In This Article:
Key Points
- Polyphenols can stimulate the growth of beneficial bacteria in the gut while inhibiting harmful ones.
- Beneficial gut microbes can transform polyphenols into bioactive phenolic metabolites.
- Polyphenols exhibit antimicrobial mechanisms, helping to modulate gut microbial communities.
- Polyphenols have prebiotic-like effects, creating a favorable environment for beneficial bacteria.
- Polyphenols can increase the production of short-chain fatty acids, which can affect the absorption of polyphenol metabolites.
Gut microbes have enzymes that help make (poly)phenols, which are good for our health, available and active in our bodies.
Research has shown how these (poly)phenols can change the microbes in our gut in a way that’s good for us.
Some probiotic strains can turn (poly)phenols into helpful metabolites, which thrive in the presence of these substrates.
Even bacteria that don’t directly metabolize (poly)phenols, like the anti-obesity bacterium Akkermansia muciniphila, benefit from them.
This review suggests the term “duplibiotic” to describe how (poly)phenols act as both antimicrobials and prebiotics, potentially helping with metabolic issues and gut problems.
This makes them a good dietary strategy with therapeutic potential.
Powerful Connection: Polyphenols and Gut Health
The gut microbiota is a vital player in maintaining host physiology, influencing various physiological axes like the gut-brain, gut-lung, and gut-skin connections 1.
This intricate relationship plays a significant role in managing diseases like cancer, intestinal inflammation, and cardiometabolic diseases 2.
Consequently, the gut microbiota has emerged as a promising therapeutic target for numerous chronic diseases.
Diet has a profound impact on shaping the intestinal microbiota 3.
Commensal microbiota fermentation results in numerous cross-feeding networks that supply essential nutrients and chemical signals for immune and metabolic processes 4.
Traditionally, prebiotics were confined to specific non-digestible carbohydrates, but now phytochemicals like (poly)phenols are recognized for their potential prebiotic effects.
These effects include stimulating beneficial bacteria and reducing disease incidence5.
As secondary plant metabolites, (poly)phenols are found in many diets, where they interact with gut bacteria to promote health 6.
They particularly stimulate crucial bacterial species like Akkermansia muciniphila, Bacteroides thetaiotaomicron, Faecalibacterium prausnitzii, Bifidobacteria, and Lactobacilli 7.
Polyphenols benefit the gut microbiota through two main actions: direct bacterial stimulation and antimicrobial effects.
Beneficial bacteria genomes contain (poly)phenol-associated enzymes (PAZymes) that metabolize (poly)phenols, thus improving bacteria fitness and persistence in the gut 8.
Additionally, (poly)phenols can selectively inhibit potential pathogenic species associated with metabolic disorders 9.
The interaction between (poly)phenols and the gut microbiota results in ecological shifts that support symbiotic relationships, further modulating microbiota composition and function.
Dietary (poly)phenol intake can enhance the presence of beneficial bacteria like Akkermansia muciniphila, showcasing its resistance to (poly)phenol’s antimicrobial action and ability to occupy ecological niches.
Furthermore, PAZymes-producing bacteria can provide beneficial metabolites for other bacteria through complex trophic cross-feeding chains.
Emerging reports suggest that certain (poly)phenols can be utilized and transformed into bioactive phenolic metabolites by beneficial gut microbes like Lactiplantibacillus plantarum, ultimately contributing to human health10.
This review introduces the term “duplibiotics” to describe (poly)phenols that modulate gut microbiota through a dual antimicrobial and beneficial bacteria stimulatory effect.
Study the effects of (poly)phenols on obesity-linked inflammatory bacteria caused by diet-induced conditions, and analyze their impact on the growth of beneficial commensal bacteria.
This article also delves into key bacterial enzymes involved in the potential prebiotic effects of (poly)phenols and their contribution to microbial trophic networks in the intestinal environment, using A.muciniphila as a model organism.
Understanding the Gut Microbiota’s Role in Human Health
The human gastrointestinal (GI) tract is home to a staggering 10^14 active bacteria, primarily consisting of Firmicutes, Bacteroidota, Actinobacteria, Proteobacteria, and Verrucomicrobia 11.
These bacteria play a vital role in our overall health, contributing significantly to metabolic processes and the immune system.
Decoding the Microbial Population
The largest bacterial phylum in humans and rodents is Firmicutes, with over 250 genera.
Bacteroidota follows, with around 20 genera, including the prominent genus Bacteroides 12.
Actinobacteria, accounting for 5% of total bacteria, contains the genus Bifidobacterium, which is a source of many probiotics 13.
