Nouf Abdullah Alharbi- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
Polyphenols, plant-derived bioactive compounds, are known for their antioxidant, anti-inflammatory, and antimicrobial properties, benefiting plant-based foods. Fermentation, driven by microbial enzymes like glycosidases, esterases, and decarboxylases, alters the chemical structure of polyphenols, enhancing their bioavailability and bioactivity. This review explores the transformation of polyphenols, particularly flavonoids and phenolic acids, during fermentation, resulting in bioactive metabolites with increased solubility, stability, and antioxidant activity, improving gastrointestinal absorption. Additionally, fermented polyphenol metabolites modulate gut microbiota by promoting beneficial bacteria such as Lactobacillus and Bifidobacterium, while inhibiting pathogens. These changes support gut health, reduce inflammation, and provide systemic benefits, including enhanced metabolic, immune, and neurocognitive functions. Despite progress, knowledge gaps remain, particularly regarding microbial pathways and the health outcomes linked to these metabolites. Future research should focus on mapping microbial biotransformation pathways of polyphenols and their impact on health outcomes. Additionally, well-controlled human intervention studies using multi-omics approaches are necessary to validate the systemic benefits of fermented polyphenol metabolites.
Graphical Abstract
1 Introduction
Polyphenols are represented by a heterogeneous class of plant-derived secondary metabolites that form one of the most abundant groups of bioactive compounds in the human diet (1, 2). These compounds are widely distributed in a wide range of foods—including fruits, vegetables, cereals, legumes, cocoa, tea, coffee, wine and many other plant-based products—wherein they are responsible for various sensory properties, i.e., color, astringency, and overall organoleptic quality (3). Beyond their technological functions, dietary polyphenols have attracted a great deal of scientific attention because of their strong antioxidant, anti-inflammatory, antimicrobial, and immunomodulatory activity, which is increasingly linked to the prevention or modulation of chronic non-communicable diseases (4). Mechanistically, polyphenols may scavenge reactive oxygen species, affect redox-dependent signaling pathways, reduce pro-inflammatory mediators, and inhibit microbial cell structures and biofilm formation. This would make polyphenols ideal therapeutic agents for maintaining health as well as for managing disorders associated with inflammation (5). However, the in vivo biological effect of polyphenols is not only dependent on their intrinsic chemical structure, but also on their stability, solubility and transformation in the gastrointestinal tract with extensive metabolism by host and microbial enzymes yielding a broad spectrum of lower-molecular-weight metabolites often with markedly different bioactivity and bioavailability to the parent compounds (6).
With the better understanding of the biology of polyphenols, fermented foods have re-emerged as key players in functional nutrition and gut health research (7). The fermented foods, which include dairy products, fermented cereals, vegetables, legumes, cocoa, tea, coffee, and alcoholic beverages, contain complex microbial ecologies. Lactic acid bacteria (LAB), yeasts, and other microorganisms ferment the raw substrates into products with unique taste, nutritional profile, and function. These foods, once valued mainly for preservation, safety, and taste, are increasingly regarded nowadays as vectors of live microbes, their metabolites, and biotransformed food components capable of modulating the gut microbiome, enhancing the intestinal barrier integrity, influencing local and systemic immune responses, and impacting systemic metabolic functions (8). Clinical and preclinical studies have suggested that regular consumption of fermented foods is associated with enhanced gut microbial diversity, promotion of barrier integrity, and diminished systemic inflammation. Indeed, this provides a basis for their role as functional foods, particularly after more clear evidence of specific health benefit(s) may be established (9). In this broader context, the importance of fermentation as a modulator of phytochemicals such as polyphenols is increased as it can result in the generation of new or more bioavailable bioactive phytochemicals within the food matrix itself (10).
Such an association of polyphenols with fermentation can be envisaged as a two-way interaction between the plant compounds and the microbes involved. Resident microorganisms of foods produce a variety of enzymes during fermentation that are associated with polyphenols such as esters, glycosidases, decarboxylases, and reductases. These enzymes cleave glycosidic bonds, release phenolics bound to the cell wall, and induce changes in the structure of phenolic acids, flavonoids, and tannins (11). These biotransformations generally result in an increase in the percentage of free or low molecular weight phenolics, changes in conjugation patterns, improvements in solubility and may also enhance antioxidant and other functional properties as compared to the native polyphenol profile of the raw substrate (12). Meanwhile, certain polyphenols could selectively promote beneficial fermentative microorganisms while suppressing spoilage or pathogenic species, thereby impacting fermentation kinetics, microbial succession and final metabolite spectrum. Consequently, polyphenol rich fermented foods are often very different from their non fermented counterparts in qualitative and quantitative composition of phenolic compounds and their derived metabolites, and recent evidence indicates that these changes are associated with increased bioactivity in in vitro and in vivo systems (13).
Polyphenol metabolites formed during fermentation and subsequent passage through the gastro-intestinal tract are now considered to be important intermediaries in relation to the health benefits previously associated with polyphenol-rich and fermented foods. Following ingestion, phenolic metabolites derived from fermentation and some un-metabolized parent compounds are transported to the gut where they are further metabolized by colonic microbiota into small phenolic acids and lactone derivatives that have characteristic absorption abilities as well as biological targets (14). These metabolites are able to produce local effects on the gut environment by modulating the composition of the microbiota, inhibiting the growth of pathogenic bacteria, reducing biofilm formation and favoring the growth of beneficial taxa such as bifidobacteria, and through antioxidant, anti-inflammatory, metabolic and neuroprotective mechanisms (15). Recent studies demonstrate that fermentation may enhance these interactions by means of preconditioning polyphenol structures in the food matrix making them more accessible to host and gut bacterial enzymes, resulting in a higher pool of absorbable or microbiota-modulating metabolites present within the colonic lumen (16). Therefore, knowledge of how fermentation under specific conditions and microbials impacts on the polyphenol profile is important to properly design fermented functional foods in order to curtail gut health or inflammation-related diseases.
