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“All disease begins in the gut.” This famous line by Hippocrates perfectly captures the immense importance of the digestive system for overall health and vitality. The digestive tract is home to the gut microbiome, a highly complex collection of bacteria and other microbes that influence immunity, inflammation, metabolism, and more. An imbalanced microbiome, also known as dysbiosis, has been connected to a myriad of conditions such as cardiovascular disease, diabetes, obesity, depression, and autoimmunity.

As the incidence of these non-communicable diseases continues to increase, it is more important than ever to implement dietary strategies that foster the health and balance of the microbiome. Plenty of research has been conducted on the benefits of using probiotics and prebiotic fibers to positively affect gut ecology, but perhaps more attention should be paid to a remarkable group of compounds known as polyphenols.

Dietary polyphenols are a large group of natural plant compounds found in a variety of foods such as fruits, vegetables, tea, coffee, spices, chocolate, and wine. Polyphenols have been well-studied for their antioxidant and anti-inflammatory properties, which can impact many of the conditions listed above. However, polyphenols also exert beneficial effects through interactions with the gut microbiota.

Polyphenols are poorly absorbed and only a small portion is absorbed by the intestines. These compounds then reach the liver where they undergo phase I and phase II detoxification before being distributed throughout the body. Most polyphenols (90-95%) are instead metabolized by the microbiota in the colon. Polyphenols exert prebiotic effects, meaning they promote the growth of specific beneficial bacteria. They also support microbial balance by inhibiting pathogenic species. Once these polyphenols have been broken down into smaller metabolites by the microbiota, they can undergo further transformation in the liver.

Polyphenols are organized into a complex web of flavonoid and non-flavonoid groups. Flavonoids comprise a large proportion of the total polyphenols in the diet and can be further categorized into flavonols, flavanols, isoflavones, and anthocyanins, among others. Stilbenes are an example of a non-flavonoid group and include phytochemicals such as resveratrol and pterostilbene.

Polyphenolic compounds exert various effects on the microbiota, making it important to include an assortment of polyphenol-rich foods in the diet. Cocoa flavanols, for example, can support the growth of beneficial bacteria such as Lactobacillus and Bifidobacterium, and the flavonol quercetin exhibits antiviral properties.

While there are many different classes of polyphenols and functions to explore, let’s first dive into the benefits for intestinal barrier integrity before looking at a few specific polyphenolic compounds.

Polyphenols and Intestinal Barrier Integrity

The prebiotic effects of polyphenols can help to support the intestinal lining, which has important implications for inflammation and immunity.

A study of older adults living in a residential care facility demonstrated that a diet rich in polyphenols positively affected intestinal barrier integrity in part due to changes to the gut microbiome. Study participants, all of whom displayed increased intestinal permeability, consumed three servings of polyphenol-rich foods per day such as berries, pomegranate juice, green tea, and dark chocolate. After eight weeks, zonulin levels (a biomarker of intestinal permeability) decreased significantly, and there was a positive correlation between polyphenol intake and the presence of bacteria that produce short-chain fatty acids, which serve as signaling molecules as well as fuel for colonic cells. Pathogenic microbes, such as Methanobrevibacter, were significantly and negatively correlated with polyphenol intake.

A separate study of healthy subjects showed that four weeks of whole grape powder supplementation (the equivalent of two servings of grapes) significantly increased the alpha diversity of the microbiome while specifically improving levels of Akkermansia muciniphila. This species is highly beneficial as it stimulates the production of mucin, which serves as a protective layer for the gut lining. In fact, participants in this study experienced a 6.1% reduction in total cholesterol while LDL cholesterol decreased by 5.9%. For this reason, Akkermansia muciniphila has been studied for its modulatory effects on weight, insulin sensitivity, inflammation, and cardiovascular health.

Interestingly, intestinal permeability during exercise may aid in increasing the levels of polyphenols found in systemic circulation. A group of walkers and runners received flavonoid supplementation (flavanols, quercetin, and anthocyanins) for two weeks prior to exercise. Walkers performed at 60% of their VO₂ max, while runners were at 70% VO₂ max. After exercise, there was an elevation in gut-derived polyphenols. Researchers think this result could have been due to the acute permeability that occurs during intense exercise, and the increase in polyphenols may aid in attenuating inflammation. Exercise has also been shown to increase microbial diversity, which can impact levels of polyphenol metabolites.

Catechins & Epicatechins

Catechins and epicatechins are secondary plant metabolites belonging to the flavan-3-ol group of flavonoids. Green tea is a rich source of catechins, but catechins and epicatechins can also be found in black tea, red wine, cocoa, and fruit such as pomegranates, pears, and cherries.

An in vitro study showed that Akkermansia muciniphila can metabolize epigallocatechin-3-gallate (EGCG) in the presence of either mucin or glucose, but not in isolation. This result not only highlights the importance of maintaining a healthy gastrointestinal mucosal layer, but also of eating polyphenol-rich foods in their whole form. While many studies look at isolated phenolic compounds, consuming whole foods that contain carbohydrates and fiber may be synergistically beneficial for the microbiota.

