Probiotic–Plant Bioactive Synergy in Gut Health: Mechanisms, Antimicrobial Activity, and Translational Challenges

Article type: Review Article

Keywords: probiotics, phytochemicals, phytoprobiotic, antimicrobial resistance, antimicrobial synergy, gut microbiota, synbiotics, plant bioactive compounds, microbiome modulation, phage therapy

Authors: Monika Elżbieta Jach ⚬, Ewa Sajnaga ⚬, Ewa Ozimek ⚬, Anna Serefko ⚬, Marcello Locatelli ⚬

Affiliations: Department of Molecular Biology, The John Paul II Catholic University of Lublin, Konstantynów Street 1I, 20-708 Lublin, Poland; Department of Biomedicine and Environmental Research, The John Paul II Catholic University of Lublin, Konstantynów Street 1J, 20-708 Lublin, Poland; ewa.sajnaga@kul.pl; Department of Industrial and Environmental Microbiology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka Street 19, 20-033 Lublin, Poland; ewa.ozimek@mail.umcs.pl; Department of Clinical Pharmacy and Pharmaceutical Care, Medical University of Lublin, Chodźki Street 1, 20-093 Lublin, Poland; anna.serefko@umlub.pl; Department of Science, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; m.locatelli@unich.it

License: © 2026 by the authors. CC BY 4.0 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.

Article links: DOI: 10.3390/nu18132112  |  PMC: PMC13363466

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (2.3 MB)

1. Introduction

Antimicrobial resistance (AMR), primarily driven by the overuse and misuse of antibiotics, is a significant global health threat. It is closely linked to increased morbidity, mortality, economic burden, disruption of the gut microbiota, and weakened host immunity. As frontline antibiotics lose their effectiveness, innovative and ecologically sustainable antimicrobial strategies are urgently needed [ref. 1,ref. 2,ref. 3].

In recent years, probiotics have gained considerable attention as potential adjuncts and alternatives to conventional antimicrobial therapies. Probiotics are live microorganisms that, when consumed in adequate amounts, confer health benefits to the host [ref. 4]. Classical lactic acid bacteria (LAB), including Lactobacillus sensu lato strains, exert broad antagonistic effects through competitive exclusion, immune modulation, biofilm interference, and production of antimicrobial metabolites such as organic acids, bacteriocins, and hydrogen peroxide. These antagonistic effects include the occupation of adhesion sites on mucus and epithelial surfaces, competition for fermentable carbohydrates and amino acids, and strain-dependent modulation of epithelial and dendritic cell (DC) responses [ref. 5,ref. 6,ref. 7]. These microbial products are relevant to the concept of postbiotics, which are defined as preparations of inanimate microorganisms and/or their components that confer health benefits to the host. In this context, probiotic-derived metabolites (e.g., organic acids and bacteriocins) released by live bacteria or after bacterial lysis contribute to postbiotic-mediated antimicrobial and immunomodulatory effects [ref. 8]. Simultaneously, non-LAB probiotics, such as Bifidobacterium spp., contribute to carbohydrate fermentation and acetate production [ref. 9,ref. 10], Bacillus spp. offer enhanced technological and gastrointestinal stability owing to spore formation [ref. 11,ref. 12], and Escherichia coli Nissle 1917 provides a well-characterized non-LAB probiotic model with distinct colonization and immunomodulatory properties [ref. 13]. These properties make them attractive candidates for clinical and biotechnological applications.

Plant-derived bioactive compounds have also gained attention because their antimicrobial, antioxidant, and immunomodulatory properties have been documented for centuries in traditional medicines. Importantly, compounds that act as antioxidants in mammalian tissues may exert pro-oxidant or redox-disruptive effects in bacterial cells, depending on their concentration, redox state, and microbial physiology [ref. 14,ref. 15]. Phytochemicals such as polyphenols, flavonoids, terpenoids, and alkaloids may inhibit pathogens through membrane disruption, virulence and quorum-sensing (QS) interference, efflux pump inhibition, and prevention or disruption of biofilm formation, among other mechanisms [ref. 16,ref. 17,ref. 18]. Owing to these antimicrobial properties, many phytochemicals have been investigated as antimicrobial-supportive agents and as natural preservatives [ref. 18]. Their potential is particularly relevant in addressing the growing challenges of antimicrobial resistance and drug-resistant pathogens [ref. 19]. Importantly, many plant extracts exhibit prebiotic properties, selectively promoting the growth and metabolic activity of beneficial probiotic strains [ref. 20,ref. 21,ref. 22]. Prebiotics are substrates selectively utilized by host microorganisms, conferring a health benefit [ref. 4]. Synbiotics are mixtures comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confer a health benefit [ref. 4,ref. 23].

Despite these advances, most studies have examined probiotics and plant extracts in isolation. Emerging evidence suggests that selected probiotic–phytochemical combinations may exert complementary or synergistic multi-target effects, including enhanced antimicrobial activity, biofilm disruption, modulation of redox and inflammatory pathways, and support for intestinal barrier integrity. In some experimental settings, such combinations may also contribute to antibiotic-sparing strategies by lowering the concentration of conventional antimicrobials required for pathogen inhibition; however, this effect requires confirmation using appropriate quantitative combination assays in future studies. This integrated strategy aligns with modern ecological and systems biology perspectives, in which the gut microbiota and its metabolic networks are viewed as dynamic ecosystems that can be modulated using complementary, bioactive agents [ref. 24,ref. 25]. In 2023, Wishna-Kadawarage et al. proposed the term “prophybiotic” to describe a formulation that combines a probiotic microorganism with a plant extract in one preparation [ref. 26]. Related terminology has also appeared in the literature; for example, Savelyeva et al. used the term “phyto probiotic complex” for a natural preparation combining probiotic and plant-derived components [ref. 27]. In this review, we use the term “phytoprobiotic” as an operational descriptor for combined formulations or intervention strategies that integrate probiotic microorganisms with plant-derived bioactives/extracts to achieve complementary effects on the gut microbiota, antimicrobial activity, and host-related outcomes. Because no standardized definition of “phytoprobiotic” currently exists, the term is used here descriptively and should not be interpreted as a formally established regulatory or consensus category.

Although several reviews have addressed probiotics, plant bioactives, or synbiotic-like approaches, fewer studies have specifically integrated evidence on probiotic–plant bioactive combinations while clearly distinguishing quantitatively confirmed synergy from additive or complementary interactions. Therefore, this review provides a focused mechanistic synthesis of the current knowledge on probiotic–phytochemical interactions, with particular attention to documented synergy, methodological limitations, and translational relevance for gut health, and their supportive role in gut-health-oriented and antimicrobial-supportive strategies. We discuss the mechanistic foundations of probiotic action, chemical diversity, and antimicrobial activity of plant bioactives and the emerging evidence for their combined effects. By integrating mechanistic, ecological, and translational perspectives, this review proposes a conceptual framework for evaluating probiotic–plant bioactive combinations as microbiota-targeted strategies in the post-antibiotic era.