Despite the rapid advances, there are still gaps in the integration of polyphenol chemistry, fermentation science and nutrition. Most of the studies have looked at broad measures, such as total phenolics or overall antioxidant capacity, and detailed metabolite-by-metabolite analysis, clearly linked to specific health outcomes, are less common. The variation between analytical methodologies, microbial strains, fermentation parameters and raw materials also makes cross-study comparison more challenging and impedes the identification of meaningful structure and function relationships for fermentation-generated polyphenol metabolite production. Furthermore, gut microbiomes and metabolism are highly variable among individuals, and thus the in vivo fate and bioactivity of these metabolites can be very different from one person to another. That adds another layer to the hurdles when trying to translate lab or animal findings to human health guidance (17). To address these challenges, the systematic mapping of microbial biotransformation pathways, a quantitative metabolomics analysis of fermented food products and samples originating from biological samples are required alongside well-designed human intervention studies taking into account both aerial matrix and microbiome context (18).
In this review, we summarize recent findings about metabolites from polyphenols in fermented foods, with particular emphasis on the action of microbial enzymes and their functions as plant-derived raw materials. The chemical composition, biosynthetic routes and health-beneficial bioactivities of polyphenol metabolites with special emphasis on gut microbiota modulating potential, attenuation of oxidative stress and inflammation are discussed. The review uncovers their systemic effects in metabolic, immune and neurocognitive health. It also highlights knowledge gaps and makes recommendations on future prospective for polyphenolic-rich fermented foods and personalized dietary intervention.
2 Polyphenol chemistry
Polyphenols represent a large group of naturally occurring compounds in plants that are structurally defined by one or more phenolic rings as shown in Figure 1 (19). They are divided into a number of families according to share molecular scaffolds, which broadly tend to affect their chemical behavior and biological response. The main groups of dietary polyphenols are flavonoids and phenolic acids, which exist in a wide variety and are present in high amounts in fruits, vegetables and fermented diet (2).
Figure 1. (A) Basic polyphenol core structure. (B) Different polyphenol compounds and their structure.
All flavonoids possess a common structure consisting of two aromatic rings (A and B) linked together by a three-carbon bridge, which may frequently cyclize to form a heterocyclic ring (C-ring). This core architecture is modified in different ways giving rise to several subfamilies. It is interesting to note that the flavan-3-ols, such as catechins, do not have a double bond between carbon 2 and 3 and exhibit antioxidant properties (20). Flavonols such as quercetin and kaempferol contain a ketone moiety and a high-hydroxyl substituent, which play important roles in their chemical reactivity and biological activity. Anthocyanins are the glycosylated products of anthocyanidin, with sugars added to the molecules at selected positions affecting their solubility and stability (21).
Phenolic acids are simpler molecules, split mainly into hydroxybenzoic acids, such as gallic acid, and hydroxycinnamic acids which include caffeic and ferulic acids. They are frequently found as glycosidic or esterified conjugates with cell wall polysaccharides, participating not only in the structural integrity of plant tissues but also in their bioaccessibility and interactions during the digestion and fermentation processes (22). These polyphenolic moieties are constituted by functional groups as a pendent which stringently govern their chemical properties. Its capacity to donate electrons and neutralize free radicals is attributed mainly to the presence of hydroxyl (–OH) groups, which form the basis for its antioxidant properties. Methoxy (–OCH3) groups modify hydrophobicity and could increase metabolic stability, wherease glycosidic linkages to sugar reduce hydrophobicity, increase water solubility, and may have an impact on absorption/disposition in humans. These glycosides are often found in plant polyphenols with glucose, rhamnose or galactose as the most common carbohydrate moiety attached (23).
Polyphenols have different physicochemical properties ranging from highly water soluble phenolic acids to less soluble (larger) flavonoid polymers, depending on size, polarity and degree of polymerization. The stability of natural colors is influenced by factors such as pH, temperature, light—anthocyanins are extremely sensitive to pH and change color and stability in function thereof. The chemical reduction capacity of the polyphenolic structures creates their action as an antioxidant, which can serve by donating electrons to scavenge reactive oxygen species and reduce oxidative stress (24). Consequently, detailed chemistry of polyphenols, its core structures and functional group diversity that leads to their varied physicochemical behavior, is critically important in relation to such biological activities as well as transformation during fermentation and digestion. This chemistry help their reactions with enzymes, microbes and other components of food matrix and thus determines a range of health functions.
3 Sources and metabolism of polyphenols in fermented foods
Polyphenols are prevalent natural ingredients of many plant-based foods and have been used as basic materials in fermentations. The different polyphenol compounds and their dietry sources are summarized in Table 1. The variety of polyphenol-rich substrates significantly affects the quality and biofunction of fermented foods because these undergo biochemical changes at the molecular level during fermentation, resulting in both structural and functional modifications. In this regard, among the readily available raw materials such as grapes, legumes, soybean, different fruits have unique polyphenol profiles on which traditional and industrial fermentation systems can be based (25). Grapes have been found to be abundant in flavan-3-ols, anthocyanins, flavonols and phenolic acids mainly located in the skins and seeds. These compounds are at the core of wine's antioxidant potential and also to its sensorial properties (26). Soybeans also represent the main source of isoflavone glycosides and phenolic acids required for the nutritional and functional properties of fermented soy products such as soy sauce, miso, or tempeh. Fruit fermentations with berries, pomegranate and tropical fruits also utilize endogenous phenolic compounds such as flavonoids and phenolic acids for flavoring and associated health benefits (27).
Table 1. Sources of polyphenols in fermented foods.
Through fermentation, the microbial enzymes are mainly responsible for biotransforming the polyphenols which in turn changes their chemical structure and increases their bioactivity. The critical enzymatic reactions involve the hydrolysis of glycosidic bonds by microbial β-glucosidase and other glycosidases, leading to the release of polyphenol aglycones which are more lipophilic and bioactive moieties (28). This transformation is of particular interest because numerous plant polyphenols are present conjugated to sugars, which in turn hinders their absorption in the gastrointestinal tract Fermentation increases the availability and activity of polyphenols through the cleavage of sugar moieties. Other microorganisms' enzymes, including tannases and esterases, play a role in the release of phenolic acids from their esterified forms as well as the depolymerization of tannins to enhance the free phenolics and low-molecular-weight compounds. The cooperative action of these enzymes not only releases bound polyphenols but can also strongly modify their antioxidant activity and interaction with the gut microbiota (11).