The phylum Verrucomicrobia, though less prominent, includes the next-generation probiotic Akkermansia spp 14.
The Extensive Genetic Code of the Gut Microbiota
It’s fascinating to note that the gut microbiota encodes approximately 40 times more genes than the human host, allowing it to break down complex dietary compounds efficiently 15.
This process is crucial for digesting plant constituents, fermenting proteins, transforming xenobiotics, and producing essential vitamins16.
Beneficial and Harmful Metabolites: A Fine Balance
The activities of the gut microbiota result in the production of beneficial metabolites like short-chain fatty acids (SCFA), neurotransmitters, and gasotransmitters 17.
SCFAs are integral to energy homeostasis, immune signaling, and even suppressing proinflammatory effects 18.
However, it’s essential to note that harmful metabolites can also be produced, such as secondary bile acids and trimethylamine-N-oxide 19.
The Immune System’s Interaction with the Gut Microbiota
The majority of the body’s immune cells are found in the colonic epithelium, where they interact closely with the gut microbiota 20.
The immune system continuously monitors the gut for potential pathogens and initiates an immune response when necessary 21.
A healthy gut microbiota, also known as eubiosis, is vital for balanced immunological interactions 22.
The link between Gut Microbiota and Chronic Diseases
Studies have consistently shown that alterations in the gut microbiota can contribute to the development of chronic metabolic diseases 23.
Specific bacterial species, like Bifidobacteria and Lactobacilli, have demonstrated the ability to reduce the severity of inflammatory diseases such as ulcerative colitis and obesity 24.
Probiotic strains like L.plantarum WCFS1 have been shown to improve inflammation 25.
Other next-generation probiotics, like A.muciniphila, B.thetaiotaomicron, and F.prausnitzii, interact closely with the host immune system, providing several benefits26.
Tapping Into the Power of Polyphenols for Gut Health
Polyphenols, comprising flavonoids and non-flavonoids, are aromatic ring compounds integral to our diet 27.
A whopping 90-95% of polyphenols, predominantly flavonoid aglycones and polymers, reach the colon where they interact with gut microbiota, showcasing their antimicrobial and prebiotic properties 28.
Revisiting the Definition of Prebiotics
Traditionally, prebiotics have been restricted to non-digestible carbohydrates like inulin and FOS.
However, recent developments by the International Scientific Association for Probiotics and Prebiotics (ISAPP) highlight that polyphenols too can be classified as prebiotics.
The reason being, polyphenols encourage the growth of gut bacteria beneficial to our health29.
Foods rich in polyphenols can help mitigate metabolic and inflammatory diseases, boost intestinal mucus production, promote gut antimicrobial peptides, and even modulate hepatic bile acids and gut immunoglobulins 30.
The Dual Effect of Polyphenols on Gut Microbiota: Introducing Duplibiotics
A remarkable aspect of polyphenols is their dual antimicrobial and growth-stimulating effects on gut microbiota, rightly termed as ‘duplibiotics’.
This term, which we propose, accurately represents the synergistic antimicrobial and prebiotic properties of polyphenols.
For instance, red wine polyphenols have been shown to increase the abundance of beneficial gut bacteria like Bifidobacteria and Lactobacilli.
while inhibiting harmful ones in metabolic syndrome patients 31.
Unlocking the Antimicrobial Power of Polyphenols
Polyphenols, complex compounds found in our diet, exhibit a range of antimicrobial mechanisms that significantly modulate gut microbial communities 32.
These compounds can interact with bacterial proteins to inhibit nucleic acid synthesis, modify cell walls, affect cell metabolism, and prevent biofilm formation 33.
Furthermore, polyphenols can disrupt bacterial communication, known as quorum sensing 34,
and chelate essential metals like iron, copper, and zinc that are vital for bacterial metabolism 35 .
As a result, polyphenols act as powerful inhibitors of opportunistic pathogens, safeguarding the intestinal epithelium and restoring microbiota balance in several diseases.
Polyphenols: Shaping Microbial Genetic Responses
The antimicrobial action of polyphenols influences various microbial genetic responses, including antibiotic resistance, metabolic pathways, and stress response mechanisms36.
For instance, a study found that quercetin, a type of polyphenol, affected the growth patterns and genetic expression profiles of gut bacteria 37.
Similarly, cranberry polyphenol extracts were found to down-regulate genes encoding for outer membrane proteins in Escherichia coli O157:H7 38.
These extracts also had bactericidal effects against Salmonella strains, reducing the expression of virulence genes and affecting cell wall/membrane biogenesis 39.