2. Methodology of the Review—Narrative Literature Review with a Structured Search Strategy

The literature used in this narrative review with structured search was collected over a period of three months using databases and platforms available through the library system of the John Paul II Catholic University of Lublin (KUL), including Scopus, PubMed, EBSCO, Google Scholar, De Gruyter, Springer Nature, Oxford University Press—Medicine Collection, SAGE Premier, Science, SpringerLink, Taylor & Francis, Wiley Online Library, and open repositories. The search covered publications from January 2016 to April 2026. Keywords were used individually and in Boolean combinations, including: “probiotics”, “postbiotics”, “metabolites”, “synbiotic”, “randomized controlled trials”, “meta-analyses”, “phytochemicals”, “plant extract”, “in vitro”, and “antimicrobial action”, for example: (probiotic* OR Lactobacillus OR Bifidobacterium OR Bacillus) AND (phytochemical* OR plant extract* OR polyphenol* OR flavonoid*) AND (synerg* OR FICI OR checkerboard OR time-kill OR co-culture) AND (gut OR microbiota OR inflammation OR chronic disease). The inclusion criteria primarily focused on clinical trials (RCTs), in vitro studies, animal studies, meta-analyses, and mechanistic reviews of the concurrent use of probiotics/postbiotics and plant-derived substances for gut health and chronic disease prevention. Non-peer-reviewed articles, case reports, and publications not available in English were excluded.

Additionally, operational definitions were used in this review:

• Synergy: FICI ≤ 0.5, or ≥2 log10 CFU/mL reduction versus the best single agent in time-kill assays.
• Additive effect: 0.5 < FICI ≤ 1.0;
• Indifference: 1.0 < FICI ≤ 4.0;
• Antagonism: FICI > 4.0.
• Complementary interaction: mechanistically consistent interaction without a formal synergy test.

3. Mechanisms of the Antibacterial Action of Probiotic Microorganisms

Probiotic microorganisms employ a wide range of antibacterial strategies that work together to suppress harmful bacteria, influence the balance of microbial communities, and enhance the host immune system. These mechanisms are multifaceted, often overlapping, and involve both direct antagonism toward pathogens and indirect modulation of host–microbe interactions [ref. 28]. Understanding these mechanistic layers is essential for elucidating the antimicrobial and host-related functions of probiotics and provides a mechanistic basis for interpreting their potential interactions (Figure 1).

3.1. Production of Organic Acids and Environmental Acidification

LAB and Bifidobacterium species produce lactic, acetic, and other short-chain fatty acids (SCFAs) that lower gut pH, creating unfavorable conditions for acid-sensitive pathogens [ref. 28]. Quantitative analyses demonstrated strain-dependent differences in secretion of organic acids, including SCFAs. For example, the Lacticaseibacillus rhamnosus strain 484 isolated from human breast milk produced 14.11 mg/mL (≈14.1 g/L) of L-lactic acid after 24 h of cultivation, exceeding the production observed for the reference L. rhamnosus GG strain (12.89 mg/mL), highlighting the inter-strain variability in acidification capacity [ref. 29]. Interestingly, L. rhamnosus GG predominantly produces L-lactate and no D-lactate was detected after 48 h of cultivation, with L-lactate concentrations exceeding 100 mmol/L, supporting its favorable metabolic profile for probiotic applications [ref. 29,ref. 30]. Furthermore, Lactiplantibacillus plantarum AC11S produced approximately 18 g/L of lactic acid during lactose fermentation at pH 6.5 and 30 °C, illustrating the high acidification potential characteristic of many lactic acid bacteria [ref. 31]. In vitro HPLC-MS/MS measurements showed that Limosilactobacillus reuteri DSM 17938 and Bacillus clausii T produced the highest amounts of acetate (644.3 ± 7.2 and 602.0 ± 54.2 ng/mL, respectively), whereas B. clausii strains also secreted detectable levels of propionate (up to 1.21 ± 0.38 ng/mL) and butyrate (2.70–3.04 ng/mL), highlighting the metabolic diversity among probiotic microorganisms [ref. 32]. Not all probiotic-mediated acidification relies predominantly on lactate production. For example, the probiotic strain Clostridium butyricum MIYAIRI 588, which belongs to lactate-utilizing bacteria (LUB), contributes to intestinal acidification mainly through butyrate production, thereby supporting colonization resistance and illustrating metabolic complementarity among probiotic species [ref. 33]. Such diversity may be beneficial, as excessive D-lactate accumulation by certain lactic acid-producing bacteria has been associated with D-lactic acidosis in susceptible individuals, particularly in patients with short bowel syndrome [ref. 33,ref. 34]. Similarly, another LUB strain, C. butyricum TO-A, efficiently converted lactate and acetate into butyrate, reaching concentrations of 5.05 ± 0.82 mM in the presence of both substrates and 7.64 ± 0.67 mM in the presence of D-lactate and acetate, demonstrating the strain’s capacity to act as an efficient butyrate supplier and emphasizing the metabolic diversity among probiotic species [ref. 35].

Beyond simple acidification, undissociated organic acids diffuse across bacterial membranes, dissociate in the neutral cytoplasm, and disrupt intracellular pH homeostasis, thereby impairing key metabolic pathways [ref. 36]. This acidification is mainly local and depends on fermentation intensity, buffering capacity, and intestinal region [ref. 28,ref. 36,ref. 37]. Acid-sensitive pathogens include Clostridioides difficile, pathogenic E. coli, Listeria monocytogenes, and Salmonella [ref. 28,ref. 36]. Intracellular acidification disrupts enzyme activity, ATP generation, amino acid transport, and proton-gradient-dependent metabolism [ref. 36]. SCFAs, particularly butyrate, support tight junction (TJ) proteins, including occludin, claudin-1, and ZO-1, inhibit NF-κB partly through histone deacetylase (HDAC)-dependent mechanisms, and modulate cytokines such as IL-6, IL-8, TNF-α, and IL-10 [ref. 37,ref. 38].

3.2. Bacteriocin Production and Antimicrobial Peptides

Many probiotic and food-associated bacteria produce antimicrobial peptides (AMPs), known as bacteriocins [ref. 39]. Representative examples include nisin, produced mainly by Lactococcus lactis [ref. 40], plantaricin, produced by L. plantarum strains [ref. 41], and pediocins, produced by Pediococcus spp. (e.g., pediocin PA-1 produced by P. acidilactici strains) [ref. 42]. These small, cationic, amphiphilic peptides primarily disrupt target cell membranes, induce pore formation, inhibit cell wall or envelope synthesis; in some cases, indirect effects on QS-regulated phenotypes have also been reported [ref. 43,ref. 44,ref. 45,ref. 46]. For example, bacteriocin Abp118 produced by Ligilactobacillus salivarius UCC118 has been reported to exhibit anti-listerial activity in animal models, whereas enterocin CRL35 produced by Enterococcus mundtii RL35 showed activity against Listeria spp. and selected viral pathogens, highlighting the broad antimicrobial spectrum of bacteriocins [ref. 47]. Similarly, pediocin PA-1 displayed potent anti-listerial activity, with a minimum inhibitory concentration of 45 nM against L. monocytogenes, and effectively suppressed pathogen growth in a model of the human gut environment [ref. 42]. Furthermore, the two-peptide bacteriocin plantaricin NC8 αβ permeabilized bacterial membranes and exhibited potent activity against Staphylococcus aureus and Staphylococcus epidermidis, illustrating the membrane-targeting mode of action characteristic of many bacteriocins [ref. 48]. Given the structural diversity of bacteriocins, only representative mechanisms and antimicrobial targets are discussed here and summarized in Figure 1.