Fermentation also leads to the production of multiple, metabolic-pathway polyphenol metabolites. In addition to direct hydrolysis, other complex transformations like decarboxylation, ring cleavage, reduction, methylation and dehydroxylation take place during fermentation and give rise to new phenolic acid and flavonoid derivatives having different biological and sensory properties (29). For example, proanthocyanidins and polymeric flavonoids in raw materials can be degraded into small phenolic acids such as caffeic acid, ferulic acid and p-coumaric acid with increased bioavailability and antioxidant properties. Likewise, flavonoid aglycones produced during fermentation may get modified that make them more potent in modulating oxidative stress and inflammatory pathways of the human gut. These metabolites are generally found at higher concentrations in fermented by-products compared to their unfermented counterparts, indicating fermentation as a bio-enhancing processing step (30).
Various types of polyphenolic compounds, such as phenolic acids, flavonoids and stilbenoids are subjected to different microbial conversions during fermentation, mediated by certain microbial groups i.e., lactic acid bacteria (LAB) and yeasts. LAB species are known to be the major producers of β-glucosidase that is important in hydrolysis of isoflavone glycosides in legumes into more biologically active aglycone forms (31). The higher level of daidzein and genistein resulting from the enzymatic action during soy fermentation may increase the anti-inflammatory and antioxidant capacities of soy products. Demethylation and ring cleavage reactions are also performed by yeast, providing other enzymatic activities that transform flavonoids to create both sensory and bioactives in fermented beverages such as wine or kombucha. Stilbenoids such as resveratrol, despite their low content, may also be released or formed during fermentation that contribute to the functional variety of fermented foods (32). This interaction of microbial enzymes to polyphenolic substrates is strain dependant and also dependent on fermentation conditions such as pH, temperature and time of fermentation which makes it possible to produce desired metabolite profiles by tailored production (33).
In conclusion, the origins and metabolism of polyphenols in fermented foods illustrate a complex biochemical interplay between plant-derived compounds and microbial enzymatic machineries. More diverse starting materials such as grapes, soybeans, and fruits rich in polyphenols can also be used as substrates within this host, microbial fermentation itself causes structural changes by enzymatic hydrolysis and the generation of new metabolites. These conversion improve polyphenol bioaccessibility, change the antioxidant and anti-inflammatory effect, and generate metabolites with novel potential health benefits. Insight into these processes also offers a scientific foundation for optimizing fermentation approaches toward the production of functional foods that are rich in bioactive polyphenolic metabolites with known health benefits.
4 Bioavailability and bioactivity of fermented polyphenol metabolites
Bioavailability and bioactivity of polyphenols are key determinants of their health benefits, but the majority of naturally occurring dietary polyphenols exhibit low bioavailability, extensive metabolism, and rapid excretion. Fermentation has been increasingly recognized as a promising method to circumvent these drawbacks via enzymatic transformation of polyphenols into more soluble, stable and bioaccessible forms in addition to leading to the generation of new metabolic products harboring unique biological properties. Therefore, fermented foods and beverages are often reported to contain higher amounts of bioaccessible phenolic compounds than non-fermented products derived from similar raw materials (66).
4.1 Improved bioavailability via fermentation
One of the main processes with which fermentation enhances polyphenol bioavailability is to release conjugated forms into free aglycones and low-molecular-weight derivatives. In plant tissues, flavonoids and isoflavones are largely present as glycosides or esterified molecules, that show low intestinal permeability. Through fermentation, microbial β-glucosidases, esterases and tannase hydrolyse glycosidic and ester linkages resulting in aglycones and de-esterified phenolic acids with higher lipophilicity and better capacity for passive-diffusion or carrier-mediated absorption in the small intestine (67). For instance fermentation of tea, cocoa and fruit-based substrates has been found to enhance the levels of flavonoid aglycones and/or simple phenolic acids in vitro which also translates into improved in vitro bioaccessibility as well as higher plasma concentrations of these metabolic products in animal or human time interventions. Soy-derived isoflavone glycosides are converted into aglycones such as daidzein and genistein when soy-based products are subject to fermentation, thus having higher absorption and greater estrogenic activity together with antioxidant action, highlighting how fermentation can “release” bioactive activity from these class of polyphenols (68).
Fermentation also affects physicochemical characteristics, favoring bioavailability such as solubility and stability. The microbial metabolism may produce more polar or hydrophilic derivatives which enhance solubility in aqueous intestinal environment, Or smaller and less complex molecules that are less likely to precipitate and have a more favorable interaction with transport systems (69). Furthermore, fermentation might also contribute to stability by converting very labile molecules into less labile metabolites in the face of pH-related degradation, enzymatic oxidation or thermal degradation and thus increase how much of the parent polyphenol material is left after processing and gastric transit. This combined effect of deglycosylation, depolymerization and stabilization causes a higher bioavailability of phenolics and their metabolites in fermented foods and beverages (70).
4.2 Biological activities of fermented polyphenol metabolites
Polyphenol metabolites originating from fermentation can have several biological activities once absorbed or present in the gut lumen. All of these activities are either increased or qualitatively different than the non-fermented material, due to structural changes leading to modified redox properties, receptor interactions and microbial targets. The standard reductions and oxidation potentials and chemical accessibility of hydroxyl moieties that can facilitate the free radical scavenging ability of fermented polyphenol metabolites are improved. Deglycosylation and depolymerization may allow for the exposure of more phenolic hydroxyls or for production of smaller phenolic acids with radical scavenging capability, leading to stronger DPPH neutralizing power. In fermented teas, cocoa products and fruit wines the inhibition of lipid peroxidation and cellular antioxidant response has been demonstrated to be superior to unfermented controls while being associated with increased presence of fermentation-derived phenolic acids and flavonoid aglycones (71).
