Plant polyphenols and gut microbiota: An interdependent relationship and its repercussions for human health

Dietary polyphenols are structurally diverse plant-derived bioactive compounds increasingly recognised for their interactions with the gut microbiota and their potential influence on human health. Although polyphenols include phenolic acids, flavonoids, stilbenes, lignans, and tannins, many exhibit limited absorption in the small intestine because of their glycosylation, polymerization, and association with the food matrix. Consequently, substantial quantities reach the colon, where gut microorganisms transform them through deglycosylation, hydrolysis, demethylation, dehydroxylation, reduction, and ring cleavage into more readily absorbed metabolites, including phenolic acids, phenyl-γ-valerolactones, urolithins, and enterolignans. This relationship is bidirectional, as polyphenols and their metabolites can also reshape microbial composition and function by promoting beneficial taxa, suppressing opportunistic pathogens, enhancing short-chain fatty acid production, and supporting intestinal barrier integrity. Their antimicrobial effects involve membrane disruption, enzyme inhibition, metal chelation, interference with adhesion and biofilm formation, and modulation of bacterial virulence. Microbiota-derived metabolites may subsequently enter systemic circulation and contribute to cardiometabolic, anti-inflammatory, and neuroprotective effects. Importantly, inter-individual differences in gut microbial composition and metabolic capacity generate distinct metabotypes, resulting in considerable variability in biological responses to polyphenol-rich foods. This review examines the chemistry, bioavailability, microbial biotransformation, microbiota-modulating properties, and health implications of dietary polyphenols, emphasizing the polyphenol- microbiota-metabolite axis. Greater integration of metabolomics, metagenomics, controlled human studies, and microbiome profiling is required to clarify causal mechanisms and facilitate the development of microbiota-informed personalized nutritional strategies for improving human health.

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Introduction

Dietary polyphenols are diverse plant-derived bioactive compounds that interact closely with the gastrointestinal environment and influence human health (Valdés et al., 2015; Wang et al., 2022) [1, 2] . Their relationship with the gut microbiota is bidirectional. Because many polyphenols are poorly absorbed in the small intestine, substantial amounts reach the colon, where gut microorganisms transform them into smaller and often more bioavailable metabolites. In turn, polyphenols and their metabolites can modify microbial composition and metabolic activity (Cano et al., 2024; Çatalkaya et al., 2020) [3,4] . This reciprocal interaction may contribute to metabolic homeostasis and protection against obesity, type 2 diabetes, dysbiosis, and inflammation (Koudoufio et al., 2020; Mahdi et al., 2025) [5, 6] . Polyphenols can promote beneficial microorganisms while suppressing potentially harmful bacteria, thereby exerting prebiotic-like effects (Rodríguez-Daza et al., 2021) [7] . Central to these effects is the "polyphenol-microbiota-metabolite" axis, in which microbial composition and functional capacity determine the type and quantity of metabolites generated from dietary polyphenols. Microbial transformation produces compounds such as phenolic acids and urolithins that may exhibit biological activities distinct from their parent compounds (Plamada & Vodnar, 2021; Ray & Mukherjee, 2021) [8,9] . Inter-individual differences in gut microbiota generate distinct metabolic phenotypes, or metabotypes, which may explain variable responses to polyphenol-rich foods and provide a basis for personalised nutrition (Narduzzi et al., 2022) [10] . Recognition of the generally low systemic bioavailability of native polyphenols has shifted attention from their direct antioxidant activity towards gastrointestinal metabolism and microbial biotransformation. Colonic reactions, including deglycosylation, hydrolysis, reduction, dehydroxylation, and ring cleavage, generate numerous bioactive derivatives (Loo et al., 2020) [11] . This review therefore examines polyphenol bioavailability, microbial biotransformation, microbiota modulation, and associated health effects, with particular emphasis on interindividual variability and microbial metabotypes as potential tools for developing personalised nutritional strategies.

Classification of Plant Polyphenols: Chemistry, Structure, and Properties of Dietary Polyphenols

The way polyphenols act in the body is closely tied to their molecular structure, including the number and position of hydroxyl groups, aromatic conjugation, glycosylation, methylation, esterification, and degree of polymerisation. These features determine their polarity, solubility, chemical stability, antioxidant and metal-chelating activity, intestinal absorption, microbial accessibility, and overall biological activity (Crozier et al., 2009) [12] . Based on their carbon skeleton and structure, dietary polyphenols are generally grouped into phenolic acids, flavonoids, stilbenes, lignans, and tannins (Del Rio et al., 2013; Shahidi & Yeo, 2018) [13] .