In addition to bacteriocins, some Bacillus strains also produce non-ribosomal lipopeptides, including surfactin and fengycin, which have biosurfactant and biofilm-disrupting properties. These lipopeptides are synthesized by non-ribosomal peptide synthetases rather than ribosomal translation. Surfactin and fengycin have been reported to affect pathogens such as Campylobacter jejuni, S. aureus, and selected Gram-negative biofilm-forming bacteria [ref. 49,ref. 50,ref. 51]. These lipopeptides destabilize microbial membranes through pore formation and surface activity, contributing to activity against both planktonic pathogens and biofilm-associated cells [ref. 49].

3.3. Competition for Nutrients and Adhesion Sites

Probiotics inhibit pathogen colonization through competitive exclusion, which involves both the occupation of ecological niches and competition for host-associated binding sites and nutrients. Many probiotic strains adhere to intestinal mucus and mucins, thereby limiting pathogen access to the mucosal surface and supporting colonization resistance [ref. 52,ref. 53]. Adhesion may involve strain-specific surface molecules, including S-layer proteins, mucus-binding proteins, exopolysaccharides, and other cell envelope structures that interact with mucin and epithelial receptors. In some models, interactions with epithelial adhesion-related molecules, such as E-cadherin- or integrin-associated pathways, have been proposed [ref. 52]. For example, the specific adhesion factors of L. plantarum strains contribute to host–microbe interactions and pathogen exclusion. The collagen-binding protein of L. plantarum Lp91 exhibited anti-adhesive activity against enteric pathogens, thereby promoting competitive exclusion and colonization resistance, whereas adhesion-related proteins identified in L. plantarum HEAL9 and 299v have been implicated in persistence within the intestinal mucus layer [ref. 54]. In addition, probiotic surface-associated microbial patterns may be recognized by host pattern recognition receptors, including Toll-like receptors (TLRs), although these interactions are highly strain- and context-dependent and should not be generalized across all probiotic taxa [ref. 52,ref. 53].

Probiotics also suppress pathogen proliferation by utilizing key nutrients, including carbohydrates and amino acids, thereby reducing the resources available for competing microorganisms [ref. 53]. For example, the probiotic strain E. coli Nissle 1917 contributed to colonization resistance by competing with enterohemorrhagic E. coli (EHEC) O157 for mucus-derived monosaccharides, including arabinose, galactose, N-acetylglucosamine, mannose, and ribose, thereby occupying the same nutrient niche and limiting pathogen colonization [ref. 55].

3.4. Modulation of Host Immune Responses

The effects of probiotics on host immunity are highly strain-specific and depend on microbial surface structures, secreted metabolites, host cell type, and inflammatory context. Selected probiotic strains interact with intestinal epithelial cells, DCs, macrophages, and other mucosal immune cells through microbe-associated molecular patterns (MAMPs) recognized by pattern recognition receptors, including TLRs [ref. 56,ref. 57]. However, these interactions should not be generalized across all probiotic taxa because different strains may induce distinct cytokine profiles and immune outcomes [ref. 58,ref. 59].

Some probiotic strains promote mucosal immune readiness by increasing secretory IgA production, modulating DC maturation, and supporting balanced innate immune responses [ref. 60,ref. 61,ref. 62]. For example, Lactobacillus delbrueckii subsp. lactis PTCC 174 and L. rhamnosus ATCC 9595 may enhance anti-inflammatory mediators, such as IL-10, while modulating pro-inflammatory cytokines, including IL-12 and TNF-α, although the direction and magnitude of these effects depend strongly on the strain, dose, and experimental model [ref. 59]. Specific probiotic strains have been shown to support epithelial barrier integrity by modulating TJ-associated protein expression and reducing epithelial barrier dysfunction [ref. 63,ref. 64,ref. 65,ref. 66]. For example, L. rhamnosus GG and Lacticaseibacillus paracasei IMPC2.1 mitigate lipopolysaccharide (LPS)-induced epithelial barrier dysfunction in Caco-2 cells by regulating TJ protein expression and autophagy-related pathways [ref. 63]. A multi-strain formulation containing L. rhamnosus LR32, Bifidobacterium animalis subsp. lactis BL04, and Bifidobacterium longum BB536 also improved epithelial barrier function by modulating tight and adherens junction proteins [ref. 64]. In addition, Wang et al. demonstrated that even closely related strains of the same species, such as L. plantarum P1 (CCFM200) and P2 (CCFM8610), differed in their ability to restore TJ integrity in dextran sulfate sodium (DSS)-induced colitis. Similar variability was observed for Lacticaseibacillus casei C1 (CCFM9) and Limosilactobacillus fermentum F1 (CCFM437), highlighting that barrier-protective effects cannot be inferred solely from species identity [ref. 65].

3.5. Quorum Sensing Interference (Quorum Quenching)

Several probiotic strains have been shown to disrupt QS, a critical communication system that controls bacterial virulence, toxin synthesis, and biofilm development. By breaking down or capturing autoinducers (AI), such as acylated homoserine lactones (AHLs) and AI-2, probiotics can diminish pathogen virulence without applying the selective pressure typically linked to antibiotic use [ref. 67]. Mechanistically, quorum-quenching may involve enzymatic degradation of AHLs by lactonases or acylases, interference with AI-2 signaling, adsorption or sequestration of signaling molecules, and suppression of QS-regulated virulence gene expression [ref. 67,ref. 68]. For example, L. reuteri LR21-derived reuterin suppressed Clostridium perfringens QS- and toxin-related genes (agrB, luxS, cpa, and pfo), whereas L. reuteri RC-14-derived cyclo-dipeptides inhibited Staphylococcus aureus virulence regulation by targeting the agr, tst, and SaeRS systems. In Gram-negative models, Levilactobacillus brevis 3M004 and Bacillus paralicheniformis ZP1 interfered with Pseudomonas aeruginosa QS through AHL degradation or lactonase-mediated AHL hydrolysis, leading to reduced biofilm formation and repression of QS-controlled genes, including lasA, lasB, and phzAB [ref. 69].

These observations indicate that quorum-quenching is not restricted to a single mechanism but may involve the enzymatic degradation of signaling molecules and indirect modulation of virulence-associated pathways. Importantly, interference with QS does not necessarily inhibit bacterial growth directly but rather attenuates pathogen fitness and pathogenicity, potentially reducing the selective pressure for resistance development. Such antivirulence effects have been reported against clinically relevant pathogens, including P. aeruginosa, S. aureus, and C. perfringens, highlighting quorum-quenching as a complementary mechanism of probiotic-mediated pathogen control [ref. 67,ref. 68,ref. 69].

3.6. Inhibition and Disruption of Biofilms

Biofilms confer antibiotic tolerance and persistence to bacteria [ref. 70]. Probiotics counteract biofilm formation through multiple mechanisms, including the secretion of biosurfactants, competitive adherence, production of SCFAs that weaken extracellular polymeric substances (EPS), and enzymatic degradation of biofilm matrices [ref. 71,ref. 72,ref. 73]. For example, Zhang et al. showed that cell-free supernatants from Amylolactobacillus animalis LMEM6, L. plantarum LMEM7, Lactobacillus acidophilus LMEM8, L. rhamnosus LMEM9, and L. fermentum MTCC 9748 inhibited biofilm formation by MDR Klebsiella pneumoniae in a chemostat system, partly by reducing intracellular c-di-GMP levels and modulating biofilm-associated genes, including yfiN and mrkJ [ref. 72]. Bacillus spp. produce potent biosurfactants, such as surfactin, which decrease surface tension, interfere with biofilm stability, and promote biofilm dispersion. Surfactin has been reported to affect biofilms formed by pathogens, including P. aeruginosa and S. aureus [ref. 74]. Recent studies further support the anti-biofilm potential of probiotics. For example, L. reuteri DSM 17938 and ATCC PTA 5289 reduced the biomass of dual-species biofilms formed by clinical isolates of Streptococcus sobrinus and Candida albicans by approximately 35%. This effect was accompanied by decreased microbial counts and downregulation of virulence-associated genes, such as gtfI and HWP1, indicating that probiotic-mediated biofilm inhibition may involve both structural disruption and attenuation of virulence-associated pathways [ref. 75].