Once absorbed or active in the gut lumen, fermentation-derived polyphenol metabolites exert a range of biological activities. Many of these activities are enhanced or qualitatively different compared with non-fermented forms because structural modifications alter redox properties, receptor interactions, and microbial targets (72). Fermented polyphenol metabolites usually exhibit higher antioxidant power in chemical and cellular systems as a result of enhanced redox potential and accessibility of hydroxyl groups. After deglycosylation and depolymerizaiion, phenolic hydroxyls are exposed and neutralize reactive oxygen species and reactive nitrogen species effectively (73). Antioxidant capacity and inhibition of lipid peroxidation, has also been proved to be higher with fermented teas (theaflavins), cocoa products (polyphenols) and fruit wines than unfermented controls which had been attributed to the accumulation of phenolic acids and flavonoid aglycones derived from fermentation (71).
Fermented polyphenols and their metabolites can inhibit the inflammatory response by regulating the expression of several proteins involved in signaling pathways, including NF-κB, MAPKs and cytokine production. Fermentation-induced structural changes would enable improved bindings to the transcription factors or enzymes related to inflammation, leading in turn to downregulation of pro-inflammatory markers such as TNF-α, IL-6, and COX-2 (5). Fermented plant extracts, mainly from soy, cereals or fruits, are more potent in inhibiting inflammatory markers than non-fermented counterparts which is explained by higher levels of certain aglycones and low molecular weight phenolic acids resulting due to fermentation (74). Fermentation-mediated conversions may enhance the anticancer activity of pulse and cereal polyphenolics through production of metabolites with enhanced cellular uptake as well as enhancing effect in relation to cell proliferation and apoptosis. Fermented extracts of pulses are known to inhibit growth of cancer cells, induce cell cycle arrest and apoptosis at a lower concentration than the unfermented extract, thus possessing better anticancer activity (75). Mechanistically, these actions consist of the regulation of oxidative stress, disturbance in growth factor signaling and activation of intrinsic apoptotic pathways, where fermentation metabolites such as phenolic acids and flavonoids derivatives are shown to play a crucial role (76).
In the colon, fermentation derived polyphenol metabolites closely interact with gut microbiota functioning as substrates or effectors that modulate microbial composition and activity. Several low molecular weight phenolic acids produced during fermentation have demonstrated selective inhibition of potential pathogenic bacteria and support growth of some beneficial microoraganism such as Lactobacillus and Bifidobacterium, suggesting a prebiotic-like modulation of the microbiome (77). Additionally, fermentation increases phenolics content that support gut barrier integrity, while preventing oxidative stress in the intestinal mucosa and reducing inflammatory signals derived from the gut (78). All these effects contribute to maintain gut homeostasis and can reduce the risk of diseases like inflammatory bowel disease or metabolic endotoxemia.
Fermented polyphenol containing products may have a beneficial effect on cardiovascular and metabolic markers, as well as blood pressure, lipid profiles, and insulin sensitivity. Higher bioavailability of certain fermentation-derived metabolites has been linked to enhanced endothelial function, lower oxidative modification of LDL, and reduced levels of systemic inflammatory markers (79). Among metabolic studies, consumption of fermented foods with high levels of bioactive phenolic metabolites has been inversely associated with glucose homoeostasis and features of the metabolic syndrome in part as a result of antioxidant, anti-inflammatory and microbiota-mediated action (80). Altogether, fermentation converts polyphenols from relatively inactive or low bioavailable species to a tissue-active library of uniquely metabolized and highly diverse array of metabolites with the highest bioavailability profile and extensive array of bioactivities. Based on the optimization of fermentation conditions, responsible microbial strains and available polyphenol-rich substrates, functional fermented foods can be designed to increase their levels in beneficial metabolites for antioxidant defense, anti-inflammatory activities, gut and cardiometabolic health protection as well as potentially a decrease in cancer risk.
5 Microbial mechanisms in polyphenol biotransformation
Microbial consortia are the essence of polyphenol bio-transformation in fermented foods by converting complex plant phenolics into structurally diverse metabolites that vary in availability and bioactivity. During fermentation, bacteria, yeasts and molds produce an array of enzymes that hydrolyze, oxidize, reduce and rearrange the structures of polyphenols with LAB exhibiting a particularly significant effect (81). These microbial activities not only determine the nutritional and functional characteristics of fermented products but also affect their sensory attributes and microbial stability, rendering polyphenol metabolism an important interface between food chemistry and fermentation microbiology (9).
5.1 Role of lactic acid bacteria (LAB)
Lactic acid bacteria (LAB) are the most common starter cultures and characterize several natural fermentations of vegetables, cereals, legumes and some beverages in which they play a key role in polyphenol biotransformation. They are also known to produce glycosidases such as β-glucosidase, α-rhamnosidase, esterases and tannases which catalyze the release of flavonoid and phenolic acid conjugates from their bound forms into aglycones, or simpler phenolics with augmented biological activity (82). Lactiplantibacillus plantarum formerly known as Lactobacillus plantarum is amongst the model species commonly found in wine, olive, vegetable and cereal fermentations and acknowledged for its polyphenol rich environment tolerance, as well as versatile enzymatic arsenal. L. plantarum is able to hydrolyze flavonoid glycosides, release phenolic acids from esterlinked forms and further convert the hydroxycinnamic acid via decarboxylation and reduction producing derivatives with changed antioxidant and antimicrobial activities (83).
Liu et al. (84) reported that the sensory quality and acceptability of Aronia melanocarpa juice fermented with Lactobacillus plantarum 1243 were enhanced. Metabolic changes improve the release of phenolic acids, anthocyanins and flavonoids but not the antioxidizing activity. Liu et al., (85) found that LAB fermentation of Eucommia ulmoides tea affected the physicochemical properties, antioxidant activity, and aroma. Lactobacillus bulgaricus stimulated chlorogenic and geniposidic acids at greater antioxidant potential compared with the other strains. It also contributed to the fruit and floral flavor notes, once again revealing strain-dependent effects on functional tea quality. This research provides further confirmation that LAB-mediated enzymatic hydrolysis is a major factor in transforming glycosylated and cell wall-bound polyphenols into compounds with enhanced bioactivity. LAB can also be involved in ring-fission and reductive transformation of flavonoids and phenolic acids, also but these pathways are mapped only fragmentarily so far and they seem to be strongly strain-dependent. Direct enzymatic and indirect changes in pHand redoxconditions, LAB effectively re-modeling the migrating polyphenolic landscape during food fermentation (11).
