits and vegetables may be due to 25 consumption of a greater level and variety of polyphenols. Some health benefits may be gleaned by eating portions of plants not commonly consumed. For example, the roots, leaves, and flowers of carrot plants contain large amounts of anthocyanins (Harborne et al., 1983). Flowers of all plants tend to be very high in polyphenols. The leaves of the custard have been shown to contain high amounts of the flavonoid quercetin

(Nguyen et al., 2020).

Common Polyphenol Sources

Coffee

Coffee is one of the most popular beverages worldwide, second only to water

(Butt & Sultan, 2011). Coffee beans, particularly green coffee beans, are high in (Pimpley et al., 2020). Chlorogenic acid is an of caffeic acid, a polyphenol that has antioxidant and antimicrobial activity and may decrease signs of cognitive impairment (de Armas-Ricard et al., 2019; Ochiai et al., 2019). Regular coffee consumption has been associated with improved glycemic control and metabolic markers

(Ranheim & Halvorsen, 2005; Roshan et al., 2018), and these benefits may be partially due to polyphenol content. It is interesting to note that many studies report coffee as the highest source of dietary polyphenols in certain populations (Burkholder-Cooley et al.,

2016; Grosso et al., 2014; Miranda et al., 2016a; Jara Pérez-Jiménez et al., 2011; Taguchi et al., 2015). Coffee consumption can drastically alter the total dietary intake of polyphenols. One study found that coffee drinkers tend may consume up to 800 mg/day of hydroxycinnamic acids, a type of , while non coffee drinkers may consume less than 25 mg/day of the hydroxycinnamic acids (Clifford, 2000). Another 26 study performed on a Finnish population found that over 63% of total dietary polyphenols came from coffee, an interesting observation that shows that some populations may get more polyphenols from coffee than from fruits, vegetables, and grains combined (Ovaskainen et al., 2008).

Tea

Tea is another beverage that is consumed regularly in many regions of the world.

Tea is reported to be a primary source of polyphenols in certain populations of Japan,

France, and Poland (Grosso et al., 2014; Jara Pérez-Jiménez et al., 2011; Taguchi et al.,

2015). Green, oolong, and black teas are high in catechins (Lee et al., 2014). The (−)- epigallocatechin gallate (EGCG) phenol is found in green tea and has been studied for its anticancer properties (Ma et al., 2014; Rawangkan et al., 2018). The catechins in tea have been especially well studied in the prevention of lung cancer, and regular consumption of tea may also reduce the risk for development of chronic obstructive lung disease (Oh et al., 2018). Indeed, the EGCG in tea seems to account for many of the perceived health benefits of tea. Tea may be considered somewhat of a panacea as it has been implicated in the prevention of neural diseases such as Parkinson’s, metabolic syndromes such as dyslipidemia, cardiovascular complications such as vascular degeneration, and inflammatory diseases such as Irritable Bowel Disease (Caruana & Vassallo, 2015; Oz et al., 2013; Pan et al., 2016; Stangl et al., 2006).

Herbs and Spices

Seasonings and spices tend to have the highest polyphenol content by weight

(Pérez-Jiménez et al., 2010). Many medicinal herbs are also high in phenolic compounds. 27

Ephedra, a plant traditionally used to treat cancer, shows high levels of gallic acid

(Jaradat et al., 2015). Leaves and herbs often contain a diverse array of polyphenols as well as large amounts of these compounds. For instance, Camptotheca acuminate, a

Chinese tree studied for its inti-tumor properties, contains 32 polyphenols as well as other metabolites (Pu et al., 2020).

Fruit

Fruits have a large quantity of polyphenols and they tend to be more biologically active than those in vegetables (Vinson et al., 2001). have the highest total of all fruits by fresh weight (Vinson et al., 2001). Polyphenols have many functions in plants. Studies show that they are often responsible for the vibrant colors of many types of produce. Cyanidin , for example, are known to give red, purple, and yellow pigmentation to many plants, including flowers and fruits like

(Saito et al., 1985). Bananas are also good sources of anthocyanins (Simmonds, 1954).

Alcoholic Beverages

Alcoholic beverages also tend to be high in polyphenols. Some researchers suggest that variations between nations in the consumption of red wine and tea has the single greatest impact on variations of average polyphenol intake between countries

(Pietta, 2000). Moderate wine consumption is thought to have a favorable impact on cardiovascular health. Red wine is known to contain several categories of flavonoids as well as non-flavonoid phenols such as resveratrol, cinnamates and gallic acid (Arranz et al., 2012). Research shows that many types of beer also contain large amounts of 28 catechins and other antioxidants (Vinson et al., 2003). Regular consumption of these compounds is associated with cardiovascular health.