Polyphenols: A Key Player in Preventing Obesity-related Gut Dysbiosis
The antimicrobial properties of polyphenols play a crucial role in preventing gut dysbiosis linked to obesity 40.
A study revealed that a black raspberry phenolic extract inhibited the growth of 10 bacterial genera from the phylum Firmicutes while increasing the abundance of A.muciniphila in mice fed an obesogenic diet.
Furthermore, treatment with oolong tea polyphenols significantly altered the gut microbiota in mice, promoting a healthier balance of bacterial taxa 41.
Additionally, the dietary administration of epigallocatechin-3-gallate (EGCG), a type of polyphenol, significantly lowered the abundance of certain bacterial genera.
while increasing the abundance of beneficial genera, improving bile acid regulation in the process42.
Harnessing the Power of Polyphenols as Prebiotics
Polyphenol-rich extracts have a stimulatory effect on beneficial bacteria such as Lactobacilli and Bifidobacteria 43.
These effects result from polyphenols altering microbial ecological niches, rebalancing pro- and anti-inflammatory forces in the mucosa, inhibiting pathogenic bacteria, or being directly utilized by gut bacteria.
However, it’s essential to differentiate true prebiotic effects from indirect prebiotic-like impacts 44.
Understanding True Prebiotic Action
According to the International Scientific Association for Probiotics and Prebiotics (ISAPP), a compound is considered a prebiotic only if its benefits are derived from its selective utilization by gut microbiota.
This definition excludes antimicrobial and antibiotic compounds, even if they positively affect microbiota structure and activity.
Therefore, the selective utilization of polyphenols by gut bacteria needs to be evaluated to avoid misinterpreting their antimicrobial activity as a prebiotic effect.
Polyphenols and Beneficial Bacteria
In vitro studies have shown that polyphenols positively impact beneficial bacteria in pure culture
Strains of Lacticaseibacillus, Lactiplantibacillus, and Lactobacillus grow faster in the presence of purified polyphenols 45.
Similarly, Bifidobacteria strains are promoted by polyphenols in vitro, with both Lactobacilli and Bifidobacteria being recognized probiotics with known health benefits46.
Polyphenols promote bacterial growth by providing carbon sources, acting as electronic acceptors, or generating proton motive forces during their metabolism.
Polyphenols and the Bloom of Beneficial Bacteria
Polyphenols also promote the growth of Bacteroides spp in vivo, with B.thetaiotaomicron from this genus recognized as a next-generation probiotic due to its carbohydrate-catabolic abilities 47.
Furthermore, dietary polyphenols have been shown to induce a bloom of beneficial bacteria expressing polysaccharide utilization loci (PAZymes), although more research is needed to fully understand this interaction.
Powerful Polyphenols and Their Prebiotic Potential
Polyphenols have a fascinating relationship with gut health.
They activate PAZymes (Polymer-AssociatedZymes), like tannase and quercetinase, to produce bioaccessible phenolic metabolites that foster microbial cross-feeding interactions in the gut 48.
A Symphony of Interactions
These polyphenol-rich compounds enhance the growth of specific bacterial families, such as Eggerthellaceae and Coriobacteriaceae, which are adept at breaking down polyphenols into growth factors 49 50.
Notable species like Gordonibacter spp, Eggerthella lenta, and Adlercreutzia equolifaciens thrive as they metabolize ellagic acid and flavan-3-ols51.
Similarly, blueberry polyphenols have been shown to promote the growth of Bifidobacteria and Lactobacilli strains, linking back to their polyphenol-metabolizing capabilities.
A Closer Look at Lactobacillus plantarum
Among probiotic bacteria, L.plantarum is exceptionally well-studied.
It is found in polyphenol-rich environments like plants, fermented vegetables, dairy foods, and the human gut.
Its genome is equipped with numerous genes encoding enzymes to utilize polyphenols, such as intracellular tannase, gallate decarboxylase, and aryl glycosidase 52.
When exposed to plants, L.plantarum adapts its metabolic pathways, showcasing an interesting interplay between its survival mechanisms and the polyphenol-rich environment 53.
Unraveling the Mysteries of Tannases in Gut Health
Tannases, or tannin acyl hydrolases, belong to a broad enzyme family known for its extensive substrate specificity.
These enzymes can hydrolyze a range of gallate and protocatechuate esters found in tannins and other phenolic compounds 54.
Moreover, tannases play a crucial role in transforming compounds that can potentially enter microbial cells, such as methyl gallate and epicatechin gallate, among others 55.
Intriguingly, lean individuals exhibit higher microbial intestinal tannase activity compared to those with obesity, implying the significant impact of gut microbial composition on enzyme activity 56.