5.2 Importance of other microbes
Non-LAB microorganisms, especially yeasts and molds, are also critical contributors to polyphenol biotransformation in the process of fermentation, frequently cooperating with LAB for the generation of complex metabolite patterns. Yeasts such as Saccharomyces cerevisiae and different non-Saccharomyces species are the main actors of alcoholic fermentations of wine, beer, cider, kombucha in which glycosidases, oxidoreductases, lyases acting on phenolics exist. These enzymes are able to de-glycosylate flavonols and anthocyanins, as well as oxidize or reduce phenolic structures, and produce volatile phenolic compounds that have an impact on aroma and flavor (86). Yeast-mediated fermentations of cocoa and coffee modify the oxidation state and polymerization of endogenous polyphenols, resulting in modifications of astringency, bitterness, antioxidant activity and shelf stability. Thus by selectively modifying phenolic molecules, yeast metabolism contributes to sensory development as well as to the functional attributes of fermented products (87).
Molds such as Aspergillus, Rhizopus and Penicillium are particularly important in fermentations like miso, soy sauce tempeh and some types of cheeses, where the produce a vast range of extracellular enzymes that degrade plant cell wall matrices to release bound phenolic compounds as shown in Figure 2. Furthermore, koji molds like Aspergillus oryzae are source of β-glucosid, tannase, and feruloyl esterase activities releasing isoflavone aglycones and phenolic acids from soy and cereal-based source to enhance the bioactive compounds concentration along with flavor complexity development (88). Co-cultivation of LAB with enological yeasts improves functional and flavor parameters of multi-substrate beverages (89). Pichia kluyveri PK7 could enhance fermentation, amino acid level and even hypolipidemic effect. Kluyveromyces marxianus KM20 enhanced the antioxidant ability and ester production, highlighting that strain-specific synergistic effects of co-fermentation. These non-LAB microbes, together with LAB, constitute a functional consortium, which ultimately determines the composition of the final polyphenol metabolites found in fermented foods.
Figure 2. Microbial mechanisms in polyphenol biotransformation.
5.3 Integration of multi-omics methods
Multi-omics strategies offer a strong system to unravel the intricate webs of microbial community elements that convert polyphenols during fermentations, enabling to connect “who is there” with “what they are doing” and “which metabolites are formed”. Rather than looking at single enzymes or a few strains in isolation, multi-omics includes metagenomics, metatranscriptomics, proteomics and metabolomics to create fermentation as a dynamic system within many layers. This systems view, is especially relevant for polyphenols, as these molecules are a structurally diverse group that occurs in various conjugated forms and undergoes sequential or cooperative metabolism by distinct microbes (90).
Metagenomics provides the description of the taxonomic and functional gene inventory of the fermentation microbiome. By total DNA sequencing of the fermenting matrix, it is possible to identify dominant as well as subdominant taxa of fermentation microorganism such as Lactiplantibacillus spp., Leuconostoc spp., Saccharomyces spp, Aspergillus. The gene annotation may reveal genes encoding enzymes in polyphenol metabolism including β-glucosidases, α-rhamnosidases, esterases, tannin acylhydrolases tannases decarboxylase, dehydrogenase and reductase. Comparative metagenomics among different time points or fermentation conditions provides indications of variations in community structures and relative abundance of these functional genes, and can thus suggest which organisms may have the capacity to lead specific steps of polyphenols biotransformation. Meanwhile, metagenomics cannot by itself reveal whether these genes are active, so it is typically paired with expression-level data (91). Metatranscriptomics fills this gap by sequencing community RNA to assess which genes are transcribed during individual fermentation states. By quantification of transcripts of genes for expression of β-glucosidase or phenolic acid decarboxylase can detect the changes in the phenolic profiles. This is particularly beneficial in mixed fermentations where multiple strains may possess the same genes, metatranscriptomic data can indicate which taxa are active with respect to transcription under particular conditions (92).
Proteomics goes one step further by the direct quantification of proteins and enzymes, thereby brid ging between gene expression and catalytic activity. Shotgun or targeted proteomics can help to reveal the precise enzyme machinery participating in polyphenol catabolism, including particular β-glucosidase isoforms, tannases, feruloyl esterases or dehydrogenases that play a role at different time points during fermentation or when using distinct fermentation conditions. Post-transcriptional regulation, protein stability and enzyme secretion can all affect functional output, so that proteomic data frequently refines or counters conclusions based on transcript-level analysis alone (93). Functional metagenomic screening combined with glycoanalytics resulted into the identification of enzymes that cleaved sulfated N-glycans. xCGE-LIF enabled high-resolution glycomic profiling, confirming that the enzyme is specific for GlcNAc-6-SO4 modifications. This multi-omic approach shows the improvements in analyses of structure and function of the glycans which can be made when genomics is combined with glycomics (94).
Metabolomics specifically collects the fermentation-induced alterations of polyphenols and their metabolites. Metabolomics with LC–MS/MS, UHPLC–HRMS or NMR-based platforms profiles the parent polyphenols such as flavonoid glycosides, proanthocyanidins and phenolic acid esters, as well as intermediates and end products of metabolism including free phenolic acids, aglycone flavonoids, ring-fission products and small aromatic acids. Time-resolved metabolomics allows to map transformation pathways by tracking the disappearance of substrates and the occurrence of product alongside, in many cases, multi-step events populated by distinct element groups (95). Taken together, the integration of metagenomics, metatranscriptomics, proteomics, and metabolomics provides a mechanistic picture on how fermentation systems process complex polyphenol mixtures into specific bioactive metabolite profiles and how these changes are linked to microbial community dynamics. This understanding allows for the rational development of starter cultures, co-cultures, and process parameters through control of polyphenol biotransformation into targeted metabolites that have potential beneficial effects on fermented food quality and human health.
