How can flavonoids improve gut health?

February 15th, 2023

Flavonoids are important polyphenols that can exert beneficial effects in the body. Due to their antioxidative properties and metabolism, they can improve gut health and change the gut microbiome. In this article, we will describe how flavonoids, and especially hesperidin and naringin, can change the gut microbiome composition, increase gut barrier function, enhance the immune system, and altogether improve gut health.

What are flavonoids?

Flavonoids are a group of phytonutrients (chemicals of plants) that are found in almost all fruits and vegetables. Flavonoids give color to fruits and vegetables, but are also found in cacao, coffee and tea. There are more than 6,000 types of flavonoids.

Since there are many types of flavonoids, they also have a wide range of beneficial effects, such as reducing chronic inflammation, and reducing risks associated with cancer and cardiovascular diseases (1, 2). Thus, implementing different flavonoids in your daily diet could be beneficial your health.

Flavonoids and gut health

Gut health and the gut microbiome have gained a lot of interest in the past years, since the gut microbiome and its metabolites are recognized as important regulators of host health.

The gut barrier is an important barrier because it acts as a physical defence against toxins and microorganisms. This barrier should remain intact to function properly.

Flavonoids may improve intestinal barrier function via inhibition of inflammatory proteins such as nuclear factor-kappa B (NF-κB), and via reduction of oxidative stress.

Flavonoids also contribute to the preservation of the intestinal tight junction barrier and structure, which is important for remaining the physical barrier for pathogens (3).

Flavonoids can stimulate short chain fatty acids to increase gut health

Additionally, it is found that flavonoids can increase faecal short chain fatty acids (SCFAs), which may be a result of increased SCFA production in the gut. SCFAs have different beneficial effects for the host and gut health. These benefits include serving as energetic fuel for intestinal epithelial cells, and improving intestinal barrier function (4, 5).

An important SCFA for gut health is butyrate. It can bind to G-protein coupled receptors. Upon binding, different anti-inflammatory signalling pathways can be promoted in macrophages and dendritic cells, which are important cells in the immune system of the colon (6).

Thus, flavonoids can increase gut barrier function and SCFA production, and potentially enhance the immune system via butyrate. Therefore, they are beneficial for gut health and it’s also shown in human studies that they can be used for inflammatory bowel diseases! (3)

Two flavonoids for gut health; What are hesperidin and naringin?

Hesperidin and naringin are flavanones , a subclass of flavonoids. These flavanones are mostly present in freshly prepared juices of citrus fruit, such as grapefruit, oranges and lemons. But it’s worth noting that hesperidin can be obtained in higher concentrations than naringin. Both compounds are even more abundant in the peels of these citrus fruits.

After oral consumption, hesperidin and naringin reach the colon almost completely intact, because they are difficult to degrade by the enzymes in the stomach and the small intestine.

This means the gut microbiota can digest them. They do this by releasing α-rhamnosidase, which converts hesperidin and naringin to hesperetin and naringenin. These metabolites are more bioavailable to the body, resulting in higher uptake by the gut into the blood, meaning they can be used by other tissues (7).

Hesperidin and naringin can feed specific bacteria, meaning they can influence the microbiome. It was shown that naringin could reduce microbial dysbiosis caused by high fat diet in mice. This means that harmful bacteria were reduced and there was an increase in beneficial bacteria (8). The same was shown for hesperidin in rats (9).

Hesperidin and naringin also play a role in immune system regulation. They can inhibit gut inflammation and oxidative stress by increasing antioxidant levels. By bringing gut inflammation down, the gut barrier stays intact as a physical defence against pathogens.

That hesperidin and naringin reduce gut inflammation was not only shown for them individually, but also when they were combined in mice.

Hesperidin and naringin: Hero flavonoids of MicrobiomeX®

Hesperidin and naringin are the focus of many clinical trials done by BioActor, as the product MicrobiomeX® is a natural extract from Citrus sinensis & paradisi, consisting of both flavonoids.