Phenolic Acids

Phenolic acids are simple dietary polyphenols classified as hydroxybenzoic acids (C6-C1), including gallic, protocatechuic, vanillic, and syringic acids, and hydroxycinnamic acids (C6-C3), such as caffeic, ferulic, pcoumaric, and sinapic acids. Their biological properties depend largely on hydroxylation and methoxylation patterns. Catechol structures, as in caffeic acid, enhance antioxidant and metalchelating activity (Rice-Evans et al., 1996) [14] , whereas methoxylation can influence lipophilicity and metabolic stability. Phenolic acids occur in free or conjugated forms in cereals, fruits, vegetables, and coffee. Bound hydroxycinnamic acids, particularly ferulic acid, often reach the colon, where microbial esterases release and transform them into bioactive metabolites.

Flavonoids

Flavonoids are the largest and most structurally diverse class of dietary polyphenols, characterised by a C6-C3-C6 skeleton comprising two aromatic rings linked through a heterocyclic Cring (Panche et al., 2016) [15] . Structural alterations distinguish flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, isoflavones, and chalcones. Their antioxidant activity depends mainly on B-ring catechol groups, C2=C3 conjugation with a 4oxo group, and hydroxylation, with quercetin exhibiting particularly strong radical-scavenging activity. Most dietary flavonoids occur as Oglycosides, which influence solubility and intestinal absorption. Unabsorbed flavonoids reach the colon, where microbial glycosidases hydrolyse them and facilitate further biotransformation into smaller metabolites (Del Rio et al., 2013) [13] .

Stilbenes

Stilbenes possess a characteristic C6-C2-C6 skeleton, with two aromatic rings connected by an ethylene bridge. Resveratrol (3,5,4′-trihydroxystilbene), the best-characterised dietary stilbene, occurs as cis and trans isomers, with trans-resveratrol being more stable and extensively studied. Its conjugated double bond promotes molecular planarity and electron delocalisation, while hydroxyl groups contribute to antioxidant activity. Although resveratrol is efficiently absorbed, its systemic bioavailability is low because of rapid intestinal and hepatic glucuronidation and sulfation (Walle, 2011) [16] . It also occurs as the glucoside piceid (polydatin), which requires hydrolysis before absorption.

Lignans

Lignans are formed by coupling two phenylpropanoid (C6-C3) units, commonly through a β-β′ linkage, producing a (C6-C3) framework. Major dietary lignans include secoisolariciresinol,₂ matairesinol, pinoresinol, and lariciresinol, commonly found in flaxseed, sesame seeds, whole grains, legumes, fruits, and vegetables. Plant lignans primarily act as precursors of mammalian enterolignans. Gut microbiota transform them through deglycosylation, demethylation, dehydroxylation, and dehydrogenation into enterodiol and enterolactone (Rowland et al., 2018). These readily absorbed metabolites can interact with estrogen receptors, giving them phytoestrogenic activity and demonstrating the close relationship between lignan structure, microbial metabolism, and biological effects.

Tannins

Tannins are high-molecular-weight polyphenols rich in phenolic hydroxyl groups and are classified into hydrolysable and condensed tannins (Serrano et al., 2009) [17] . Hydrolysable tannins include gallotannins and ellagitannins, generally containing a glucose core esterified with gallic acid or hexahydroxydiphenoyl groups. Ellagitannins release ellagic acid, which gut microbiota convert into bioactive urolithins. Condensed tannins, or proanthocyanidins, are polymers of flavan-3-ols such as catechin and epicatechin linked mainly through C4-C8 or C4-C6 bonds. Their large molecular size limits intestinal absorption, allowing substantial amounts to reach the colon, where microbial metabolism produces smaller phenyl-γ-valerolactones and phenolic acids that can be absorbed systemically (Del Rio et al., 2013; Mena et al., 2018) [13, 18] .