6 Functional roles of polyphenol metabolites in gut health
6.1 Gut microbial modulation
Polyphenol metabolites generated by food fermentation and further gut microbiota metabolism become key effectors modulating the intestinal ecosystem through impact on microbial composition and host inflammatory conditions. These metabolites can also function as selective growth factors for commensal to help and maintain health of the gut and provide systemic benefits (96). Polyphenol-metabolites mediated fermentation acts directly within the gut to exert selective pressures on enteric microbiota, as commensals and pathogens differ substantially in their capacity to use such metabolites as substrates or be antimicrobially impacted by them. Individual, small phenolic acids and flavonoid catabolites can be utilized by beneficial genera such as Bifidobacterium and Lactobacillus to support their growth and metabolic activity, while higher local concentrations of particular phenolics inhibit pathogenic organisms such as Clostridioides difficile, Escherichia coli or other Enterobacteriaceae (97). Post fermentation phenolic plant metabolites promoted increased populations of Lactobacillus and Bifidobacterium in experimental models, while reducing pro inflammatory and proteolytic taxa involved in dysbiosis (98). Also, fermented polyphenol extracts increased the population of beneficial LAB and bifidobacteria in the colon as well as reduced the populations of inflammatory and endotoxin-producing microorganisms and exert prebiotic-like effect (99). These observations showed that polyphenol metabolites contribute to influence a particular microbiota profile toward one more favorable for barrier function, short chain fatty acid production and decreases susceptibility to infection.
6.2 Reduction of gut inflammation
Polyphenol-derived metabolites also aid in reducing gut inflammation by acting directly on host cells and indirectly through the modulation of microbiota. The fermented and microbiota-derived phenolic acids possess anti-inflammatory effects, such as inhibiting NF-κB activation, reducing pro-inflammatory cytokines likes TNF-α, IL-1β, IL-6 expression and increasing the synthesis of anti-inflammatory mediators like IL-10 on intestinal epithelial cells and immune cells (100). Polyphenol-rich substrates fermented by LAB-derived metabolites that dampen the expression of inflammatory markers and oxidative stress in intestinal cell models and experimental colitis were associated with simultaneous increased levels of beneficial and decreased levels of pro-inflammatory bacteria (101). Li et al. (133) has also reported that certain microbial polyphenol metabolites could attenuate aspects of inflammatory bowel disease (IBD) in pre-clinical models by strengthening the tight junction, decreasing mucosal oxidative damage, and modulating of the microbial community toward a more anti-inflammatory profile. By such pathways, fermented food-derived polyphenol metabolites may alleviate chronic low-grade gut inflammation and as adjuncts in regimens aimed at IBD and diseases with similar pathology.
6.3 Synergy between polyphenols and probiotics
Probiotics and polyphenols seem to exert a synergistic effect on gut barrier function and mucosal immunity. Probiotic strains like Lactobacillus and Bifidobacterium not only survive better in polyphenol-rich conditions, but are also able to convert the polyphenols into metabolites that exhibit more biological activity and conversely, most of polyphenols and their derivatives can improve the adhesion, stress tolerance and competitive exclusion of pathogens by probiotics (102). Likewise, the combination of probiotics with polyphenol-rich foods or extracts also enhanced the expression of tight junction proteins likes occludin and claudins and reduced intestinal permeability over both alone. All these combinations also facilitated more robust immune modulation, in terms of promoting sIgA generation and maintaining Th17/Treg balance, thus enhancing mucosal protection (103). As a result, fermented functional foods combining specific probiotic strains with customized polyphenol profiles in recent years are considered potential contributors to the targeted manipulation of gut microbiome composition and host immunity (104). These findings support a selective effect of fermentation-derived polyphenol metabolites, particularly in combination with probiotics toward beneficial gut bacteria along with attenuation of inflammatory processes and enhancement of the intestinal barrier function to provide a comprehensive way into gut health.
7 Health implications and functional food applications
Polyphenol metabolites, formed during fermentation and subsequent gut microbial metabolism, act not just within the intestine but afar too, affecting cardiovascular, metabolic, neurocognitive and cancer-related pathways systemically (76). Their better bioavailability and structural diversity than dietary natural polyphenols make them to interact with various molecular targets, rendering the fermented polyphenol-rich foods as promising sources for functional food development and disease risk modulation as shown in Figure 3 (105).
Figure 3. The molecular signalling pathway of polyphenol metabolits.
7.1 Systemic health benefits
7.1.1 Cardiovascular health
Polyphenol consumption showed the improved cardiovascular health while fermentation-based metabolites have been shown to reinforce those associations by improving bioavailability as well as potency (106). Phenolic acid and flavonoid aglycone generated during fermentation process may contribute to the improvement of endothelial function through the upregulation of eNOS expression, enhancement of NO bioavailability, and attenuation of oxidative inactivation of NO, which results in vasodilation and blood pressure regulation. These metabolites also prevent LDL oxidation and downregulate the expression of adhesion molecules and inflammatory markers in vascular endothelium, which is crucial to atherogenesis (107). The consumption of fermented teas, cocoa beverages or polyphenol-enriched fermented dairy and plant-origin drinks demonstrate changes in blood pressure (BP), flow-mediated dilation (FMD) or circulating oxidized low-density lipoprotein (LDL) and C-reactive protein lower than those recorded for non-fermented equivalents thereby increasing the evidence to suggest that fermentation-derived polyphenols help reducing cardiovascular risk markers, what is indeed making an impression on mechanisms of protection against CVD's by fermentative polyphenolic-containing foods in health promotion programs (108).
