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By Dennis Cladis

Polyphenols are present in virtually all fruits and vegetables and have been associated with many beneficial health effects.1 The Mediterranean Diet includes many polyphenol-rich foods including red wine (containing resveratrol), olive oil (containing oleuropein and hydroxytyrosol), and berry fruits (containing flavonoids). The defining feature of these molecules is the presence of at least one phenol group.2

Examples of polyphenols in foods commonly eaten as part of the Mediterranean Diet. All polyphenols have at least one phenol group (shown on the left) as part of their chemical structure.

Polyphenols are associated with many beneficial health effects. Recent studies show that diets high in polyphenols improve brain and heart health as well as digestion and even bone health.3,4 Right now, polyphenols are a “hot topic” for research, and our understanding of their influence on our health has grown exponentially over the last 25 years.

As we continue to learn about polyphenols, we are also learning how they can work in our bodies to cause health benefits. We now know that polyphenols are extensively metabolized in the gut and that this metabolism is what produces the beneficial forms of these molecules that are responsible for their health benefits. And, we’ve recently learned that most of this metabolism occurs in our colon, where the gut microbiome feeds on polyphenols to help generate these health-promoting metabolites.2

With all the health benefits attributed to polyphenols, many people are trying to get more polyphenols in their diets. This has led to increased use of plant-based herbal and botanical dietary supplements.5 These supplements often contain high amounts of polyphenols and allow people to increase their consumption of these compounds. However, there are many unknowns regarding dietary supplement usage, including their safety and metabolism.

Our lab recently conducted a series of studies using blueberries. Blueberries are one of the richest sources of polyphenols and provide a good model to test the effect of polyphenols at low and high amounts in the diet.

In one of our studies, we looked at extracted blueberry polyphenols as may be present in dietary supplements. We used a “dietary” dose that was equivalent to an adult consuming 1-2 cups of fresh, whole blueberries, and then used doses that were 5x and 20x higher than the dietary dose to represent higher doses of polyphenols that may be present in dietary supplements. We administered these different doses to rats just once to see how the different doses were metabolized after just a single exposure. Then, we monitored the metabolism of these polyphenols by collecting blood and urine over two days. We were surprised to learn that the metabolism of each of these different doses varied so much! Some metabolites were more prevalent in lower doses, while other metabolites were more prominent at the higher doses. Additionally, we noticed that some metabolites were seen within minutes, whereas other metabolites weren’t seen until 24 hours after dosing. What we learned is that the dose of polyphenols has a big impact on which metabolites are produced and that these metabolites are produced in all parts of small and large intestines.6

Metabolites produced after a single dose of blueberry polyphenols in rats. There was a shift in the metabolites formed at low, middle, and high doses.

Based on our results from just a single dose, we predicted that repeated dosing over three months would not only continue to change how polyphenols are metabolized but would also potentially be toxic at extremely high levels. To test this, we used the same doses and gave extracted blueberry polyphenols to rats once a day for three months. To compare the extracted polyphenols to what is present in whole blueberries, we added another group of rats that received whole blueberries. Throughout the study, we collected urine to monitor polyphenol metabolism. We also collected feces to see how these different doses affected the gut microbiome. Finally, we ran numerous tests to check for any abnormalities or toxicity that may have occurred.7,8

This study resulted in several key insights. First, even the highest dose of blueberry polyphenols was safe and showed no evidence of toxicity, meaning that consuming the equivalent of polyphenols in 30 cups of fresh blueberries each day is likely safe. Second, we saw the same patterns of metabolites as in the single dose study, and these patterns were consistent from the beginning to the end of the study. Interestingly, we noticed that the whole blueberries showed different patterns of metabolites than the extracts, which led us to conclude that there is something about the whole blueberry that causes it to be metabolized in a different way than the extracts. Finally, we saw that the lower doses benefited the gut microbiome, while the highest dose was actually worse for the gut microbiome. Taken together, these findings showed that while high doses of blueberry polyphenols are safe, higher doses are not necessarily better for us – they alter how our bodies process and metabolize these powerful health promoters.7,8 As the saying goes, “everything in moderation”.

Metabolites produced from beginning to end of intestines. The amounts of metabolites produced throughout the intestine differed based on the dose and whether it was a whole berry (top section) or an extract (low, middle, or high dose).

Polyphenols play an important role in promoting health as part of the Mediterranean Diet. Our work with blueberry polyphenols helps us better understand how these compounds interact with our bodies (and especially our gut microbiome). Moving forward, our work demonstrates the importance of getting the right amount of polyphenols in our diets. This is very important, especially as more people are using dietary supplements that may contain high doses of polyphenols. Blueberries and other polyphenol-rich foods are important parts of the Mediterranean Diet, though we need to consume them as part of a balanced diet to maximize their health benefits.

Dennis Cladis

Dennis Cladis, PhD, is currently a postdoctoral research associate in nutrition at the University of Minnesota. His research focuses on metabolites produced by the gut microbiome in Chronic Kidney Disease after different dietary intakes. Prior to coming to the University of Minnesota, he completed his MS and PhD at Purdue University. His earned his first MS in synthetic inorganic chemistry, studying redox active uranium complexes. He then earned a second MS in food science, studying fatty acids and mercury in fish. For his PhD, he studied blueberry polyphenol metabolism in a variety of models. He has published 15 papers in peer reviewed journals, 2 book chapters, and presented 25 first-author abstracts at national and international conferences. He can be reached by email at dcladis@umn.edu.


  1. Slavin & Lloyd. 2012, Adv. Nutr, 3(4): 506-516.
  2. Cladis et al. 2020, Nutr Today, 55(5): 234-243.
  3. Oyebode et al. 2014, J Epidemiol Community Health, 68(9): 856-862.
  4. Spencer. 2010, Br J Nutr, 104: 540-547.
  5. Council for Responsible Nutrition. 2017. https://www.crnusa.org/2017-annual-report
  6. Cladis et al. 2020, Molec Nutr Food Res, 64(12): 2000031.
  7. Cladis et al. 2020, Food Chem Toxicol, 139: 111254.
  8. Cladis et al. 2021, Food Funct, DOI: 10.1039/D0FO03457F


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