3.7. Coaggregation and Pathogen Entrapment

Coaggregation refers to the ability of probiotic cells to physically bind to pathogens. This mechanism entraps pathogens, limiting their motility, aggregation, and adherence to host tissues. Coaggregation facilitates pathogen removal via peristalsis or mucosal turnover [ref. 76,ref. 77,ref. 78]. For example, L. rhamnosus 1B06 and L. paracasei 8A12 coaggregated with oral pathogens such as Fusobacterium nucleatum, Porphyromonas gingivalis, and Prevotella, aiding in pathogen displacement [ref. 79]. Coaggregation is highly strain-dependent and may involve surface-associated proteins, lipoteichoic acids, S-layer proteins, and exopolysaccharides that facilitate cell-to-cell interactions. In addition to limiting pathogen adhesion, coaggregates may create physical barriers that restrict nutrient access and enhance pathogen clearance from mucosal surfaces [ref. 76,ref. 77,ref. 78,ref. 79]. Further evidence highlights the strain-specific nature of coaggregation. For example, L. acidophilus Lb2 and L. fermentum Lb8 exhibited strong coaggregation with enteric pathogens, including E. coli, Shigella sonnei, and Providencia alcalifaciens, reaching coaggregation rates of up to 100% after 24 h of incubation. These interactions facilitate pathogen entrapment and contribute to colonization resistance [ref. 80]. A multi-strain probiotic formulation containing L. plantarum PBS067, L. rhamnosus LRH020, and B. animalis subsp. lactis BL050 showed rapid coaggregation with Gardnerella vaginalis, E. coli, and C. albicans, with visible aggregates forming within 15 min. Scanning electron microscopy further demonstrated close physical interactions between probiotics and pathogens, including the partial surrounding of C. albicans cells by L. rhamnosus LRH020 and the embedding of fungal cells within the probiotic biofilm, supporting the role of coaggregation in pathogen sequestration and colonization resistance [ref. 81].

3.8. Metabolic Crosstalk and Production of Antimicrobial Metabolites

In addition to classical AMPs and acids, probiotics produce a spectrum of metabolites such as acetaldehyde, diacetyl, hydrogen peroxide, and reuterin that inhibit a wide array of pathogens [ref. 82,ref. 83,ref. 84]. Acetaldehyde and diacetyl, volatile antimicrobial metabolites, contribute to the preservation of fermented foods [ref. 85]. In some cases, acetaldehyde can be further metabolized into ethanol by certain strains such as L. reuteri DSM 20016 [ref. 86]. Hydrogen peroxide-producing lactobacilli contribute to pathogen control by generating reactive oxygen species (ROS), which disrupt bacterial cell envelopes and interfere with cellular metabolism [ref. 87,ref. 88]. For example, L. reuteri DSM 17938 produces reuterin through glycerol metabolism, and this compound exhibits broad-spectrum activity against Gram-positive and Gram-negative bacteria, fungi, and protozoa. Reuterin acts primarily by inducing oxidative stress and disrupting thiol-dependent metabolic pathways, thereby inhibiting microbial growth [ref. 84].

Recent studies have further illustrated the metabolic diversity underlying probiotic antimicrobial activity. For example, the pdu-cbi-cob-hem gene cluster responsible for reuterin biosynthesis was identified in L. reuteri E81, and the production of reuterin and related 3-hydroxypropionaldehyde (3-HPA)-derived metabolites was confirmed by NMR analyses. Additionally, reuterin-producing L. reuteri E81 reduced E. coli counts from 6.4 log CFU/g to undetectable levels after 30 days, supporting reuterin-mediated bioprotection through membrane disruption and oxidative stress [ref. 89]. The antimicrobial potency of reuterin varies depending on the producing strain and target microorganism. Reuterin produced by L. reuteri 12002 exhibited MIC values of 4 AU/mL against E. coli and 8 AU/mL against L. monocytogenes [ref. 90], whereas inhibition of E. coli DH5α and S. aureus has been reported at approximately 0.9 mM and 1.5 mM, respectively [ref. 91]. These observations indicate a concentration-dependent activity against both Gram-negative and Gram-positive bacteria. These findings highlight that probiotic-mediated pathogen inhibition extends beyond organic acid production and involves structurally diverse antimicrobial metabolites [ref. 89]. Although reuterin exhibits concentration- and cell type-dependent cytotoxicity, studies on mammalian cell models indicate that it does not exert significant toxicity at concentrations associated with antimicrobial activity, supporting its potential for food and therapeutic applications [ref. 92,ref. 93].

4. Antibacterial and Immunomodulatory Activity of Plant Extracts

Plant-derived extracts inhibit bacterial pathogens through several molecular mechanisms. These mechanisms are largely influenced by bioactive compounds, including alkaloids, essential oils, flavonoids, polyphenols, and tannins, which target bacterial structures and functions such as membranes, enzymes, energy metabolism, and communication systems [ref. 94]. Many plant-derived compounds described as antioxidants in host tissues may exert context-dependent pro-oxidant or redox-disruptive effects in bacterial cells. Therefore, their antioxidant activity in mammalian systems does not conflict with the generation of antibacterial ROS; instead, the ultimate effect is determined by factors such as the type of target cell, concentration of the compound, availability of metals, and microbial redox state [ref. 94,ref. 95].

In addition to their antibacterial properties, plant-derived extracts exhibit antiviral, antioxidant, and immunomodulatory properties [ref. 96,ref. 97,ref. 98,ref. 99]. Their extensive biochemical versatility allows them to simultaneously target multiple cellular pathways, presenting promising strategies for combating multidrug-resistant (MDR) pathogens [ref. 100,ref. 101], including E. coli, K. pneumoniae, and S. aureus [ref. 102,ref. 103]. In contrast to conventional antibiotics, many phytochemicals operate through multisite mechanisms, reducing the risk of resistance development and complementing the actions of probiotics [ref. 104,ref. 105,ref. 106,ref. 107,ref. 108].

4.1. Direct Antibacterial Mechanisms of Plant Phytochemicals

Plant-derived bioactive compounds can affect bacterial survival, virulence, and adaptation through multiple complementary mechanisms. Rather than acting on a single cellular target, many phytochemicals simultaneously influence several bacterial processes, including disruption of membrane integrity, interference with metabolic activity, inhibition of QS, and prevention of biofilm formation [ref. 94,ref. 109]. The examples discussed below include cinnamon-derived cinnamaldehyde [ref. 110,ref. 111,ref. 112], green tea epigallocatechin gallate (EGCG) [ref. 113,ref. 114], oregano-derived carvacrol and thymol [ref. 115,ref. 116], turmeric-derived curcumin [ref. 117,ref. 118], grape seed proanthocyanidins [ref. 119,ref. 120], and pomegranate ellagitannins [ref. 121,ref. 122], which have been investigated for their antibacterial, anti-biofilm, and antivirulence properties [ref. 94]. The following sections summarize the principal mechanisms through which phytochemicals may contribute to pathogen control and potentially complement probiotic-derived antimicrobial activity.