Structural Determinants of Polyphenol Bioavailability

The bioavailability of dietary polyphenols depends largely on their chemical form and molecular structure, including molecular weight, hydroxylation, methylation, glycosylation, esterification, and polymerisation (Del Rio et al., 2013) [13] . Larger and highly polymerised compounds, such as proanthocyanidins, generally show poor intestinal absorption. Glycosylation and esterification influence solubility and may require hydrolysis before absorption, while association with dietary fibre increases delivery to the colon (Crozier et al., 2009) [12] . After absorption, polyphenols undergo extensive phase II metabolism, mainly glucuronidation, sulfation, and methylation. Consequently, circulating polyphenol-related compounds occur predominantly as conjugated derivatives and microbial metabolites rather than unchanged parent compounds (Del Rio et al., 2013) [13] .

Gut Microbial Biotransformation and Structure-Metabolism Relationships

Polyphenols that escape small-intestinal absorption reach the colon, where gut microbiota convert them into lowermolecular-weight metabolites through deglycosylation, deesterification, demethylation, dehydroxylation, reduction, and ring cleavage. These conversions are classdependent: flavonoids yield various phenolic acids, flavan-3-ols and proanthocyanidins produce phenyl-γ-valerolactones, ellagitannins generate urolithins, and lignans form enterodiol and enterolactone (Del Rio et al., 2013; Mena et al., 2018; Rowland et al., 2018) [13,18] . Thus, structural intricacy that limits intestinal absorption increases delivery to the colon, making microbial metabolism a major determinant of polyphenol bioavailability and biological activity.

Convergence Toward a Shared Metabolic Landscape

Microbial catabolism converts structurally diverse polyphenols into a smaller pool of lowmolecular-weight metabolites, including phenolic derivatives, phenyl-γ-valerolactones, urolithins, and enterolignans (Del Rio et al., 2013) [13] . These metabolites are generally more readily absorbed than their dietary precursors and may contribute substantially to systemic effects. Their production differs among individuals because of differences in gut microbiota composition and metabolic capacity, resulting in distinct metabotypes, as demonstrated for urolithin production from ellagitannins (Cortés-Martín et al., 2020) [19] . Therefore, polyphenol bioactivity depends on chemical structure, host metabolism, and individual microbiota. Integrating metabolomics, metagenomics, and microbiome profiling may help develop personalized dietary strategies. [20,21,19] . While simple aglycones may be absorbed in the upper gastrointestinal tract, complex polyphenols require microbial enzymes, including βglucosidases, esterases, dehydroxylases, and reductases, to be transformed into more readily absorbed metabolites (Eid et al., 2017) [22] . Microbial metabolism generates phenolic acids, phenylvalerolactones, urolithins, equol, and related metabolites, which undergo phase II conjugation before entering systemic circulation and may contribute to the biological effects of polyphenol-rich diets (Monagas et al., 2010; Williamson, 2025) [23, 24] . However, metabolite production varies considerably among individuals because of differences in microbiota composition and metabolic capacity, resulting in distinct polyphenol metabotypes (Fraga et al., 2019; Corrêa et al., 2019) [25, 26] food-matrix interactions, particularly binding to dietary fibre, additionally affect microbial accessibility and absorption. Thus, polyphenol bioavailability depends on the relationship between chemical structure, food matrix, microbial biotransformation, and individual gut microbiota, with important implications regarding precision nutrition.

Intestinal Absorption of Dietary Polyphenols

The intestinal absorption of dietary polyphenols is strongly influenced by molecular size, polymerisation, glycosylation, esterification, and lipophilicity. Small, lipophilic aglycones may cross the small-intestinal epithelium by passive diffusion, whereas glycosylated polyphenols generally require hydrolysis before absorption (Del Rio et al., 2010) [27] . Flavonoid glycosides can be hydrolysed by brush-border lactase-phlorizin hydrolase (LPH) or intracellular β-glucosidases, while unabsorbed compounds reach the colon for microbial transformation (Cardona et al., 2013) [28] . Carrier-mediated transport may add to the uptake of specific phenolics. Highmolecular-weight polyphenols, particularly proanthocyanidins and tannins, are poorly absorbed and reach the colon, where gut microbiota convert them into smaller metabolites, including phenyl-γ-valerolactones, phenylpropionic acids, and phenylacetic acids, which can subsequently be absorbed (Pérez-Jiménez et al., 2013; Sharma et al., 2022) [30,29] . The food matrix further affects bioaccessibility because phenolics bound to plant cell-wall polysaccharides require enzymatic release (Lin et al., 2019; Shahidi et al., 2019) [31,32] . Following absorption, polyphenols undergo extensive intestinal and hepatic phase II metabolism, particularly glucuronidation, sulfation, and methylation. Consequently, systemic circulation contains relatively low concentrations of unchanged polyphenols and predominantly their conjugated and microbiota-derived metabolites (Del Rio et al., 2013) [13] . Schematic representation of the intestinal absorption of dietary polyphenols, illustrating passive diffusion, limited transportermediated uptake, enzymatic hydrolysis, gut microbiota-mediated degradation of complex polyphenols, phase II conjugation, and the formation of bioavailable microbial metabolites that enter systemic circulation.