In vitro simulations of the human colon with the TIM-2 system showed that MicrobiomeX® could increase butyrate producing bacteria Roseburia spp. and acetate producing bacteria B. eggerthii (9). As mentioned before, butyrate is an important SCFA for gut health.

Besides in vitro studies, there have also been done clinical trials on the butyrate increasing properties of MicrobiomeX®. All clinical trials are available in the MicrobiomeX® White Paper.

It has also been found that by consumption of MicrobiomeX® calprotectin levels went down, which could indicate that MicrobiomeX® helps to bring gut inflammation down.

MicrobiomeX® combines the benefits of the flavonoids hesperidin and naringin and is therefore an ideal ingredient for gut health. Do you wish to read more about the studies described in this blog? Download our whitepaper on MicrobiomeX® below.

Short-chain fatty acids and their importance to gut health

December 14th, 2022

Short-chain fatty acids are saturated fatty acids that play an important role in gut health. They have several functions in human metabolism. Increasing the level of short-chain fatty acids in the gut might be a beneficial strategy to support overall health. Consumption of prebiotics and/or postbiotics can lead to higher levels of short-chain fatty acids.

What are short-chain fatty acids?

The gut microbiome is the community of microorganisms that can be found living in the gut. Evidence that bacteria in the gut are important to your health is growing each day. That’s why it is important to have a good balance of different bacteria in the gut. Not having a well-balanced microbiome is an indicator for several health issues, such as obesity (1).

The bacteria in the gut partially fulfill their role in health by making short-chain fatty acids (SCFAs). SCFAs are saturated fatty acids that contain six or fewer carbon molecules.

SCFAs are produced by the microbiota when they break down dietary fibers and resistant starches that are not metabolized by the body. To break these substrates down, the microbiota do not need oxygen, which is why this process is called anaerobic fermentation.

The most important SCFAs that are produced in the gut are acetate, propionate, and butyrate, and all of them have different effects on gut health (2).

Following the production of SCFAs by microbiota, they are taken up by the first layer of gut cells. They are used directly as fuel by these gut cells and if the colonocytes don’t metabolize them, they are used elsewhere, for example as an energy source for liver cells (3).

The benefits of short-chain fatty acids

Other than being fuel for different types of cells, SCFAs have a beneficial effect on your gut health.

Short-chain fatty acids maintain the intestinal barrier

One of the benefits of SCFAs is that they help maintain the intestinal barrier. The intestinal barrier is important because it forms a layer of cells that separates the inside of your body from everything that passes through your gastrointestinal tract.

The structural integrity of the gut wall is key, as pathogens (e.g., viruses, bacteria, and toxins) can enter the body if there are gaps between cells of the gut wall.

SCFAs help preserve the intestinal barrier by feeding the cells of the gut wall and by stimulating the dilation of blood vessels, resulting in more blood flow to these cells. This is positive as the cells will get more oxygen.

Short-chain fatty acids increase mucus production in the gut

SCFAs have also been shown to increase mucus production in the gut. Mucus is a slimy substance that forms a protective layer on your gut wall.

An increase in mucus production is beneficial since the protective layer between the intestinal cells and the contents of your gut will be thicker. The thicker the better, meaning that this improves the function of the mucus and decreases the risks of pathogenic infiltration (3).

Short-chain fatty acids reduce gut inflammation

Gut inflammation is often seen in older people or people with irritable bowel syndrome. SCFAs help bring this inflammation down by altering the DNA expression of gut cells.

The result of this alteration is a decrease in the release of chemokines, which are signaling proteins that are usually involved in white blood cell attraction. Reducing the recruitment of white blood cells is an anti-inflammatory action (4).

Short-chain fatty acids can induce satiety

Researchers have demonstrated that SCFAs are able to modify food intake by promoting satiety and the SCFA responsible for that is propionate, which is also produced by the gut bacteria.

Propionate is transferred to the liver where it can bind to specific receptors and this leads the liver to start making gut hormones that induce satiety and thus lower hunger (5).