4.1.1. Disruption of Cell Membrane Integrity

Many polyphenols, including catechins and gallic acid derivatives, as well as essential oil components, such as thymol and carvacrol, interact with bacterial lipid bilayers and membrane proteins, increasing membrane permeability, altering fluidity, and impairing nutrient transport [ref. 94,ref. 123,ref. 124]. These effects may lead to intracellular ion leakage, depolarization, metabolic collapse, and bacterial cell lysis. For example, terpene mixtures containing β-myrcene and α-humulene have been shown to increase bilayer fluidity and disrupt membrane structure [ref. 125]. Moreover, selected polyphenols may exert context-dependent pro-oxidant effects in bacterial cells by promoting ROS accumulation, ATP leakage, and membrane rupture, despite their antioxidant properties in host tissues [ref. 95].

The antibacterial effect of membrane disruption is not limited to structural damage. Increased membrane permeability may result in the loss of the proton motive force, disruption of ATP synthesis, impaired nutrient uptake, and altered activity of membrane-associated enzymes and transport systems [ref. 94,ref. 126]. These effects compromise bacterial energy homeostasis and reduce the ability of pathogens to maintain their cellular integrity under environmental stress [ref. 127]. Importantly, susceptibility to membrane-active phytochemicals is often species dependent. Gram-positive bacteria are generally more vulnerable because their cytoplasmic membrane is protected only by a thick peptidoglycan layer, whereas Gram-negative bacteria possess an additional outer membrane that can partially restrict the penetration of hydrophobic compounds [ref. 94]. Consequently, the antibacterial activity of membrane-disrupting phytochemicals depends not only on the compound structure and concentration but also on the bacterial cell envelope architecture and physiological state [ref. 126,ref. 127].

Membrane perturbation may also enhance the activity of probiotic-derived antimicrobial metabolites, including organic acids, bacteriocins, and biosurfactants [ref. 126,ref. 128]. Increased permeability facilitates the diffusion of these compounds into bacterial cells and may lower the concentration required to achieve growth inhibition [ref. 127,ref. 128]. This mechanism provides a plausible explanation for the many reported additive or synergistic interactions between phytochemicals and probiotic-derived antimicrobials, particularly in studies involving biofilm-forming and MDR pathogens [ref. 117,ref. 129,ref. 130].

4.1.2. Inhibition of Bacterial Enzymes and Metabolic Pathways

Plant-derived polyphenols and other bioactive compounds can inhibit essential bacterial metabolic pathways, including protein biosynthesis, ATP production, and DNA replication and cell division [ref. 94,ref. 109]. Phenolic acids, flavonoids, alkaloids, and terpenoids may act as enzyme inhibitors by interacting with catalytic sites, altering protein conformation, and interfering with cofactor-dependent reactions [ref. 126]. Several phytochemicals have been reported to interfere with DNA gyrase, topoisomerases, and ATP-binding enzymes, thereby impairing bacterial replication, transcription, and metabolism [ref. 109,ref. 126].

A well-described example is curcumin, which inhibits FtsZ, a bacterial cytoskeletal protein essential for Z-ring formation and cytokinesis [ref. 131,ref. 132]. Interference with FtsZ polymerization disrupts septum formation, leading to defective cell division, filamentation, and growth arrest in susceptible bacteria [ref. 131]. However, curcumin activity is strongly strain- and model-dependent, and its limited solubility and bioavailability remain important constraints for its translational applications [ref. 118,ref. 133].

Phytochemicals may also disrupt bacterial energy metabolism by reducing ATP generation, inhibiting membrane-associated respiratory enzymes, and altering proton-dependent transport systems [ref. 94,ref. 126]. Essential oil constituents, such as thymol and carvacrol, can affect ATP synthesis and membrane-associated metabolic processes, contributing to growth inhibition and reduced stress tolerance in pathogens [ref. 134,ref. 135]. In addition, phenolic compounds may inhibit bacterial efflux pumps, increasing the intracellular accumulation of antimicrobial agents and reducing one of the major mechanisms of multidrug resistance [ref. 109,ref. 126].

These enzyme- and metabolism-targeting effects are particularly relevant for probiotic–phytochemical combinations because metabolic weakening of pathogens may increase their susceptibility to organic acids, bacteriocins, hydrogen peroxide, and biosurfactants produced by probiotics [ref. 128]. Probiotic-derived metabolites are increasingly recognized as important contributors to pathogen inhibition and may complement phytochemical-induced metabolic disruption [ref. 136]. Inhibition of bacterial enzymes and metabolic pathways represents not only a direct antibacterial action of plant-derived bioactives but also a potential mechanism for enhancing the effectiveness of probiotic-derived antimicrobial metabolites. This hypothesis can be evaluated using appropriate combination assays to determine whether additive or synergistic interactions occur between the two.

4.1.3. Suppression of Virulence Factors and Quorum Sensing

Many plant-derived bioactive compounds suppress bacterial virulence gene expression by interfering with QS, a cell density-dependent communication system that coordinates toxin production, motility, adhesion, and biofilm maturation [ref. 112,ref. 126]. QS networks are mediated by signaling molecules such as AHLs, AI-2, and species-specific peptide signals, which regulate collective pathogenic behavior rather than bacterial growth [ref. 68]. Therefore, plant-derived QS inhibitors may attenuate virulence without necessarily exerting direct bactericidal effects [ref. 110,ref. 137].

Several phytochemicals have been shown to interfere with QS-regulatory processes. For example, naringenin can inhibit virulence-associated signaling and biofilm-related behaviors in bacterial models, including Pectobacterium brasiliense and P. aeruginosa [ref. 138,ref. 139]. Phenolic volatiles and other plant-derived compounds may reduce bacterial virulence by interfering with LuxI/LuxR-type regulatory systems and related QS proteins [ref. 140]. Flavonoids such as quercetin may also interact with QS-related proteins, supporting their potential role in disrupting bacterial signaling pathways [ref. 141]. In addition, cinnamaldehyde, eugenol, quercetin, and related phenolics have been reported to reduce QS-dependent phenotypes, including swarming motility, toxin production, adhesion, and biofilm formation [ref. 110,ref. 111,ref. 112]. Cannabigerol (CBG) and cannabigerolic acid (CBGA) have also been investigated mainly as plant-derived anti-biofilm and antivirulence compounds; however, their direct QS-related effects require further confirmation across bacterial species [ref. 112,ref. 126].

This virulence-attenuation mechanism is particularly relevant because QS inhibition does not necessarily eliminate bacteria directly but weakens the coordinated pathogenic behaviors that facilitate infection persistence and biofilm tolerance [ref. 110,ref. 137]. By reducing toxin secretion, motility, adhesion, and biofilm maturation, phytochemicals may render pathogens more susceptible to host defenses and probiotic-derived antimicrobials, including organic acids, bacteriocins, hydrogen peroxide, and biosurfactants [ref. 110,ref. 128]. In this context, QS suppression may provide a mechanistic bridge between plant bioactives and probiotic antimicrobial activity, as probiotics may also interfere with microbial communication through AI degradation, metabolic competition, and biofilm displacement [ref. 67,ref. 68].

4.1.4. Inhibition of Biofilm Formation and Degradation of Exopolysaccharides

Plant secondary metabolites, particularly tannins, stilbenes, and flavonoids, can interfere with multiple stages of biofilm development, including initial bacterial adhesion, microcolony formation, maturation, and EPS matrix maintenance [ref. 117,ref. 129]. Biofilms represent one of the most important bacterial survival strategies because they provide protection against environmental stressors, host immune defense, and antimicrobial agents [ref. 130]. Consequently, biofilm-associated bacteria frequently exhibit substantially greater antibiotic tolerance than their planktonic counterparts [ref. 129,ref. 130].