Tissue Distribution and Elimination

Following intestinal absorption, dietary polyphenols circulate predominantly as phase II metabolites, particularly glucuronides, sulfates, and methylated derivatives, rather than native aglycones (Jiang & Hu, 2012; Ruskovska et al., 2019) [33,34] . Their pharmacokinetics vary with chemical structure and metabolic origin. Small-intestinal metabolites generally appear rapidly in plasma, whereas gut microbiota-derived metabolites emerge later following colonic biotransformation and absorption (Minatel et al., 2017) [35] . Polyphenol metabolites have been detected in the liver, kidneys, vascular tissues, adipose tissue, heart, and, for selected compounds, the brain, although distribution is highly compound-specific (Teng & Chen, 2018; Velderrain-Rodríguez et al., 2013) [36,37] . Tissue exposure depends on polarity, molecular size, membrane permeability, protein binding, and cellular transporters. OAT, MRP, and ABC transporters contribute to cellular uptake, efflux, biliary secretion, and renal elimination (Wang et al., 2018; Wong et al., 2011) [38,39] . Enterohepatic recirculation may further prolong exposure by allowing biliary conjugates to undergo microbial deconjugation and subsequent reabsorption (Heleno et al., 2014) [40] . Importantly, conjugated metabolites are not necessarily biologically inactive and may undergo local deconjugation or directly influence cellular signalling and inflammatory pathways (Muñoz-González et al., 2019; Rein et al., 2012) [42,41] . Microbial metabolites, including phenolic acids, phenylγvalerolactones, urolithins, and enterolignans, add further to to systemic exposure. Considerable inter-individual variability in microbiota, metabolic enzymes, and transporters produces distinct circulating metabolite profiles (Carregosa et al., 2022; Lorenzo et al., 2021) [43,44] . Thus, polyphenol bioavailability reflindicates a dynamicyphenol-microbiota-metabolite axis rather than exposure to native compounds alone. Overview of the systemic distribution of absorbed polyphenol metabolites, highlighting phase II conjugation, transport to peripheral tissues, enterohepatic recirculation, transportermediated uptake and elimination, tissue-specific accumulation, and factors influencing inter-individual variability in their biological activity.

Modulation of Gut Microbiota by Dietary Polyphenols

Dietary polyphenols act not only as as agentsr microbial metabolism but also as modulators of gut microbiota composition and activity. Because substantial amounts reach the colon, polyphenols and their metabolites can exert selective antimicrobial and prebiotic-like effects, potentipossibly suppressingl microorganisms while favouring beneficial taxa (Bačić et al., 2023; Duda-Chodak et al., 2015) [46,45] . Polyphenol-rich diets have been associated with increased [47,48,49] . Polyphenols influence microorganisms through multiple mechanisms, including membrane disruption, enzyme inhibition, metal chelation, and interference with adhesion, biofilm formation, and energy metabolism. Their microbial metabolites can further modify community structure and crossfeeding interactions. Such ecological changes may enhance production of short-chain fatty acids (SCFAs), particularly acetate, propionate, and butyrate, supporting epithelial barrier integrity, immune regulation, and metabolic signalling (Fava et al., 2018; İlhan, 2018) [50] .