The Biology of Polyphenols

Health Benefits and Disease Prevention

The health benefits of polyphenols have generally been attributed to their anti- inflammatory, antioxidant, antitumor, and antibacterial properties (de Armas-Ricard et al., 2019), but specific mechanisms of action of individual polyphenol classes are constantly being studied. Small polyphenols are some of the most promising areas of research for successful treatment of the coronavirus (Mani et al., 2020).

Polyphenols influence glucose metabolism and are believed to help prevent the development of type two diabetes (Rienks et al., 2018). An inverse relationship between hypertension and a high intake of , alkylphenols, lignans, and stilbenes has been observed (Miranda et al., 2016b). A high intake of polyphenols has also been associated with a decreased risk for colon cancer (Cueva et al., 2020). Researchers are currently studying the efficacy of a polyphenol-rich herbal that could be useful in the treatment of attention-deficit hyperactivity disorder (Verlaet et al., 2017). A polyphenol supplement extracted from grape pomace has shown promising affects as a natural way to improve biomarkers associated with cardiovascular disease (Annunziata et al., 2019).

Studies like these may be useful for the development of more targeted nutritional treatments. For instance, one study suggested that regular consumption of polyphenol- rich berries could lower blood pressure and have a favorable impact on high density lipoprotein levels (Erlund et al., 2008). This is because polyphenols may prevent 29 oxidation of low density lipoproteins (Vinson et al., 2001). Clearly polyphenol consumption is associated with extensive and diverse positive health outcomes. The widespread nature of these outcomes may be partially due to the interactions of polyphenols with the gut microbiota. Researchers are constantly uncovering how a healthy bacterial colonization of the gut is critical for many biological processes.

Polyphenol intake directly impacts the composition of bacteria present in the gut and can therefore be a powerful factor in supporting overall wellbeing.

The Gut Microbiome

The average human gut has 1013–1014 bacterial cells (Cani & Delzenne, 2009).

Firmicutes and Bacteroidetes are two phyla that make up 90% of the microbiota, and the gut microbiomes of individuals can be further characterized into one of three enterotypes,

Bacteroides, Prevotella, and Ruminococcus (Arumugam et al., 2011). Microbes function as enzymes that bind to polyphenols and play an important role in their metabolism

(Hervert-Hernández & Goñi, 2011). Conversely, certain polyphenols promote the growth of certain strains of bacteria (Ruggiero et al., 2007; Sourabh et al., 2014; Tzounis et al.,

2008; Yamakoshi et al., 2001). For instance, It is believed that anthocyanins increase the prevalence of Bifidobacterium spp. and Lactobacillus–Enterococcus spp. in the gut

(Hidalgo et al., 2012). Another study done on flavanols found that the (+)-Catechin monomer encouraged the growth of the Clostridium coccoides-Eubacterium rectale group, Bifidobacterium spp., and Escherichia coli in the intestine (Tzounis et al., 2008).

Some researchers suggest that polyphenol intake should be considered just as powerful a 30 force in the modulation of gut bacteria as prebiotic and probiotic intake (Marchesi et al.,

2016).

Microbiome Composition Variation

While the microbial composition of the gut is determined largely by the diet, although heredity and age are also critical factors (Wu et al., 2011). One study found that strict dietary changes can initiate changes in the gut microbiome in as few as 24 hours following dietary modification (although these changes were not observed at the enterotype level) (Wu et al., 2011). Because food plays such a key role in shaping the gut microbiota, the diversity of human cultures and diets results in a vast array of microbiome profiles. Children following a Western Style diet have pronounced variations in their microbiomes when compared to children following more whole-foods based diets

(Yatsunenko et al., 2012). However, the diversity of the human microbiome is so great that even identical twins each have incredibly distinct microbiota (Turnbaugh et al.,

2010). The differences in gut microbial composition between subjects are at least partially due to variation in intake.

Biological Functions of the Microbiome and Implications in Disease

The primary food source for bacteria in the gut is , including fiber

(Tuohy et al., 2012). Fermentation of these carbohydrates by bacteria leads to the production of short chain fatty acids, which serve as an energy source for various organs and play a role in cell development (Conterno et al., 2011). Studies on rats have shown that dietary supplementation with polyphenol-rich extracts can increase the production of short chain fatty acids in the colon (Aprikian et al., 2003; Zduńczyk et al., 2006). 31

However, production of metabolites is only one of many ways that residential bacteria impact host health. Researchers have come to realize the association between gut microbial imbalances and diseases. Dysregulation of the gut microbiome has been implicated in obesity, where obese subjects tend to exhibit a higher ratio of Firmicutes to

Bacteroidetes than non-obese individuals (Tseng & Wu, 2019). Certain butyrate- producing species of bacteria tend to be lower in individuals with type 2 diabetes (Tilg &

Moschen, 2014). Harmful gut microbes may produce toxic metabolites that contribute to cancer growth (Rajagopala et al., 2017). The gut microbiome impacts brain function via the enteric nervous system, vagus nerve, and immune system, which may explain why gut microbiome dysregulation is implicated in neurological disorders such as autism, anxiety, schizophrenia, and Alzheimer's disease (Cryan et al., 2019). The gut microbiome is a powerful factor in determining the health status of an individual. Because polyphenol ingestion represents one mechanism by which the gut microbiome can be modulated, these dietary compounds have the potential to serve as powerful nutritional therapeutics.