EGCG’s specific modulatory effects on Akkermansia muciniphila may be beneficial for cardiometabolic health. Mice fed a Western diet experienced improvement in weight, triglycerides, and cholesterol levels as well as a 500% increase in Akkermansia muciniphila after being treated with EGCG. Genetic expression related to leptin (a satiety hormone) and the development of fat tissue were also altered.

Anthocyanins

Anthocyanins are known for providing pigments to richly-colored red, blue, and purple fruits and vegetables such as blueberries, strawberries, blackberries, raspberries, apples, and red cabbage.

Researchers in New Zealand sought to further understand the role that anthocyanins play in promoting microbial diversity. They looked at the polyphenolic composition of two different apples with red and white flesh. The white-fleshed apple had higher amounts of catechins and epicatechins, while the red-fleshed apple was rich in quercetins and cyanidins. The red-fleshed apple increased the abundance of Lactobacillus and Butyricicoccusand decreased Roseburia and Ruminococcus. This is an interesting finding since Roseburia produces butyrate, an important short-chain fatty acid. The two apples also upregulated the expression of 18 genes, 16 of which were related to immunity. This study serves as a good reminder to include many kinds of foods in the diet since varieties of the same fruit can contain different phytochemicals.

Anthocyanins have been studied for their effects on metabolic health by way of the microbiome. Mice treated with anthocyanins and proanthocyanidins exhibited improved insulin sensitivity. The mice were fed a high fat, high sucrose (HFHS) diet, and those that also received proanthocyanidin supplementation experienced less weight gain and adipose tissue accumulation compared to those only on the HFHS diet. Germ-free mice that received a fecal microbiota transplant from the HFHS mice experienced consistent metabolic changes with the first group, suggesting that the microbiota was responsible for the polyphenolic effects.

Dietary analyses of adults in northern Germany demonstrated that higher intakes of anthocyanins were associated with lower levels of visceral adipose tissue, which is the fat that accumulates around organs. A higher intake of anthocyanins also correlated with greater microbial diversity and abundance. There were significant associations between lower visceral adipose tissue and specific bacterial genera such as Roseburia.

Finally, a small group of overweight and obese adults were given a mixture of inulin, beta-glucan, and anthocyanins (the equivalent of two cups of blueberries). After four weeks, participants experienced improved glucose tolerance and satiety. Short-chain fatty acids, which increased in this study, stimulate satiety hormones such as peptide YY.

Resveratrol

Resveratrol is a stilbene compound that is found in grapes, wine, peanuts, cocoa, and berries. Some of the health benefits of the Mediterranean diet may be attributed to the resveratrol found in red wine.

Trimethylamine N-oxide (TMAO) is a metabolite produced by gut bacteria that is thought to contribute to cardiovascular disease. After four weeks of resveratrol-rich grape extract supplementation, serum levels of TMAO were significantly lower in the treatment group as compared to placebo (63.6% versus 0.54% respectively).

Intra-amniotic injections of resveratrol and pterostilbene in Cornish broiler hatchlings led to alterations in gut function, mineral levels, and inflammatory cytokines. The length and diameter of the intestinal microvilli were significantly increased. The microvilli are hairlike projections that play a direct role in nutrient absorption. Liver and serum iron and zinc levels, as well as calcium and magnesium metabolism markers, were greater in the treatment group, perhaps due to the strength of the microvilli. There was also a significant increase in the diameter of goblet cells, which are responsible for producing the mucus that protects the intestinal wall. Firmicutes levels were decreased, which is noteworthy since this bacterial phylum is typically associated with obesity.

A murine model of diabetic nephropathy demonstrated the ability of resveratrol to impact intestinal permeability and inflammation by decreasing proinflammatory cytokines such as IFN-γ and TNF-α. The abundance of Bacteroides, Odoribacter, Parabacteroides, and other genera were also positively influenced.

Anti-inflammatory cytokines increased while inflammatory biomarkers decreased in a separate murine model of colorectal cancer. Resveratrol treatment significantly increased beneficial bacteria that have been negatively correlated with tumor numbers, such as Ruminococcus gnavus and Akkermansia muciniphila.

Closing Thought

A diet rich in polyphenols can help support a healthy gut, which can have far-reaching effects. Here are a few ways you can incorporate polyphenols into the diet:

• Consume an array of brightly-colored plant foods in order to be exposed to a mixture of polyphenols. Try to purchase a variety of the same foods, such as different kinds and colors of apples and onions. Switch things up each time you go to the grocery store!
• Consider the synergistic effects of a polyphenol-rich diet along with regular exercise for gut health support.
• Eat foods that are rich in the colors blue, purple, and red. Top your morning oatmeal or yogurt with some dark-colored berries or switch out green cabbage for purple the next time you make coleslaw or soup.
• Brew a warm cup of green tea on a cold, winter morning or sprinkle matcha green tea powder into a berry smoothie.
• Enjoy a square of high-quality dark chocolate (aim for at least 70% cocoa content).

If you plan to incorporate more colorful, plant-based, and/or whole foods into your daily eating, or have food allergies or questions about which foods can best support your health, talk to your doctor, nutritionist, dietician, or another member of your healthcare team for personal options based on your individual circumstances. There are certain medications that may interact with plant-based foods.