Importantly, the polyphenol-microbiota relationship is bidirectional. Gut microorganisms transform ellagitannins into urolithins, daidzein into equol, lignans into enterodiol and enterolactone, and flavan-3-ols into phenyl-γvalerolactonesand phenolic acids (Pasinetti et al., 2018) [51] . Individual differences in microbial composition produce distinct metabotypes, causing variable biological reactions to identical polyphenol-rich foods. By improving microbial balance and intestinal barrier function, polyphenols may reduce LPS translocation and metabolic inflammation (Mahdi et al., 2025) [6] . Microbial metabolites may additionally influence the gut-liver, gut-brain, gut-immune, and gut-metabolic axes (Bernardi et al., 2019; Kasprzak-Drozd et al., 2021) [52,53] . Thus, polyphenol effects reflect an integrated polyphenol-microbiotametabolite-host axis, although further human studies are required to establish clinical relevance.

Prebiotic-like Effects

Dietary polyphenols exert prebiotic-like effects by selectively modulating the gut microbiota. They can promote beneficial bacteria such as Bifidobacterium, Lactobacillus, Akkermansia muciniphila, and Faecalibacterium while controlling potentially harmful microorganisms (Fraga et al., 2019; Rodríguez-Daza et al., 2020) [25,54] . These effects depend on polyphenol structure, dose, food matrix, and the existing microbial community. Polyphenol-induced microbial changes is able to enhance short-chain fatty acid production, strengthen intestinal barrier integrity, and improve immune and metabolic regulation. Enrichment of taxa such as A. muciniphila has been associated with improved mucus-layer function and reduced inflammatory signalling (Collins et al., 2016; Roopchand et al., 2015) [55,56] . Polyphenols may also inhibit opportunistic microorganisms through membrane disruption, enzyme inhibition, metal chelation, and interference with adhesion and biofilm formation (Corrêa et al., 2019) [26] . These changes can reduce intestinal permeability and limit the translocation of lipopolysaccharide into the circulation, thereby attenuating systemic inflammation (Medina-Larqué et al., 2022) [57] . Overall, polyphenols act as selective microbial modulators rather than classical prebiotics. Their ability to reshape microbial composition, enhance beneficial metabolites, and support intestinal barrier function provides an important mechanism linking polyphenol-rich diets with better metabolic health.

Antimicrobial Activities

Plant polyphenols exhibit antimicrobial activity against diverse Gram-positive and Gram-negative bacteria through several complementary mechanisms. A major mechanism entails disruption of bacterial membrane integrity, increasing permeability, leakage of intracellular components, metabolic dysfunction, and cell death (Lessard-Lord et al., 2024) [58] . Antimicrobial potency is structure-dependent, particularly on hydroxylation, lipophilicity, and polymerisation (Bouarab-Chibane et al., 2019; Lee, 2013) [59,60] . Polyphenols can inhibit pathogens such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella Typhimurium, Clostridium perfringens, and Clostridioides difficile (Qu et al., 2018; Sánchez-Moya et al., 2024) [61,62] . Beyond membrane disruption, polyphenols can inhibit bacterial adhesion, biofilm formation, energy metabolism, and virulence. Certain flavonoids inhibit fatty-acid biosynthesis enzymes, including KAS I and KAS III, while metal chelation restricts vital nutrients such as iron (Khameneh et al., 2019; Khare et al., 2021) [63,64] . Polyphenols may additionally disrupt bacterial redox balance and inhibit multidrug efflux pumps, possibly increasing antibiotic susceptibility (Górniak et al., 2018; Maisuria et al., 2019) [65,66] . These selective antimicrobial effects may support gut microbial homeostasis by suppressing opportunistic pathogens while favouring commensals such as Akkermansia muciniphila, Lactobacillus, and Bifidobacterium (Anhê et al., 2016; Rodríguez-Daza & Vos, 2022) [67,57] . Collectively, these mechanisms underpin the antimicrobial potential of plant polyphenols (Figure 4).

Dysbiosis Modulation

The gut microbiota is usually kept balanced, called eubiosis, which assists in maintaining a healthy relationship with the immune system. In contrast, dysbiosis, which is an imbalance in the makeup, diversity, and function of gut microbes, can lead to gut and other diseases, including obesity and diabetes (Rodríguez-Daza et al., 2021; Singh et al., 2019) [7,68] . Dietary polyphenols have been found to help prevent and correct dysbiosis by acting like prebiotics. They encourage the growth of beneficial bacteria and limit harmful ones in both animal studies and humans. Polyphenols work by interfering with bacterial communication and membrane function and making microbes more sensitive to other substances, which helps shift the microbial community toward a more balanced state.