Several plant-derived compounds have been shown to disrupt biofilm architecture through complementary mechanisms. Tannins may interact with extracellular proteins and polysaccharides, thereby reducing matrix stability and bacterial adhesion [ref. 117,ref. 126]. Hydrolyzable tannins can denature surface-associated proteins involved in biofilm formation and maintenance, thereby weakening the structural integrity of mature biofilms [ref. 118,ref. 126]. Stilbenes and flavonoids may further impair biofilm development by altering bacterial signaling pathways and reducing the expression of adhesion-related genes [ref. 112,ref. 129]. In addition, several essential oil constituents, including thymol, carvacrol, and eugenol, have been shown to penetrate biofilm matrices, increase membrane permeability, and promote partial biofilm disruption in selected bacterial species [ref. 126].

The anti-biofilm activity of phytochemicals is closely linked to their ability to interfere with bacterial communication. Many plant-derived compounds inhibit the QS pathways that regulate EPS production, motility, surface attachment, and biofilm maturation [ref. 110,ref. 112]. By suppressing these regulatory networks, phytochemicals may prevent the establishment of mature biofilms and reduce the persistence of chronic infection [ref. 110,ref. 137]. Importantly, the inhibition of biofilm formation and disruption of established biofilms are distinct biological phenomena and should not be interpreted as interchangeable. Compounds that are effective against early-stage biofilm development may show limited activity against mature biofilm structures [ref. 129,ref. 130].

From the perspective of probiotic–phytochemical interactions, disrupting biofilms may enhance the activity of probiotic-derived antimicrobial metabolites, including organic acids, bacteriocins, hydrogen peroxide, and biosurfactants [ref. 128]. Reduced EPS density and increased matrix permeability may improve the diffusion of these compounds into deeper biofilm layers and enhance their antimicrobial effectiveness [ref. 117,ref. 130]. Furthermore, selected probiotic strains may compete with pathogens for adhesion sites and contribute to biofilm displacement, providing an additional mechanism through which phytochemicals and probiotics may act in a complementary manner [ref. 67,ref. 128].

However, the anti-biofilm activity of plant extracts remains highly dependent on the extract composition, concentration, bacterial species, and experimental conditions [ref. 126,ref. 129]. Therefore, claims regarding probiotic–phytochemical synergy in biofilm control should ideally be supported by quantitative biofilm assays, microscopic analyses, EPS measurements, and combination studies that demonstrate enhanced activity relative to the individual components [ref. 117,ref. 130].

4.2. Prebiotic and Microbiota-Modulating Properties of Plant Extracts

In addition to their antibacterial effects, many plant extracts act as selective prebiotic substrates that stimulate the growth and metabolic activity of probiotic bacteria. Complex carbohydrates, polyphenols, and glycosides escape upper gastrointestinal (GI) digestion and are metabolized by probiotic species into smaller bioactive molecules, including SCFAs (acetate, propionate, and butyrate), phenolic metabolites with higher bioactivity than native compounds, and anti-inflammatory catabolites that improve the host immune function [ref. 142,ref. 143,ref. 144,ref. 145]. For example, fermentation of guava leaf extract by Lactobacillus s.l. strains increased antioxidant and antiglycation activities owing to the synergistic effects between microbial metabolites and plant-derived compounds [ref. 146].

This metabolic interplay enhances probiotic colonization, promotes microbial eubiosis, and strengthens the host barrier function [ref. 147,ref. 148,ref. 149]. In synbiotic formulations, plant extracts and probiotic bacteria display reciprocal enhancement: probiotics biotransform phytochemicals into more active metabolites, whereas phytochemicals stimulate probiotic growth and metabolite production [ref. 150,ref. 151,ref. 152,ref. 153]. Interestingly, plant-derived prebiotic substrates can be metabolized by intestinal bacteria into SCFAs, including butyrate, thereby linking plant bioactives to gut barrier reinforcement, anti-inflammatory effects, and improved gut health [ref. 154,ref. 155]. Examples include inulin, fructooligosaccharides (FOS), galacto-oligosaccharides (GOS), resistant starch, pectins, arabinoxylans, and β-glucans, which can be metabolized by intestinal bacteria, including members of the genera Bifidobacterium, Faecalibacterium, Lactobacillus, and Roseburia, into SCFAs such as acetate, propionate, and butyrate [ref. 156,ref. 157]. This transformation may also enhance probiotic adhesion by reinforcing the gut barrier and mitigating inflammation [ref. 154,ref. 155]. For example, B-type lotus seedpod oligomeric procyanidins enhanced the adhesion of Lacticaseibacillus rhamnosus GG to IPEC-J2 intestinal epithelial cells while simultaneously reducing the adhesion of enterotoxigenic E. coli (ETEC), supporting competitive exclusion and intestinal colonization resistance [ref. 155].

4.3. Immunomodulatory Effects of Plant Compounds

Plant extracts influence both innate and adaptive immunity through several pathways, including the modulation of inflammatory signaling in immune cells, as shown for ginger-derived bioactive compounds [ref. 158]. The potential of plant extracts as natural immunomodulators has been demonstrated, with applications in managing inflammation, enhancing resistance to infections, and supporting overall immune health [ref. 159,ref. 160,ref. 161,ref. 162].

4.3.1. Antioxidant and Anti-Inflammatory Modulation

Polyphenols scavenge ROS, inhibit NF-κB activation, and downregulate pro-inflammatory cytokines, including IL-1β, IL-8, and TNF-α, thereby mitigating pathogen-induced inflammation and supporting mucosal recovery [ref. 158,ref. 163,ref. 164,ref. 165,ref. 166]. Enhanced antioxidant activity may also contribute to the stabilization of epithelial TJ and maintenance of intestinal barrier integrity [ref. 119,ref. 167,ref. 168,ref. 169]. In addition to direct radical scavenging, several polyphenols regulate intracellular inflammatory signaling pathways. For example, catechins, quercetin, and resveratrol have been reported to modulate NF-κB- and the mitogen-activated protein kinase (MAPK)-related signaling and reduce the expression of pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, and IL-8, depending on the compound, cell type, and type of inflammatory stimulus [ref. 158,ref. 170]. These effects may contribute to reduced inflammation-associated epithelial damage and improved mucosal recovery.

In addition to their direct antioxidant activity, polyphenols may influence cellular redox homeostasis by activating endogenous defense mechanisms. Several flavonoids and phenolic acids have been shown to stimulate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, leading to increased expression of antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1 [ref. 126,ref. 158]. Activation of these cytoprotective pathways may reduce oxidative stress–induced epithelial injury and improve resistance to inflammation-associated barrier dysfunction [ref. 119]. Importantly, the biological effects of polyphenols are often dose- and context-dependent, and their antioxidant activity in host tissues does not necessarily translate into identical effects within microbial cells [ref. 126].

Maintenance of epithelial barrier integrity is another important consequence of antioxidant and anti-inflammatory modulation. Oxidative stress and chronic inflammation may disrupt TJ proteins, including occludin, claudins, and zonula occludens-1 (ZO-1), resulting in increased intestinal permeability and translocation of microbial products [ref. 38,ref. 119]. By attenuating inflammatory signaling and oxidative damage, plant-derived polyphenols may help preserve the TJ architecture and support epithelial regeneration [ref. 158]. These effects are particularly relevant in GI disorders characterized by impaired barrier function and low-grade chronic inflammation. However, the magnitude of these interactions remains strain-, compound-, dose-, and host-dependent, and requires validation in well-controlled mechanistic and clinical studies [ref. 171,ref. 172].