7.1.2 Neuroprotective effects
Fermented polyphenol metabolites might exert neuroprotection through direct antioxidative and anti-inflammatory effects in the central nervous system, as well as by modulating the gut-brain axis. Some plogenol acids and flavonoid metabolites representative of microbial metabolism have been shown to be more efficient in their blood-brain barrier penetration with respect to their parent molecules, where they may act directly against ROS, modulate neuronal signaling pathways such as Nrf2, ERK/CREB, and also reduce microglial activation (109). Gut-derived metabolites feed backward from the lumen to shape the composition and metabolic activity of microbiota, resulting in differential production of neuroactive intermediates including short-chain fatty acids (SCFAs), tryptophan derivatives and microbial neurotransmitter analogs signaling directly or indirectly via neural, endocrine and immune pathways with brain impacting effects. Fermented polyphenol-rich diets result in beneficial effects on cognitive performance, reduction of neuroinflammation and attenuation of pathology in models related to neurodegenerative disorders, which are predominantly linked with not only systemic antioxidant status but also favorable alterations in the gut microbiota (110). The molecular signaling pathway of polyphenol metabolits shown in Figure 4.
Figure 4. Health implications and functional food applications.
7.1.3 Prevention of chronic metabolic and neoplastic diseases
Polyphenol metabolites produced through fermentation also are involved in the prevention or reduction of chronic diseases, likes type 2 diabetes, obesity and selected cancers at specific molecular levels. In metabolic control, they can also be beneficial to insulin sensitivity modulating insulin signaling cascades such as PI3K/Akt, increasing glucose uptake and decreasing hepatic gluconeogenesis (111). They may also modulate adipogenesis and energy expenditure by promoting phosphorylation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs), which in turn limit triacylglycerol accumulation, improve lipid profiles (112). Glycemic management fermented pulse and cereal products enriched with bioactive phenolic acids reported improvements in glycemic control, decrease in postprandial glucose, significant changes on markers of metabolic syndrome when compared with non-fermented controls (113).
In cancer protection, fermentation may lead to higher levels of phenolic metabolites impacting chemical carcinogen metabolism and the modulation of cell proliferation and apoptosis. Some fermentation-derived phenolic acids and flavonoid derivatives cause cell cycle arrest, activate the intrinsic apoptosis pathway, restrict angiogenesis, and obstruct signaling circuits including NF-κB, STAT3, MAPKs in cancer cell lines. On the other hand, fermented pulse polyphenols such as lupins are reported to have a higher anticancer effect in vitro than non-fermented extracts as they needed lesser concentration to induce apoptosis and inhibit tumor cell growth, which would be due to the microbial modification of phenolic profile (114). These findings provide support for fermented polyphenol-rich foods as a component of integrated cancer prevention approaches. Different phenolic compound and their health implications are summarized in Table 2.
Table 2. Health implications of fermented polyphenol compounds.
7.2 Industrial applications as functional foods
There has been growing commercial interest in polyphenol-enriched fermented foods and beverages, plant-based dairy alternatives, and nutraceutical preparations. For example, fermented teas, kombucha-type beverages, and fruit wines have been shown to be rich sources of catechins along with also higher quantities of phenolic acids or other flavonoids which are typically lower in concentration changes during fermentation leading to an increase in antioxidant potential and better sensory properties (115). Likewise, yeast- and bacteria-mediated transformations are employed for enhancing flavor and for evolving the composition of bioactive phenolics and therefore sensory quality associations with functional attributes have been established in fermented cocoa and coffee products (116).
Plant-based dairy substitutes, e.g., fermented soy, oat or almond drinks nowadays be prepared with starter cultures that have been selected for their potential to release and convert inherent or added polyphenols (117). Delivering probiotics with phenolic metabolites by fermentation such as the symbiotic bacteria that produce lactic acid and bifidobacteria can be subjected to co-culture in a fermentation environment with polyphenol-rich substrates in order to generate “synbiotic” beverages that incorporate live bacteria and phenolic metabolites released through the process of bacterial fermentation into one or multiple biologically active compounds targeting well-defined gut, cardiometabolic, and immune health effects (118). Fermentation of plant based drinks preparation or grain based existing beverages with selected microbial consortia not only enhanced the contents of free phenolic acids, antioxidant activities but also improved shelf life, which may facilitate marketing of these functionalized products on a large scale (119).
In addition to beverages, polyphenol-enriched fermented powders, capsules and extracts are being commercialized as a dietary supplement or ingredient for the fortification of bakery, snack and dairy products (120). These compounds are frequently obtained by the fermentation of a fruit, vegetable or pulse matrix with specific strains, drying and standardizing to specific phenolic markers. This strategy permits the boosting of bioactive metabolite levels at more constant doses and their incorporation into a broader range of food formats without potential sensory hurdles linked to high native polyphenol contents, such as astringency or bitterness (121). The industrial application of fermentation to improve polyphenol functionality endorses a well-developing area of the functional food and nutraceutical sectors.
7.3 Sustainability aspect of plant-based fermented polyphenols
Fermentation of plant-based polyphenol substrates is also among sustainable food trends as fermentation facilitates production and intake of value-added, food-based products that serve as functional alternatives to animal-based food components and make more efficient use of farming resources. A large number of polyphenol-rich fermentation substrates, such as fruit pomace, cereal bran and legume by-products and other side streams are residues from food processing that would require disposal or be underutilized. Microbial fermentation can valorize such feedstocks to value-added products by releasing phenolics in the bound forms, producing new metabolites and rendering them safe thereby extending shelf life (122). For instance, grape pomace, olive mill waste or cereal bran fermented with LAB, yeasts or molds can lead to powders and extracts rich in bioactive phenolic acids and flavonoids for incorporation into foods, beverages or supplements, thereby reducing any waste generated by the process while uncovering new pathways to revenue.
When compared to many animal-derived functional foods niche likes dairy and meat products, plant fermented polyphenols can potentially involve lower greenhouse gas emissions, land and water footprints especially when based on agroforestry side flows or low input crops. It also targets consumer request for plant-based, “clean label” functional alternatives that meet societal or environmental preferences, or personal dietary needs (123). Through integrating microbiology, food technology and sustainability, fermentation therefore represents an approach to creating functional foods that achieve systemic health effects with a minimum degree of environment burden. Polyphenol-rich fermented foods are now being promoted as potential, possibly sustainable alternatives or supplements to conventional animal-based functional products.