Polyphenols are being studied as potential prevention or treatment for a variety of diseases such as Alzheimer’s (Dhakal et al., 2019), diabetes and obesity (Jin et al., 2018), strokes and cardiovascular disease (Tressera-Rimbau et al., 2017), and cancer (Ko et al.,

2017).

32

Metabolism and Bioavailability

The of the polyphenol determines how it is chemically modified. The consequence of this fact is that certain types of polyphenols tend to be absorbed at certain locations along the digestive tract (Williamson & Clifford, 2017).

Most ingested polyphenols exist in foods as and are metabolized to aglycones and further modified by a host of intestinal microbiomes (Rowland et al., 2018). After passing through the stomach, polyphenols reach the small intestine. They may be chemically altered and shuttled directly to the liver, or they may pass through the small intestine intact and undergo chemical hydrolysis in the large intestine (D’Archivio et al.,

2010). The polyphenols that pass through the small intestine unabsorbed move into the colon and have a pre-biotic like effect on the gut microbiome that resides there (Dueñas et al., 2015). After passing through the intestine, polyphenols and their metabolites are usually processed by the liver, where they can be further modified and sometimes recycled back into the colon by hepatic circulation (Murota et al., 2018). This process is illustrated in Figure 2.

33

Figure 2

Polyphenol Absorption and Metabolism

From “Bioavailability of the Polyphenols: Status and Controversies” by M. D’Archivio, C. Filesi, R. Vari, B. Scazzocchio, & R. Masella, 2010, International Journal of Molecular Sciences, 11(4), 1321–1342. doi: 10.3390/ijms11041321. CC BY-NC-SA 3.0.

The bacteria in the gut perform enzymatic hydrolysis on polyphenols which can lead to both an increase or a decrease the biological activity of these molecules

(Possemiers et al., 2011). Certain metabolites often have a greater biological activity than their parent molecules (Trošt et al., 2018). The metabolites formed are usually aglycones.

Not only are these metabolites better absorbed than their parent molecules, they also tend to be more bioactive after this chemical process (Murota et al., 2018). For instance, aglycones from rutin and quercetin have been shown to reduce the formation of blood clots more effectively than the unmodified rutin and quercetin molecules (Kim et al.,

1998). Other factors that impact the bioactivity of a polyphenol are the individual structures of these molecules (Manach et al., 2009) and the variation of intestinal 34 microbiota from subject to subject (Possemiers et al., 2011). The food matrix may also impact polyphenol absorption and activity. and fiber may block polyphenol absorption, while fats and carbohydrates may increase polyphenol absorption (Bohn,

2014). Polyphenols are absorbed and eliminated fairly quickly, so frequent consumption may be another factor in increasing their biological activity (Hidalgo et al., 2012).

Previous Research

Polyphenol Estimation and Databases

The burgeoning research on polyphenols has led to a need for polyphenol quantification. Researchers have developed different ways to address this need. Some studies examine general dietary patterns associated with polyphenol intake (Pham et al.,

2019). Many studies use the Phenol-Explorer database (Castro-Barquero et al., 2020;

Wisnuwardani et al., 2020; Zamora-Ros et al., 2020). One meta-analysis estimated polyphenol intake based on reported ranges (Rienks et al., 2018). One study generated a database using Phenol-Explorer and USDA databases (Castro-Acosta et al., 2019).

Another study established an original polyphenol database in which total polyphenol contents were calculated as catechin equivalents (Taguchi et al., 2020). The present study will rely on the Phenol-Explorer database (version 3.6), which is generally recognized as the most comprehensive phenol database currently in existence (Rothwell et al., 2013).