Microbial Biotransformation of Polyphenols

Because most dietary polyphenols occur as glycosides, esters, or polymers, a large proportion escapes small-intestinal absorption and accumulates in the large intestine, where it is extensively metabolised by the gut microbiota (Wan et al., 2020; Lopes de Freitas et al., 2022) [49,69] . This biotransformation is a defining feature of the two-way polyphenol-microbiota interaction: the microbiota converts parent compounds into absorbable catabolites with improved bioactivity, while the compounds simultaneously shape microbial composition and function (Wan et al., 2020; Rodríguez-Daza et al., 2021) [49,7] . The formation of these microbial-derived metabolites is central to the metabolic outcomes of polyphenol-rich diets, positioning the gut microbiota as a metabolic engine for phenolic activation.

Catabolic Pathways

Once polyphenols reach the colon, the resident microbiota dismantles their complicated structures glycosides, esters, and polymers through extensive enzymatic biotransformation, generating smaller catabolites with improved absorbability and bioactivity (Wan et al., 2020; Zhang et al., 2022) [49] . Specific bacterial taxa mediate defined conversions: ellagitannins and ellagic acid from berries, pomegranate, and walnuts are metabolised by gut bacteria into urolithins, with taxa such as Gordonibacter implicated within this transformation, while dietary lignans are converted to the bioactive enterolignans (Selma et al., 2017; Corrêa et al., 2019) [70,26] . Characterising these catabolic routes has become central to predicting which bioactive metabolites an individual will generate from a given phenolic intake.

Bioactive Metabolites

Despite the enormous structural diversity of dietary polyphenols, microbial metabolism converges them into a relatively small number of circulating catabolites, including phenolic acids, phenylvalerolactones, urolithins, and enterolignans, whose formation is increasingly recognised as a principal mediator of the health effects of polyphenol-rich diets (Rodríguez-Daza et al., 2021; Wan et al., 2020) [7,49] . Among them, urolithin A has been proposed as a metabotype biomarker of reduced cardiometabolic risk and exerts anti-inflammatory activity in vitro and in vivo, as well as antimicrobial and antiquorum-sensing effects that may further support gut homeostasis (Selma et al., 2017; Rodríguez-Daza et al., 2021) [70, 7] . These microbial-derived metabolites are thus central to translating phenolic intake into systemic metabolic outcomes.

Inter-individual Variability

Microbial biotransformation varies markedly between individuals as a function of gut microbial composition, dietary habits, age, and health status, generating distinct gut metabotypes. For ellagitannins, three urolithin metabotypes A, B, and 0 have been described, which associate with specific bacterial strains and predict cardiometabolic responses (Selma et al., 2017; Landberg et al., 2019) [70,71] . Notably, metabotype-B individuals respond to pomegranate ellagitannins with significant decreases in cardiometabolic risk biomarkers, whereas metabotype-A individuals do not. Similarly, isoflavone-metabolising phenotypes that yield equol or Odesmethylangolesin display differing cardiometabolic risk profiles. These observations show that the biological effects of polyphenols depend more on the efficiency of microbial metabolism than on the quantity consumed.

Health Implications

The polyphenol-microbiota crosstalk translates into wideranging effects on host health, as colonic metabolites influence gut barrier integrity, immune function, and systemic metabolic regulation (Wan et al., 2020; Kasprzak-Drozd et al., 2021) [49,53] . Changes in gut microbiota functions, particularly those linked to polyphenol metabolism, have marked repercussions on host well-being and are associated with reduced inflammation in the context of obesity. By restoring a balanced microbial community and favouring the production of bioactive catabolites, dietary polyphenols contribute to the homeostasis of both the intestinal environment and distal tissues, positioning the gut microbiota as a primary node linking phenolic intake to metabolic outcomes.