8 Challenges and future directions
The investigation of fermented polyphenols is confronted with several challenges, such as the incomplete knowledge on the particular microbial pathways that transform distinct polyphenol structures into bioavailable metabolites. Although several types of enzymes likes β-glucosidases, tannases or decarboxylases have been detected only in poly-fermentations, degradative conversion was typically achieved by a variety of microbial consortia showing redundancy in their capability to convert substrates and contribute toward cooperative or linear degradation processes. This restriction constrains not only mechanistic knowledge but also the rational design of starter cultures toward producing desired polyphenol metabolites. Furthermore, fluctuations in the traditional fermentation process driven by differences in raw material and substrate used, diversity of inocula, factors related to environment and processing also cause inconsistency between the designs and metabolite profiles achieved between different batches. Such variation hinders reproducibility, impedes dose-response knowledge and may allow the production of off-flavors or contaminants, underlining the necessity for controlled and standardized fermentations. Furthermore, there is a lack of effective translation from good in vitro and animal experimental evidence to strong human clinical data. Current human studies are studying products that are often of variable batch and content, not well phenotyped for their polyphenol profile and experiencing great per individual differences in microbiota, genetics and life-style which determine responsiveness. In the absence of comprehensive omics data spanning these trials, it is difficult to definitively connect specific fermentation-derived polyphenol metabolites to clinical effects and illustrates how urgently require controlled multi-arm human studies with accurate compositional and functional readouts.
Further developments will depend on precision fermentation, which involves using specific microbial communities, standardized substrates and controlled conditions that allow for the repeated synthesis of selected polyphenol metabolites. Through careful selection of strains with defined enzymatic profile and fine-tuning pH, temperature, nutrient concentration, specific transformations likes isoflavone deglycosylation, hydroxy-cinnamic acid de-esterification can be promoted over non-desirable side products. Adaptive control of fermentation by analytical technologies for real-time monitoring and specification-based corrective action can move from empirical to predictable “fermentation”. Synthetic biology offers a suite of advanced tools to tailor-make microbes with either enhanced or unprecedented polyphenol-transforming pathways that are more efficient and reliable at producing particular bioactive metabolites. However, regulatory, safety and acceptance among consumers poses careful consideration before use of engineered strains will be widely accepted.
Broadening multiomics systems including integrated metagenomics, metatranscriptomics, proteomics, and metabolomics applications is transforming the capabilities to understand fermentation systems through community composition, gene expression, enzyme activity, and metabolite dynamics connections. Time-resolved multi-omics at high resolution allows for predictive mechanistic modeling and rational optimization of fermentations by providing insights into how the microbial ecology and metabolic pathways respond to variation in strain choice, substrate composition, or environmental conditions. Integrating multi-omics into clinical nutrition also offers potential advances in precision diets through linking fermented food metabolite profiles to the changes in gut microbiome, host metabolic responses, and health status. Although real-time monitoring and adaptive interventions are technically challenging, these constitute the frontier for personalized nutrition with fermented polyphenols. And lastly, the incorporation of safety evaluations and sustainability concepts is critical. Contaminant profiling for mycotoxins and biogenic amines helps guarantee that fermented products are safe for broad consumption. By the same token, the valorization of agri-food by-products and side streams from plants for polyphenol fermentation is in line with a circular economy approach minimizing environmental footprints compared to animal-based functional foods. Multi-criteria assessments including nutrition, health, safety and environmental impact will be used to guide the design of effective, safe and sustainable fermented polyphenol-based products. In conclusion, the current bottleneck of mechanistic understanding, standardization and clinical validation can be tackled by precision fermentation, synthetic biology and by comprehensive multi-omics to reveal the full potential of fermented polyphenols. This integrated pipeline promotes the exploration of new generation functional foods and personalized nutrition interventions for better public health.
9 Conclusion
Polyphenols, bioactive compounds in plant-based foods, are known for their antioxidant, anti-inflammatory, and antimicrobial properties, but their bioactivity and bioavailability are limited by their complex structures. Fermentation enhances polyphenols' bioavailability and bioactivity by converting them into more bioavailable metabolites with improved solubility, stability, and antioxidant properties. These transformations increase their absorption and health benefits. Fermented polyphenol metabolites also modulate gut microbiota, promoting beneficial bacteria like Lactobacillus and Bifidobacterium, supporting gut health, reducing inflammation, and offering systemic benefits, including improved metabolic, immune, and neurocognitive health. However, gaps remain in understanding the microbial pathways of polyphenol transformation and their health outcomes. Future research should focus on detailed metabolite analysis, multi-omics approaches, and human clinical trials to validate these health benefits. Advancements in fermentation technology, including precision fermentation, can further optimize polyphenol-enriched functional foods, utilizing underutilized food by-products and offering sustainable solutions for both health and environmental challenges.
Author contributions
NA: Conceptualization, Data curation, Formal analysis, Funding acquisition, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgments
The researcher would like to thank the Deanship of Graduate Studies and Scientific Research at Qassim University for financial support (QU-APC-2025).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: bioavailability, fermentation, gut microbiota, microbial enzymes, polyphenols
Citation: Alharbi NA (2026) Polyphenol metabolites in fermented foods: biotransformation, bioavailability, and functional roles. Front. Nutr. 13:1767453. doi: 10.3389/fnut.2026.1767453
Received: 14 December 2025; Revised: 29 December 2025;
Accepted: 05 January 2026; Published: 29 January 2026.
Edited by:
Brij Pal Singh, Chandigarh University, IndiaReviewed by:
Mukul Machhindra Barwant, Sanjivani Arts, Commerce and Science College, IndiaSamridhi Lal, Amity University Haryana, India
Muhammad Saqib, Xi'an Jiaotong University, China
Copyright © 2026 Alharbi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Nouf Abdullah Alharbi, bm91Zi5hbGhhcmJpMkBxdS5lZHUuc2E=