Exploring the Unique Properties of Gallate Decarboxylases
Gallate decarboxylases, prominent in lactic acid bacteria, transform gallic acid into pyrogallol, thereby supporting energy uptake in L.plantarum by generating a proton motive force during gallic acid metabolism 57.
Fascinatingly, these enzymes have been observed to enhance the metabolic benefits induced by gallic acid and its rich (poly)phenols 58.
Additionally, gallate decarboxylase-producing probiotic bacteria may significantly boost pyrogallol production in the gut, thereby offering potential antiobesity and anticarcinogenic effects 59.
The Versatile World of Feruloyl Esterases in Nutrition
Feruloyl esterases, or hydroxycinnamoyl esterases, are known for their hydrolyzing capacities toward hydroxycinnamic acid esters found in plant cell walls, such as wheat bran and berries60.
These enzymes improve the bioavailability of functional compounds, with reports of their presence in various bacterial strains, such as Bifidobacterium longum and Lactobacillus acidophilus 61.
Furthermore, supplementation with feruloyl esterase-producing probiotic strains can significantly enhance intestinal esterase activity and oxidative stress parameters in supplemented mice 62.
Unlocking the Health Benefits of Phenolic Acid Reductase
Phenolic acid reductases are specialized enzymes that reduce hydroxycinnamic acids to produce substituted phenylpropionic acids, which have been found in the urine and plasma of subjects following supplementation with a green and roasted coffee blend 63.
Remarkably, these enzymes provide an energetic advantage for bacteria, as they can utilize these phenolic acids as external electron acceptors in the pentose-phosphate pathway 64.
The resulting (poly)phenol-derived metabolites have also been shown to exhibit antiplatelet properties and prevent monocyte endothelial adhesion 65.
The Integral Role of α-L-rhamnosidases and β-glucosidases
α-L-rhamnosidases and β-glucosidases are essential enzymes that play a crucial role in the human digestive system
The former releases aglycones and glucose by cleaving the terminal α-L-rhamnoses present in glycosylated phenolic molecules 66,
while the latter enables bacteria to obtain carbon sources from glucosides catabolism, thereby releasing sugars and aglycones 67.
These enzymes are vital for transforming specific rhamnose glycosides frequently found in citrus fruits and for increasing the bioaccessibility of phenolic glucosides during food fermentation 68.
The Power of Polyphenols: How Our Gut Microbiota Unlocks Their Health Benefits
Just as native compounds do, microbial phenolic metabolites can possess antioxidant, anti-proliferative, and anti-inflammatory properties, which are essential for our health 69.
The production of these beneficial metabolites depends on the PAZyme production by our gut microbiota, creating what is known as a metabotype.
This concept has been explored in-depth elsewhere 70.
This differentiation in metabotypes can explain why people experience different health outcomes following polyphenol intake
For polyphenols to reach their full health potential, the presence of polyphenol-degrading bacteria in the gut microbiota is crucial
These bacteria can produce beneficial compounds such as equol from daidzin, enterolactones from lignans, 8-prenyl naringenin from xanthohumol, and urolithins from ellagitannins 71.
Moreover, the bioactivity of PACs can be enhanced by gut bacteria to produce active isomers of valerolactones.
These metabolites, which include phenyl-γ-valerolactones and phenylvaleric acid derivatives, are derived from the fecal fermentation of PACs.
Rocchetti et al 72 utilized advanced analysis techniques to establish a link between the chemical structure of polyphenols and the colonic pathways they engage in.
The results showed how PAC C-ring fission of the flavan-3-ol-backbone occurs, resulting in the formation of phenyl-γ-valerolactones.
These compounds undergo further oxidation to produce lower-molecular-weight phenolic acids.
Valerolactone isomers have recently been shown to play a role in reducing monocyte adhesion in vascular endothelium, potentially preventing atherosclerosis 73.
They may also pass the blood-brain barrier, contributing to the neuroprotective effects of polyphenol-rich diets 74.
Additionally, urolithin A, a metabotype biomarker derived from ellagitannins degradation, has been associated with reduced cardiometabolic risk 75.
Urolithins can also exhibit antimicrobial and anti-quorum sensing activities, which can disrupt the behavior of harmful bacteria, potentially contributing to the reestablishment of gut dysbiosis76.
This inhibitory action on opportunistic bacteria, coupled with polyphenol-induced changes in the gut barrier and immune responses, can promote the proliferation of beneficial gut bacteria.
Power of (Poly)phenols: Their Prebiotic-Like Effects
When we talk about (poly)phenols, we’re looking at natural compounds that can reshape the landscape of our gut microbiota, promoting a balanced and healthier ecosystem within us 77.