In short, SCFAs are relevant for gut health, but for overall health as well, which means it is valuable to raise the level of SCFAs in the gut. One way to achieve a higher level of SCFAs is by consuming prebiotics and, less familiar to most people, postbiotics.

What are prebiotics?

Prebiotics are non-digestible food ingredients that have a health benefit to the host. There are different types of prebiotics, and they have several health benefits. These health benefits range from supporting your immune system to providing energy to microbiota that help maintain gut health.

Prebiotics are food compounds, such as fibers and starches, that are not digested by the human digestive system. This means that the prebiotics reach the gut and the microbiota while still intact. The microbiota can digest them, leading to the creation of substrates that can be useful for human health.

How can prebiotics lead to higher levels of short-chain fatty acids?

Prebiotics go through anaerobic fermentation, which results in SCFA production. This means that taking prebiotics can help increase SCFA levels in the gut. As we have mentioned above, there are several reasons why you would want this! 

There are several food products that contain high levels of prebiotic fibers, but it is also possible to increase prebiotic intake by taking supplements.

One example of a prebiotic fiber food is chicory root. It contains high amounts of prebiotic fiber inulin. Other good foods are arabinoxylan rich foods, such as wheat, corn, rice and oat. Arabinoxylans have a lot of health benefits and they have strong prebiotic properties.

The downside of prebiotics is that everyone has a different microbiome composition, which means that everyone also experiences different outcomes of prebiotic consumption.

For this reason, research has been done on alternatives. This led to an increase in interest in something that is more unknown than prebiotics, namely postbiotics.

Postbiotics are bacterial products, meaning that they aren’t fermented by the gut microbiota after consumption. An example of postbiotics are different short-chain fatty acids, as these are products of the microbiota.

Do you want to know more about postbiotics? Read this article.

How can MicrobiomeX® support SCFA levels?

MicrobiomeX® is an ingredient based on citrus flavonoids that can boost the immune system and improve gut defense. It has several ways to boost gut health and your immune system.

One way MicrobiomeX® helps is by promoting the growth of butyrate-producing strains of bacteria in the gut. Among these are the Faecalibacterium prausnitzii, Clostridium leptum and Roseburia. As mentioned before, butyrate is a SCFA that has several health benefits on the host.

Want to read more about MicrobiomeX®? Click here!

The benefits and challenges of synbiotic dietary supplements

November 8th, 2022

In the last years, synbiotic supplements have emerged as an interesting approach to improve gut health. Instead of using only pre- or probiotics, synbiotic products combine both. There are two types of synbiotics, namely complementary and synergistic synbiotics. Currently, most of the synbiotics on the market are complementary products since the formulation and research of synbiotics are quite challenging. In this article, we will explain synbiotic supplements in more detail, including the benefits and formulation challenges.

What are synbiotic dietary supplements?

The international scientific association for Probiotics and Prebiotics (ISAPP), defines synbiotics as: “a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host” (1).

There are two types of synbiotic products: complementary and synergistic synbiotics. Complementary synbiotics are the most found on the market. This type should contain pre- and probiotic compounds that clinically show a health benefit together, but also when used independently from each other. Hence, they do not have to interact with each other.

On the other hand, synergistic synbiotics do not necessarily contain pro- or prebiotic compounds. Instead, they should contain microorganisms and substrates that are selectively utilized by the provided bacteria in the product. In this case, the combination should have a greater beneficial effect than the microorganisms or substrates independently (2).

Curious to know about prebiotics? Find out more!

What are the benefits of synbiotic dietary supplements?

Pre- and probiotic products can have beneficial effects on gut health, immune function and the production of beneficial metabolites such as short-chain fatty acids. Synbiotic products could have the same health effects, and they potentially decrease cardiovascular risk factors, markers of insulin resistance and prevalence of metabolic syndrome as well (3).