This database includes data on polyphenols from over 600 peer reviewed journal articles that have been critically evaluated based on the samples, methodology, and precision of reported results (Neveu et al., 2010). The information in this database comes from articles that clearly define the food sample under study. Most of the articles consist of 35 studies that analyzed foods using some form of or spectrophotometric analysis. The polyphenol content of foods is reported in mg/100 g fresh weight or mg/100 ml. Several other studies have utilized this database and assumed that any food substances not listed contains only trace amounts of polyphenols (Castro-Barquero et al.,

2020; Tresserra-Rimbau et al., 2014). The USDA has developed a flavonoid database that contains values for 506 food items and 5 classes of dietary flavonoids (USDA

Department of Agriculture, n.d.) Some European databases contain information on polyphenol content (European Food Information Resource, n.d.), however polyphenol content may vary across databases due to differences in food production and geography.

Estimation Studies

The recent development of polyphenol databases has made population-wide studies on total dietary polyphenol intake a much more feasible project. However, evaluating the overall diet of any cohort of people presents certain difficulties and studies tend to be limited. Several studies have been performed on European populations (Grosso et al., 2014; Karam et al., 2018; Miranda et al., 2016a; Jara Pérez-Jiménez et al., 2011) as well as a few studies in Asia and North America (Burkholder-Cooley et al., 2016;

Taguchi et al., 2015). The results of these studies varied greatly, with the highest average polyphenol intake reported as 1756.5 mg/day and the lowest reported as 332 mg/day.

Table 1 lists characteristics and findings of these studies. One difficulty involved in these studies was the diversity of food eaten. Although the databases are designed to encompass a wide range of foods, many of the studies noted several food items such as tequila, honey, mineral oil, coconut milk, tapioca, cottonseed oil, and wheat gluten were 36 not available in the literature (Burkholder-Cooley et al., 2016; Miranda et al., 2016a; Jara

Pérez-Jiménez et al., 2011). The items were not included in the calculations, and researchers suspected that they did not significantly contribute to the dietary polyphenol load (Burkholder-Cooley et al., 2016).

37

Table 1

Studies on Polyphenol Intake of Various Populations

Study Average Largest Population Reference Population Polyphenol Dietary Size Intake Contributor(s) (mg/day) (% of Polyphenol Intake)

Poland 1756.5 ± 695.8 coffee (40), tea 10,477 (Grosso et al., (27), chocolate 2014) (8) Japan 1492 ± 665 coffee (43.2), 610 (Taguchi et tea (26.6), beer al., 2015) (2.9), red wine (2.2)

France 1193 ± 510 coffee (44), tea 4,942 (Jara Pérez- (9), red wine Jiménez et (6) al., 2011)

North America 801 ± 356 coffee (35), 74,668 (Burkholder- fruit (17), Cooley et al., (17) 2016) Brazil 377.5 ± 15.3 coffee (70.5), 1,103 (Miranda et citrus fruit al., 2016a) (4.6), tropical fruit (3.4) Spain 332.7 ± 237.9 red wine 211 (Karam et al., (17.7), 2018) artichokes (6.2), soy milk (5.4)

Most of these studies used the Phenol Explorer database to calculate the total polyphenol load of the population under study. However, the researchers in one study developed a 38 polyphenol database based on their own chemical analysis (Taguchi et al., 2015).

Interestingly, when researchers compared the average polyphenol load calculated with their database to the average polyphenol load calculated with Phenol Explorer, it was noted that the average according to Phenol Explorer was 531 mg less than the average according to the researcher’s database. Researchers suggested that the main source of this discrepancy was variation in the reported measurements of polyphenol content in coffee.

This illustrates how the dietary polyphenol load can be significantly impacted by the quality or presence of a single food item. This fact was also demonstrated in a study performed on a population of 7th day-Adventists (Burkholder-Cooley et al., 2016). The average polyphenol intake was 801 mg/day. However, for the non-coffee drinking subset of the population, the average was only 541 mg/day. For the coffee drinking portion of the population, the average was 1370 mg/day. That a single food items can so severely impact polyphenol load may account for the wide variation of average polyphenol intake between study populations. It should also be considered that individual populations tend to have distinct diets and dietary polyphenol load can vary drastically even among people groups that reside within close geographical proximity to one another. 39

Chapter 3: Methodology

Recruitment

Participants for this project were between 18 and 50 years of age, not pregnant, not diabetic, with no unresolved infections or diseases (diabetes, cardiovascular disease, inflammatory or autoimmune disease), and were nonsmokers. Participants were free from anti-inflammatory and corticosteroid use for at least 2 months and had not taken antibiotics within the last year. Participants were randomized into four groups: group that received tart cherry juice, group that received juice placebos, group that received tart cherry capsules, and group that received capsule placebos. Procedures were explained to participants during the first intervention, and the informed consent forms were distributed at that time. Participants underwent 30 days of supplementation. Diet logs were recorded between day 14 and day 30.