This is evident from studies where mice fed with (poly)phenol-rich foods show a positive shift in their gut microbiota composition,
supporting the growth of beneficial bacteria and suppressing the opportunistic ones 78.
One of the fascinating aspects of (poly)phenols is their indirect prebiotic-like effects.
These compounds can create a hospitable environment for beneficial bacteria by eliminating harmful pathogens, strengthening the mucosal barrier, and reducing oxidative stress 79.
A shining example of this is the relationship between (poly)phenols and Akkermansia muciniphila, a beneficial gut bacterium.
Akkermansia muciniphila has been shown to thrive in the presence of (poly)phenols, with various studies highlighting the positive impact of grape (poly)phenols, apple PACs,
and other (poly)phenolic compounds on the growth of this bacterium 8081.
This relationship seems to work both ways, as Akkermansia muciniphila has developed resistance to (poly)phenols, giving it a competitive edge in colonizing the colon 82.
The mechanisms behind this relationship are still a subject of ongoing research.
Interestingly, a recent study has shed some light on this by identifying two genes in Akkermansia muciniphila linked to the degradation of the flavonol quercetin, suggesting a potential ability of this bacterium to utilize (poly)phenols 83.
Impact of Polyphenol-Rich Foods on Gut Health
Polyphenols, a diverse group of chemical compounds found in plant-based foods, have a significant impact on the microbial ecology of our gut.
The chemical structure and degree of polymerization of these polyphenols greatly influence the production of phenolic metabolites and their further catabolism by gut microbiota 84.
For instance, human fecal fermentation of grape seed fractions rich in flavan-3-ols monomers resulted in the generation of specific metabolites, which were subsequently degraded by colonic bacteria.
This process led to the growth of beneficial bacteria like Lactobacillus and Enterococcus, while inhibiting harmful ones like H.histolytica 85.
Most of the polyphenols we ingest are bound to plant cell walls and reach the colon as polyphenolic fibers.
These fibers, when fermented, lead to the production of short-chain fatty acids (SCFAs) and release non-extractable polyphenols 86.
Studies have shown that these fibers and polyphenol-derived metabolites act synergistically to improve host health, such as reducing hepatic cholesterol levels and inhibiting harmful bacteria in the gut 87.
Polyphenols can also increase the production of SCFAs, which in turn affects the absorption of polyphenol metabolites.
The mechanism behind this is not fully understood, but it is hypothesized that polyphenols may inhibit mouth amylase, leading to an increased concentration of complex carbohydrates reaching the gut,
or by increasing the number of anaerobic bacteria in the gut environment 88.
This leads to a polyphenol prebiotic pathway, resulting in the production of SCFAs
Furthermore, polyphenol and carbohydrate substrates can facilitate cooperative interactions between different bacteria in the gut
For example, a study showed that the presence of starch increased the quercetin-degrading activity of Eubacterium ramulus, resulting in the production of beneficial metabolites and SCFAs 89.
Polyphenols: Your Guide to Gut Health
Polyphenols, found in various foods, play a crucial role in maintaining a healthy gut microbiota.
To understand the ecological role of these polyphenols, or “duplibiotics,” simplified microbiotas or key microbial consortia co-cultures can be used 90.
These studies help identify the antimicrobial activity and prebiotic effect of polyphenols on gut microbiota.
Additionally, whole microbiota stabilized in intestinal in-vitro systems like SHIME have been utilized to assess polyphenols’ impact on microbiota composition and function 91.
While in-vitro models lack direct interactions with the host, they are essential tools in uncovering the health benefits induced by polyphenol-rich food intake.
Future human clinical studies are crucial to confirm these benefits 92 93.
Discussion and Conclusion
- Polyphenols have been shown to have a positive impact on gut microbiota by stimulating the growth of beneficial bacteria and inhibiting harmful ones.
- Beneficial gut microbes can transform polyphenols into bioactive phenolic metabolites, contributing to human health.
- Polyphenols exhibit antimicrobial mechanisms, modulating gut microbial communities and promoting a healthier balance of bacteria.
- Polyphenols have prebiotic-like effects, creating a favorable environment for beneficial bacteria by eliminating pathogens, strengthening the mucosal barrier, and reducing oxidative stress.
- The interaction between polyphenols and the gut microbiota can lead to the production of short-chain fatty acids, which can affect the absorption of polyphenol metabolites.
These findings highlight the potential of polyphenols in promoting gut health and suggest that they can be considered as prebiotics.
Further research is needed to fully understand the mechanisms and optimize the health benefits of polyphenols in relation to gut microbiota.
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