Furthermore, synbiotic formulations must contain living bacterial strains and the substrates that can be used by these bacterial species specifically. In this way, the species have the chance to feed themselves, proliferate, and adhere to the intestinal wall of the host.

Another advantage of such synergistic dietary supplement formulations, is that they could address the “responder/non-responder” phenomenon (2).

The “responder/non-responder” phenomenon means that some subjects respond to a pre- or probiotic product, whereas others do not experience any beneficial effect. The difference could be caused by the fact that everyone has a unique microbial composition in the gut and therefore reacts differently to the treatments.

By providing the bacterial strains and their substrates simultaneously, the supplied bacteria will have an advantage compared to other bacterial strains that were already present in the gut, since they already have their selectively fermentable substrate to grow on. They could subsequently outcompete some resident microbial strains and establish a niche in the gut.

In other words, the substrate serves as a sort of fertilizer for the supplied bacterial strains and increases the chance that the bacterial strain will colonize and establish in the gut. In this way, it may be more likely that a subject will respond to the supplement or product and experience a beneficial effect!

The main challenges in formulating synbiotic dietary supplements

Although synergistic synbiotics have a lot of potential, formulating them comes with some challenges:

• Prebiotics or substrates often need to be consumed in larger amounts to have a beneficial effect, which may go along with gastro-intestinal complaints such as feeling bloated or flatulence. To limit these complaints, prebiotics may be added in lower doses, risking the loss of their beneficial health effects.

• Microorganisms are highly sensitive to the environment, which makes it difficult to store the synbiotic products under many circumstances.

• The water activity of the substrate: Water activity is a measure of water in a product that is available to react with or attach itself to other material, also known as ‘free’ water. Products with a higher water activity are more likely to be affected by bacteria and fungi. Therefore a substrate with a low water activity should be chosen (4).

Besides formulation challenges, researching the synergistic synbiotic effects comes with some difficulties.

The synbiotics that are now often used in studies have been formulated based on criteria such as shelf life, cost, and availability, rather than on metabolic, functional or other characteristics of the microorganisms or substrates.

In most studies, Lactobacilli and Bifidobacteria are included as the probiotic component and inulin, various oligosaccharides, or dietary fibres are chosen as prebiotic ingredient, yet only one human trial showed beneficial effects (5, 6).

To screen for new promising synbiotics, in vitro studies will first be performed because clinical trials are very expensive and time-consuming. In vitro models simulating the lower and upper gastrointestinal can be helpful, such as the TIM1 and TIM2 model. The TIM-2 model is a dynamic gastrointestinal model, which is used for in-vitro research.

These models can be used to assess the survival of a probiotic through the gastrointestinal tract and the effect of synbiotics on gut microbiota.

MicrobiomeX®: the ingredient of choice for your synbiotic formula

To limit the gastro-intestinal complaints caused by high dosages of substrates, other substrates that have beneficial effects in lower dosages, such as polyphenols, could be used. The polyphenols can be transformed into bioactive molecules or into metabolites that can be used by other microorganisms, eventually resulting in a health benefit for the host.

MicrobiomeX® is a first-in-class Flavobiotic® researched and developed by BioActor. It is a natural ingredient from citrus, consisting of two active flavanones: hesperidin and naringin. BioActor combined these two powerful phenolic compounds in a unique complex ideal for the formulation of synbiotic dietary supplements in doses ranging from 250 to 500 mg.

Thanks to its proven high stability in combination with probiotics and its low water activity, MicrobiomeX® is an ideal ingredient to formulate synbiotic dietary supplements. Specifically, MicrobiomeX® can be used as a substrate, and can be metabolized in the gut by bacteria possessing the ramnosidase enzymes such as Lactobacillus acidophilus LA-5, Lactobacillus Brevis and B. animalis ssp. Lactis (7).

After being metabolized, not only does MicrobiomeX® promote the growth of beneficial bacteria in the gut, but the active metabolites that are released in the gut exert a direct antioxidant and anti-inflammatory effect resulting in improved overall gut health.