Supplementation Protocol

Juice Consumption

Participants were provided with 14, 240 ml (8 oz.) bottles (Berlin Packaging, IL) of juice per week for 4 weeks. Six refrigerated bottles were provided, while 8 were frozen. Participants were instructed to keep the juice refrigerated/frozen until consumption. Participants were instructed to drink two 8 oz. bottles per day, approximately 8 hours apart and not within an hour of exercise. Tart cherry juice was prepared by diluting concentrate (King Orchards, Traverse City, MI) 1:7 v/v with filtered water. The placebo was prepared by combining 48.3 g each of dextrose (Gordon Food

Service, Wyoming, MI) and fructose (Archer Daniels Midland Company, Chicago, IL), 40 food-grade red and blue (2.0 and 0.1 mL, respectively; McCormick & Company,

Inc.), lemon powder (0.8 g; True Citrus), powdered black cherry drink mix (4.0 g; Kraft

Foods Group, Inc., Chicago, IL), and filtered water to produce 1 L of carbohydrate- and calorie-matched placebo beverage.

Capsules

Placebo capsules contained 460 mg cornstarch while tart cherry capsules (King

Orchards, Traverse City, MI) contained 500 mg of freeze-dried tart cherries. Participants were provided with an undisclosed number of capsules and instructed to take two capsules with breakfast each day for a total serving size of approximately 1000 mg and to return unused capsules at their next visit. Table 2 displays the nutritional information for each of the supplements.

Table 2

Supplemental Nutrition Information

Total Energy Carbohydrate Fiber Polyphenol Protein (kcal) (g) (g) Content (g) (mg) Juice 77.37 18.32 0.00 0.00 1.39

Juice Placebo 67.33 16.99 0.00 0.00 N/A

Tart Cherry 1.65 0.35 0.118 0.352 30.4 Capsule Capsule 1.75 0.42 0.00 0.00 N/A Placebo

41

Diet Tracking

Logs and Questionnaire

The 12-month food frequency questionnaire (FFQ) was a Dietary History

Questionnaire (DHQ) III, taken from the National Cancer Institute. It asked subjects to monitor portion sizes and provided average daily micronutrients and macronutrients consumed. The 3-day diet log was distributed to participants between 14 and 30 day visits. The participants were asked to include food data from two weekdays and one weekend day. Individuals were asked to record the volume and type of food and beverage consumed. This data was put into the Food Prodigy software and transferred to the Food

Processor Nutrition Analysis software (ESHA Research). It was then converted to an excel file for analysis of polyphenol content. This was performed using the polyphenol database (J Pérez-Jiménez et al., 2010, p. 100) and the USDA flavonoid database.

Analysis

Polyphenol Content Estimation

The Phenol Explorer data was imported into an Excel format. The 3-day diet logs were also converted into Excel files. There were several foods not included in the database. Polyphenol contents of these items were found in the literature. For instance, , mushrooms, and tofu were not included in Phenol Explorer and had to be found in literature outside of the polyphenol database. (For a full list of foods found in outside literature, see appendix C. See appendix D for article references). To calculate the polyphenol content of a food item listed in a food log, it was first necessary to locate the food item in the Phenol Explorer Excel file. Foods were listed categorically by group and 42 sub-group. Each food in Phenol Explorer had a row which specified the total polyphenol content of that item in mg/100 mg or mg/100 mL. This number was input into the diet log next to the corresponding food. Each log gives a volume and weight measurement of the food listed. The polyphenol weight per 100 grams of food item was multiplied by the weight of the food item to calculate the polyphenol total of that food item. For food items that had multiple ingredients, recipes were used to estimate the percent for each ingredient of the total weight of the reported food. The individual weight of these ingredients was used to calculate polyphenol content. The polyphenol content of all food items in each log was summed. The result was the 3-day polyphenol load of the subject.

Statistical Analysis

The polyphenol load of the diet was calculated as a mean with standard deviations. Polyphenol intake was calculated for the entire study group as well as the separate groups (tart cherry juice versus placebo). Statistical analysis was performed using an analysis of covariance (ANCOVA) test to compare total polyphenol dietary load between groups that received supplement and groups that received placebo. The

ANCOVA also tested for interactions of supplement formulation (capsule vs juice), gender, and age.

A non-parametric one-way analysis of variance (Kruskal-Wallis) was used to compare means between the four supplemented groups. Independent t tests (Mann-

Whitney) were used to test for significant differences within the supplement formulation

(capsule vs juice) group, the gender group, and the age group. Subjects were divided into age groups of 18 to 25 and 26 to 52. A p value < 0.05 was considered significant. 43

Chapter 4: Results

A total of 50 participants were available for the final analysis. There were 24 subjects that received tart cherry supplements (11 = capsule, 13 = juice), and 26 subjects that received a placebo (13 = capsule, 13 = juice).