4.3.2. Enhancement of Epithelial Barrier Integrity

Flavonoids, such as quercetin and kaempferol, upregulate proteins involved in TJ assembly, including occludin, claudins, and ZO-1, thereby strengthening epithelial barrier integrity and reducing intestinal permeability [ref. 38,ref. 119]. An improved barrier function may reduce pathogen translocation, limit the passage of microbial toxins and LPS, and support overall mucosal homeostasis [ref. 119,ref. 173,ref. 174,ref. 175,ref. 176]. These effects are particularly relevant because the disruption of epithelial TJ is associated with chronic inflammation, increased intestinal permeability, and dysregulated host–microbiota interactions in several GI disorders [ref. 119,ref. 158]. In addition to directly regulating TJ, selected plant-derived flavonoids may enhance epithelial barrier function by reducing oxidative injury and modulating epithelial signaling pathways associated with barrier repair and regeneration [ref. 126]. For example, puerarin prevents ethanol-induced TJ dysfunction in a Caco-2 cell model by preserving junctional protein expression and attenuating oxidative stress responses [ref. 66,ref. 177]. Similarly, apigenin alleviates intestinal ischemia/reperfusion injury by activating Nrf2-dependent cytoprotective pathways and promoting TJ integrity [ref. 178]. Other flavonoids, including quercetin and luteolin, have been reported to regulate myosin light-chain kinase (MLCK), NF-κB, and MAPK-associated pathways, which are closely linked to epithelial permeability and inflammation-induced barrier dysfunction [ref. 126,ref. 158].

The maintenance of epithelial integrity is also closely associated with immune regulation. By preserving the mucosal barrier, plant-derived bioactives may reduce the exposure of underlying immune cells to luminal antigens and microbial products, thereby limiting excessive inflammatory activation [ref. 119]. This effect may contribute to improved epithelial recovery following infection, inflammatory injury, or microbiota imbalance [ref. 38]. These mechanisms may complement probiotic-mediated reinforcement of the intestinal barrier and contribute to improved gut homeostasis in inflammatory conditions.

4.3.3. Activation of Antimicrobial Immune Pathways

Certain phytochemicals may modulate antimicrobial immune pathways by influencing macrophage and DC activity, enhancing phagocytosis, and promoting AMP production, including defensins and cathelicidins [ref. 126,ref. 158]. For example, β-defensins play an important role in controlling microbial colonization at mucosal surfaces [ref. 158]. Increased AMP production may enhance protection against opportunistic pathogens while contributing to immune homeostasis and balanced inflammatory responses [ref. 126]. These innate immune mechanisms constitute an important component of the first line of defense against enteric pathogens and contribute to maintaining mucosal homeostasis [ref. 67]. By strengthening antimicrobial surveillance while simultaneously limiting excessive inflammatory responses, plant-derived bioactives may help improve host resistance to infection without directly targeting bacterial viability [ref. 126]. Such effects are particularly relevant in the GI tract, where the maintenance of an effective but controlled antimicrobial response is essential for preserving microbiota balance and epithelial integrity.

Several phytochemicals have been reported to influence macrophage polarization, cytokine production and phagocytic activity. For instance, a hydroalcoholic extract derived from oregano triggered a combined anti-mycobacterial and anti-inflammatory response in innate immune cells, suggesting that selected plant extracts may simultaneously enhance pathogen control while reducing inflammatory tissue damage [ref. 165,ref. 179]. Similar immunomodulatory effects have been described for various polyphenols and terpenoids, which regulate macrophage activation and contribute to a more balanced innate immune response [ref. 126,ref. 158].

Selected plant-derived compounds may also regulate TLR2- and TLR4-associated signaling cascades or LPS-related signaling, thereby influencing the downstream activation of NF-κB, MAPK, and cytokine-mediated inflammatory responses [ref. 126,ref. 158,ref. 180,ref. 181,ref. 182,ref. 183,ref. 184]. For example, dehydrocostus lactone attenuates excessive inflammatory responses associated with TLR signaling [ref. 181], whereas 1′-acetoxychavicol acetate inhibited LPS-induced inflammatory activation [ref. 184]. By modulating these pathways, phytochemicals may support immune surveillance while preventing excessive inflammation that could otherwise compromise epithelial barrier integrity and tissue repair.

4.3.4. Modulation of Gut Immune-Microbiota Crosstalk

Phytochemicals and their microbiota-derived metabolites may influence immune cell differentiation and gut immune homeostasis, including the expansion of regulatory T cells (Tregs) and attenuation of Th17-associated inflammatory responses [ref. 185,ref. 186]. These effects are particularly important at the intestinal mucosal interface, where continuous communication between microbial communities, epithelial cells, and immune cells is required to maintain immune tolerance while preserving effective antimicrobial defense [ref. 67]. Through interactions with microbiota-produced metabolites, especially SCFAs, plant-derived bioactives may contribute to establishing a balanced immunological environment and improving mucosal resilience [ref. 185,ref. 186,ref. 187,ref. 188,ref. 189].

A substantial proportion of dietary polyphenols reach the colon largely unmetabolized and undergo extensive biotransformation by gut microorganisms [ref. 186,ref. 190]. This microbial metabolism generates various smaller bioactive compounds, including phenolic acids, valerolactones, and urolithins, which often exhibit biological activities distinct from those of their parent compounds [ref. 185,ref. 190]. Several metabolites are associated with anti-inflammatory effects, improved epithelial barrier integrity, and modulation of immune cell signaling pathways involved in intestinal homeostasis [ref. 185,ref. 186]. Consequently, the biological effects of many phytochemicals depend not only on their original chemical structure but also on the metabolic capacity of the host’s microbiota.

Plant-derived compounds may also indirectly shape immune responses by altering the composition and metabolic activity of the microbial community. Polyphenol-rich diets have been associated with an increased abundance of beneficial microorganisms and enhanced production of anti-inflammatory metabolites, while simultaneously reducing dysbiosis-associated inflammatory signaling [ref. 119,ref. 186,ref. 188,ref. 189,ref. 191]. These microbiota-mediated effects may contribute to reduced intestinal inflammation, improved epithelial barrier function, and restoration of microbial homeostasis in conditions characterized by chronic, low-grade inflammation [ref. 119,ref. 185]. These mechanisms are particularly relevant because chronic inflammatory and metabolic disorders are frequently associated with impaired barrier integrity, altered microbial metabolism, and persistent immune activation [ref. 186,ref. 187,ref. 189]. In this context, plant-derived bioactives may complement probiotics by supporting metabolite-mediated communication between microbiota, epithelial cells, and mucosal immune cells [ref. 188,ref. 189].

From the perspective of probiotic–phytochemical interactions, microbiota-derived metabolites may serve as important mediators linking dietary bioactive compounds with host immune responses. Probiotic microorganisms may enhance the biotransformation of selected phytochemicals, increase the production of SCFAs and other bioactive metabolites, and influence the signaling pathways involved in immune regulation and epithelial homeostasis [ref. 67,ref. 192]. Consequently, probiotic–phytochemical combinations may influence gut immune–microbiota communication through multiple interconnected mechanisms involving microbial metabolism, epithelial signaling, and immune cell regulation.