Cardiometabolic Benefits

Microbial-derived phenolic metabolites are increasingly implicated in cardiovascular protection. Urolithin A has been positively correlated with apo A-1 and intermediate HDL cholesterol, whereas isourolithin-A and urolithin-B correlate with total cholesterol, LDL, and oxidised LDL, consistent with higher cardiometabolic risk in metabotype-B individuals. Valerolactone isomers reduce monocyte adhesion to vascular endothelium and may prevent atherosclerosis. Human studies published over the past decade consistently associate isoflavone and ellagitannin metabotypes with more favourable cardiovascular risk factors. Moreover, gut microbial metabolism of polyphenols is directly linked to reduced cardiometabolic risk, supporting microbiota-directed strategies for cardiovascular disease prevention.

Gut and Systemic Inflammation

Polyphenol-derived metabolites exert anti-inflammatory effects at multiple sites, including the gut, vascular tissues, and neuronal tissues. Microbiota xenobiotic metabolism linked to polyphenols is associated with reduced inflammation and improved gut health in the context of obesity, and probiotic strains such as Lactobacillus plantarum WCFS1 lower plasma proinflammatory cytokines. Mechanistically, polyphenols modulate intestinal barrier function, innate and adaptive immune responses, and inflammatory signalling pathways, attenuating both local and systemic inflammation. Combined with prebiotic restructuring of the microbial community, these actions likely underlie the anti-inflammatory outcomes of polyphenol-rich dietary patterns in chronic disease.

Neuroprotective and Other Effects

Gut-derived phenolic metabolites can cross the blood-brain barrier and have been proposed to modulate neurotransmitter signalling, reduce neuroinflammation, and improve neural plasticity. Microbial-derived compounds such as 3hydroxyphenylacetic acid show neuroprotective effects in neuronal cell models, and polyphenolic products of the microbiota have been linked to cognitive vigor in rodents. Through the microbiota-gut-brain axis, polyphenols influence microbial composition and metabolite output relevant to the prevention of Alzheimer's and Parkinson's disease. Because hepatic and colonic metabolites reaching the brain are more bioavailable than their parent compounds, (poly)phenols remain strong candidates for cognitive health across the lifespan.

Future Views and Conclusions

A growing body of evidence indicates that the gut microbiota governs the bioavailability and bioactivity of dietary polyphenols, with inter-individual metabotype differences explaining much of the heterogeneity in response to phenolic interventions. Future research integrating metabolomics, metagenomics, and microbiome profiling will clarify the causal processes linking specific microbial ecologies to cardiometabolic and neurocognitive outcomes. We conclude that moving beyond native polyphenol intake toward microbiota-informed dietary strategies represents the next frontier in nutritional science. Developing these approaches will require establishing how individual microbial functional capacity determines the production of health-promoting metabolites such as urolithins and enterolignans.

Research Gaps and Challenges

Despite considerable progress, the detailed processes linking polyphenol intake, microbial metabolism, and human health remain incompletely defined. Most evidence derives from animal models, with few well-controlled human trials, and the majority of studies concern obesity and metabolic syndrome, leaving other pathologies underexplored. The human gut bacteria responsible for most polyphenol transformations remain unknown, and the polyphenol-microbiota interrelationship is not yet fully elucidated (Corrêa et al., 2019; Pinaffi-Langley et al., 2024) [72,26] . Interventional studies with isolated microbial metabolites are scarce, and standardised methods for assessing metabotypes are lacking, limiting the translation of mechanistic insights concerning clinical practice.

Clinical and Nutritional Applications

This information opens practical paths for exact nutrition:identifying an individual's metabotype could guide the selection of polyphenol-rich foods most likely to yield health-promoting metabolites such as urolithins (Pinaffi-Langley et al., 2024; Landberg et al., 2019) [72,71] . Delivery strategies including encapsulation and targeted colonic release are being developed to improve polyphenol solubility and transport, improving their potency in dysbiosis-associated disorders. Polyphenol-enriched foods and supplements could be formulated to restore eubiosis and barrier function in at-risk populations. Ultimately, personalised dietary strategies designed for an individual's microbial functional capacity will be essential to maximise individual responses and standardise future dietary interventions (Cardona et al., 2013; Lopes de Freitas et al., 2022) [28,69] .

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Classification of plant polyphenols based on chemical structure and their gut microbiota-mediated biotransformation into bioactive

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Intestinal absorption mechanisms of dietary polyphenols

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Tissue distribution and systemic fate of dietary polyphenol metabolites.

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