There were 142 food items analyzed with data from the polyphenol database or outside resources. There were 140 food items excluded from the analysis. Some commonly consumed products high in polyphenols were coffee, bananas, spinach, and butter. Coffee accounted for 20.1 % of total polyphenol intake, bananas accounted for 4.1% of the total polyphenol intake, spinach accounted for 2.3% of the total polyphenol intake, and peanut butter accounted for 1.0% of total polyphenol intake.

Mean and median polyphenol intakes for the total population were 4642 mg/day and 3931 mg/day, respectively. The descriptives of perspective groups are shown in

Table 3.

44

Table 3

Descriptives of Groups

Mean (mg/day) Standard Deviation Min-Max (mg/day) (mg/day) Cherry Supplement 5,964 4,192 842-18,061

Juice 6,789 5,280 842-18,061

Capsule 4,988 2,240 1,548-9,613

Placebo 3,423 2644 297-9,618

Juice 3,227 2,335 575-6,370

Capsule 3,619 3,004 297-9,618

Age

18-25 3,763 2,993 297-13,850

26-52 6,077 4,266 575-18,061

Gender

Male 5,342 4,367 575-18,061

Female 4,093 2,980 297-9,618

The ANCOVA test gave a p value < 0.05, indicating that there was a statistically significant difference between the mean of the group that supplemented with tart cherry and the mean of the group that had the placebo (F = 5.28, p = .03), however there was no impact of age (F = 3.67, p = .06) or gender (F = 1.24, p = .27) on polyphenol load. 45

The Kruskal-Wallis indicated that there was no difference between tart cherry juice and capsule (p = .14). T tests indicated that there was a significant difference between the polyphenol load of the group that received a placebo and the group that received cherry supplement (U = 193, p = .02). The polyphenol load was not significantly different between males and females (U = 262, p = 0.377); however, there was a significant difference between the means of age groups (U = 188, p = 0.033) (Table 3). 46

Chapter 5: Discussion

This is the first study to estimate the dietary polyphenol intake of a population from the Ohio area. The average reported polyphenol intake of this study (4642 mg/day) was higher than the reported values of the previous studies from Poland (1756.5 mg/d),

Japan (1492 mg/day), France (1193 mg/day), North America (801 mg/day), and Spain

(332.7 mg/day) (Burkholder-Cooley et al., 2016; Grosso et al., 2014; Karam et al., 2018;

Jara Pérez-Jiménez et al., 2011; Taguchi et al., 2015). A possible explanation could be that this Ohio population consumes high levels of coffee, and coffee accounted for a large portion of the polyphenol intake (20.1%). Coffee was a primary source of polyphenols in much of the previous research as well, as can be seen in Table 1, which summarizes the largest sources of dietary polyphenols among populations in the literature. While coffee has the potential to dramatically increase the total polyphenol load, it does not necessarily contribute significantly to the diversity of polyphenols consumed. The majority of polyphenols found in coffee are phenolic acids, while fruits and vegetables generally contain more flavonoids (Manach et al., 2004). Studies have shown that various polyphenols have unique biological functions, and, in order to reap the full benefits of a polyphenol-rich diet, a diverse array of polyphenols should be consumed (Amiot et al.,

2016). Furthermore, there is a wide range of bioavailability between polyphenol types, so the polyphenols that are consumed in the largest quantities are not necessarily those that are the most utilized by the body (Manach et al., 2005). It should also be noted that different studies have varying methodologies in assessing polyphenol content which may 47 result in differences in the reported polyphenol content of certain foods, including coffee.

Future studies would benefit from an expanded list of the polyphenol content of foods.

There was a significant difference between groups that supplemented with tart cherry products and the groups that supplemented with a placebo. Tart cherry supplementation may serve as an effective way to increase the total dietary polyphenol load in persons interested in gleaning the health benefits of these compounds. Tart cherries are an appropriate food choice for supplementation due to their unusually high level of anthocyanins. In the study of the French population, whole cherries accounted for

23% of the total anthocyanin intake of the population, and these drupes were second only to red wine, which accounted for 41% of total dietary anthocyanins (Pérez-Jiménez et al.,

2011). The anthocyanins found in cherries have a high antioxidant capacity (Blando et al., 2004), and subjects with high intakes of these polyphenols may be less likely to develop type 2 diabetes (Guo et al., 2016), coronary heart disease (Cassidy et al., 2016), and overgrowth of Clostridium histolyticum, a pathogenic bacterial species, in the gut

(Igwe et al., 2019). Tart cherry supplementation may be beneficial not only because it increases the level of polyphenols in the diet, but also because it provides flavonoids that may not be commonly found in other foods.

There was no effect of age or gender on total polyphenol load. However, the polyphenol load of older participants (ages 26-52) was significantly larger than the polyphenol load of younger participants (ages 18-25). Previous research has demonstrated that, with energy adjusted intakes, those who are older age (typically >65 years), tend to consume more polyphenols than younger individuals (Karam et al., 2018). 48

Other research has found that, for energy adjusted intakes, adult women tend to consume more polyphenols than adult men (Ziauddeen et al., 2019). However, the overall body of literature shows mixed results for the impact of age and gender on polyphenol intake, and researchers note that large differences in the food selections of populations may account for the variability between studies (Del Bo’ et al., 2019).

Individual diets differed greatly in this study, and there is potential that one diet may be impacted by tart cherry supplementation more than another diet. The polyphenol intake of individuals varied widely, with the lowest intake reported at 297 mg/day and the highest intake reported at 18061 mg/day. This is not surprising, as the types and quantities of food consumed by participants varied considerably. Several of the participants were non-coffee drinkers while others reported drinking up to 16 cups in the three-day period. Another difference between diet logs was the intake of plant or animal foods. Several participants consumed no animal products, while others ate at least one animal product with every meal. The diversity of foods eaten varied from subject to subject as well. Some individuals reported as few as 10 food items consumed, while others reported up to 47. Supplementation with polyphenol-rich substances may be beneficial for some, but the impact of supplementation will still depend on the genetics and diet of the individual.

This study was limited in its ability to account for the polyphenol content of all foods. Certain foods were not listed in the polyphenol database and could not be located in the literature. While some of these foods, such as meat, did not contain polyphenols, some products may have contained trace amounts of polyphenols. There is little research 49 available on the polyphenol content of highly processed plant foods (see appendix B).

There are also limitations associated with self-reported diet logs. Individuals may have recorded inaccurate quantities of food. Participants may also have eaten unusual foods during this period that did not reflect their average dietary intakes. There is also uncertainty associated with the reported polyphenol content of foods. The polyphenol content of foods can vary with growing method, environment, and processing method.

Although the database and literature provide reasonable estimates for the polyphenol content of food products, the exact polyphenol content of individual foods cannot be determined without direct measurement. 50

Conclusion

This study suggests that supplementation with tart cherry products can significantly increase the total polyphenol dietary load and may provide certain health benefits as a result. This study also provides insight into how dietary patterns such as food choice and supplementation can affect the polyphenol load of the diet. These elements should be further studied and evaluated as new research emerges which illustrates the biological functions and health benefits of polyphenols.

51

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Appendix A: Example Polyphenol Estimation

Each diet log is an Excel file. These files consist of columns that give information on when the participant ate certain foods and how much of this food was eaten. To calculate the polyphenol content of a serving of strawberries, for example, the polyphenol content of strawberries (per 100 grams) must be located and put into the selected column as shown below.

The polyphenol content of strawberries is located in the Phenol Explorer 3.6

Excel file. Foods are categorized by groups and sub-groups. Once the food is located in the Phenol Explorer database, the average polyphenol content per 100 grams of that food item can be seen in one of the columns to the right. The location and polyphenol content of strawberries in the database is shown below.

This average number should then be entered into the diet log as shown below.

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This average can be multiplied by the total weigh of the food to give the total amount of polyphenols in this serving of strawberries. A separate column will report this number as shown below.

The total polyphenol content of each serving of food can be calculated and reported in this last column. After the polyphenol content of each food in the log is calculated, the polyphenol total column can be summed for each log. This total will be divided by one hundred (to correct for the fact that the polyphenol content of foods is given in mg/100 g), and this number will represent the total polyphenol load of the diet log.

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Appendix B: List of Excluded Foods

Alfredo sauce Chocolate chip Homemade Pretzel dips with Almond milk waffles vegetable casserole chocolate Animal crackers Chocolate milk Ice cream (all Protein powder Apple butter Cinnamon breakfast flavors) Pumpkin seeds Bagels (any flavor) biscuit Quesadilla Banana bread Cinnamon cereal Italian dressing Ramen noodles Barbeque chips Clams Jams/Preserves Ranch dressing Bean sprouts Coconut Jerky Ravioli Bechamel sauce Coconut ice cream Kefir Reuben sandwich Beef (prepared any Coffee cake Kettle corn Rice paper wrapper way) Cookies Lasagna Scone Beef chalupa Corn chips Latte Sesame sauce (for Beef fritos Crab rangoon Lemonade chicken) Bottled tea Creamer Lemon bar Shrimp Breakfast biscuit Doughnut Lo mien Snack mix Breadstick Eggs dairy drink Snow pea Breath mints Egg noodles Maca Soda (all flavors) Brownie Egg rolls Machiatto Sour cream Buffalo sauce Fajitas Margerine Soy meats Butter Falafel Marshmallows Soy sauce Cake (all flavors) Fiber Marshmallow rice Sports drinks Candy (supplemental) treat Spring roll Candy bars (except Fish (all varieties) Mayo Sriracha sauce plain chocolate) Frappachino Microgreens Steak sauce Candy mint parfait Fruit punch Milk Syrups (flavored) Cheese (all Fungi meat Miso soup mix Tartar sauce varieties) substitute Multigrain/soy Teriyaki sauce Cheesecake Gin cereal Toaster pastries Cheese puffs Ginger-maple Nutritional yeast Toffee candy bar Cheese sauce Tonic Onion rings Vanilla protein bar Cheese tortellini Gluten-free Peanut butter cups Vegan cheese soup pancake mix Peanut butter Vegetable broth Chewing gum Gluten-free pasta protein bar Vegetable meat Chicken (prepared Gnocchi Peanut butter substitutes any way) Graham crackers sandwich crackers Vitamin water Chicken broth Granola bars Peanut oil Vodka Chocolate chip (commercial) Pepperoni Wheatberry cereal cookie Half and half Pizza Whey protein Chocolate chip Hazelnut chocolate Pork (prepared any Wonton soup muffin spread way) Yogurt Chocolate chip Heavy whipping chips Zucchini bread pancakes cream Potato roll Appendix C: List of Polyphenol Content of Foods from Literature

Balsamic vinegar = 321.7 mg/ 100 g (Liu et al., 2019) Barley (pearl) = 55 mg/100 g (Fujita et al., 2002) Black rice = 336 mg/100 g (Yu et al., 2020) Bread wheat bran = 920.852 mg/100 g (Žilić et al., 2012) Champagne = 18.5 mg/ 100 mL (Chamkha et al., 2003) Chia seeds = 116 mg/100 g (Oliveira-Alves et al., 2017) Chickpeas = 165.455 mg/100 g (Fratianni et al., 2014) Clementine = 55 mg/ 100 g (Costanzo et al., 2020) Coconut milk = 200 mg/ 100 mL (Nadeeshani et al., 2016) Coconut oil = 1.1 mg/100 g (Seneviratne & Dissanayake, 2008) Coffee (medium roast) =3600mg/100 g (Dybkowska et al., 2017) Corn (sweet) = 36.5 mg/100 g (Zhang et al., 2017) Couscous (wheat semolina) = 89.9 mg/100 g (Carcea et al., 2017) Dulse = 1.03 mg/100 g (Yuan et al., 2005) Edamame (from database, not total) = 71.58 mg/ 100 g Flaxseed meal (from database, not total) = 646.87 mg/ 100 g Garlic powder = 14.33 mg/100 g (Sangwan et al., 2010). Honey (manuka) = 43 mg/100 g (Moniruzzaman et al., 2013) Hemp seeds = 16.67 mg/100 g (Babiker et al., 2020) Kombucha = 41.225 mg/ 100 mL (Ivanišová et al., 2020) Maple syrup = 1.494 mg/100ml (St-Pierre et al., 2014) Mung bean = 325 mg/100 g (Tajoddin et al., 2014) Mustard seed = 2950 mg/100g (Ishtiaque et al., 2015) Mushrooms (crimini) = 989 mg/100 g (Dubost et al., 2007) Mushrooms (portabella) = 1065 mg/100g (Dubost et al., 2007) Mushrooms (white) = 800 mg/100 g (Dubost et al., 2007) Nori = 3000 mg/100 g (García-Casal et al., 2008) Onion powder = 169 mg/100 g (Manohar et al., 2017) Oven dried tomatoes = 458.06 mg/ 100 g (Tan et al., 2021) Peas = 84.9717 mg/100 g (Hegedusova et al., 2015) Popcorn = 593 mg/100 g (Coco & Vinson, 2019) Soy milk = 71.5 mg/100 g (Arques et al., 2016) Spring onion = 12.04 mg/ 100 g (not total) from database Stevia = 146.4 mg/100 g ( Kim et al., 2011) Sprouted wheat = 110 mg/100 g (Alvarez-Jubete et al., 2010) Sunflower seeds = 3350 mg/100g (Nadeem et al., 2011) Tea bag (black) = 65 mg /bag (assume 2 gram bag) (Nikniaz et al., 2016) Tempeh = 400 mg/100 g (about 4 days fermentation time) (Kuligowski et al., 2017) Tofu = 65 mg/100 g (Somdee et al., 2017) Wheat bulgar = 59.5 mg/100 g (Tacer Caba et al., 2012) White rice = 30.5 mg/100 g (Petroni et al., 2017) Wild rice = 141.81 mg/100 g (Yu et al., 2020)

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