However, these effects remain highly dependent on host microbiota composition, phytochemical bioavailability, dietary background, and individual metabotypes [ref. 185,ref. 186,ref. 190]. Considerable inter-individual variability exists in the capacity to generate microbiota-derived metabolites, such as urolithins, which may partly explain the heterogeneous responses observed in human intervention studies [ref. 185,ref. 190]. Progress in this field depends on integrating microbiome, metabolomic, and immunological analyses to clarify how probiotic–phytochemical combinations modulate host–microbiota interactions across diverse physiological and pathological contexts.

4.4. Potential Synergy of Plant Extracts with Probiotics

The antibacterial and immunomodulatory activities of plant extracts provide a mechanistic basis for potential complementary or synergistic interactions with probiotic strains (Table 1). Many phytochemicals weaken pathogen membranes or interfere with QS, making pathogens more susceptible to probiotic-derived bacteriocins, organic acids, and biosurfactants [ref. 140,ref. 193,ref. 194,ref. 195,ref. 196]. Phytochemicals also enhance probiotic growth and metabolic performance.

These multi-target interactions suggest that plant extracts may act as complementary co-adjuvants, capable of supporting the antimicrobial potential of probiotic strains against antibiotic-resistant pathogens.

5. Interactions Between Probiotics and Phytochemicals: From Complementarity to Synergy

Interactions between probiotic microorganisms and plant-derived bioactive compounds range from complementary or additive effects to quantitatively confirmed synergy, representing a promising area for developing microbiota-targeted antimicrobial strategies (Table 2). These biological systems, rather than functioning independently, can enhance each other’s roles in antimicrobial activity, immune regulation, and ecological functions. This interaction results in complex effects that surpass the capabilities of each individual component [ref. 286,ref. 287,ref. 288]. Such interactions may be particularly relevant in the context of antibiotic resistance, as multi-target antimicrobial strategies can reduce selective pressure on single bacterial targets and support antibiotic-sparing approaches when confirmed by appropriate combination assays [ref. 136].

5.1. Complementary Mechanisms Enhancing Antibacterial Activity

Probiotics and phytochemicals frequently target different cellular pathways in pathogens. When applied together, their effects converge to produce additive or synergistic outcomes, depending on the experimental model, antimicrobial endpoint, and quantitative confirmation method [ref. 309] (Figure 2). For example, essential oils from Murraya koenigii and Allium sativum showed enhanced antibacterial activity against S. aureus when combined with selected probiotics, such as L. casei ATCC 12116, L. plantarum NRRL/ATCC 8014, and Bifidobacterium bifidum NRRL/ATCC 29521 [ref. 310].

5.1.1. Membrane Destabilization and Increased Pathogen Susceptibility

Membrane perturbation and virulence attenuation induced by phytochemicals may increase pathogen susceptibility to probiotic-derived bacteriocins, thereby promoting complementary or potentially synergistic interaction [ref. 127,ref. 128,ref. 311,ref. 312,ref. 313,ref. 314,ref. 315,ref. 316]. However, such interactions should be interpreted as true synergy only when supported by quantitative assays such as checkerboard, FICI, or time-kill analyses. For example, plantaricin JLA-9 produced by L. plantarum JLA-9 disrupts membrane integrity and inhibits oxidative metabolism in germinating Bacillus cereus spores, illustrating how probiotic-derived bacteriocins can enhance pathogen inactivation [ref. 317].

5.1.2. Amplification of Probiotic Metabolite Production, Adhesion, and Functional Traits

Certain phytochemicals may enhance probiotic growth and metabolic activity, thereby increasing the production of antimicrobial metabolites and strengthening pathogen inhibition [ref. 318,ref. 319]. For example, tea polyphenols have been shown to promote the growth and metabolic activity of L. plantarum CICC 6253 while simultaneously inhibiting S. aureus and E. coli, illustrating how selected phytochemicals may enhance probiotic fitness and antimicrobial performance [ref. 320]. Similarly, plant-derived prebiotics may enhance adhesion-related colonization resistance by modifying probiotic surface properties or stimulating bacterial growth and metabolism [ref. 321]. For example, short-chain FOS enhanced the adhesion-related properties of L. rhamnosus NCDC 298 and, in combination with this strain, reduced the virulence of ETEC in HT-29 intestinal epithelial cells. FOS alone also reduced ETEC adhesion, indicating that plant-derived prebiotic substrates may support colonization resistance by promoting probiotic functional traits and limiting pathogen attachment [ref. 322].

5.2. Biofilm Inhibition Through Multi-Target Synergy

Both probiotics and plant extracts can independently inhibit biofilm formation, but their combination has been shown to exert enhanced anti-biofilm effects. For example, the synergistic mixture of L. acidophilus and pomegranate peel extract demonstrated stronger anti-biofilm effects against P. aeruginosa than did the individual components [ref. 323]. Moreover, the combination of L. plantarum and compound plant extracts promoted biofilm formation, which was beneficial for probiotic activity while inhibiting pathogenic biofilms, highlighting a dual regulatory effect [ref. 324].

Phytochemicals such as carvacrol, cinnamaldehyde, eugenol, tannins, thymol, and selected flavonoids have been shown to disrupt EPS architecture, reduce bacterial adhesion, and inhibit biofilm formation by affecting cell-surface interactions and QS pathways [ref. 325,ref. 326]. When combined with probiotics or conventional antimicrobials, these mechanisms may contribute to enhanced biofilm control. Plant extracts may also enhance the efficacy of antibiotics against biofilm-forming pathogens. Documented examples include pomegranate and rosemary extracts combined with ciprofloxacin, levofloxacin, gentamicin, or ceftazidime against P. aeruginosa biofilms, where complementary anti-biofilm effects were associated with the disruption of biofilm architecture and enhanced antibiotic susceptibility [ref. 327]. Additional examples include tea polyphenols combined with L. plantarum CICC 6253 and eugenol combined with L. plantarum Zs2058, both of which were associated with enhanced antimicrobial and anti-biofilm activities [ref. 320,ref. 328]. Nevertheless, the efficacy of such combinations is influenced by multiple factors, including phytochemical composition, formulation, and pathogen characteristics [ref. 327,ref. 329].

5.2.1. Probiotic Biosurfactants + Plant Polyphenols

Bacillus biosurfactants (surfactin and fengycin) disrupt biofilm architecture. Polyphenols inhibit QS, thereby reducing EPS production. Upon their combined use, pathogens experience both EPS destabilization and weakened intercellular signaling, which may contribute to biofilm destabilization [ref. 330,ref. 331,ref. 332]. Recent evidence suggests that combinations of probiotic microorganisms with polyphenols, such as proanthocyanidin-rich plant compounds, may enhance anti-biofilm or antifungal activity, although the effects appear to be matrix- and compound-specific and require further validation across different phytochemical sources [ref. 169].

5.2.2. Enhanced Coaggregation and Entrapment

Plant polysaccharides can enhance the coaggregation of probiotics and pathogens by strengthening cell–cell and cell–matrix interactions, thereby promoting the formation of mixed microbial aggregates and facilitating pathogen removal via mucosal turnover. This creates a cooperative “entrap and eliminate” mechanism that may reduce pathogen access to epithelial surfaces and limit their colonization. In addition, selected plant-derived polysaccharides and dietary fibers (e.g., inulin, pectins, arabinoxylans, β-glucans, and resistant starch) can stimulate probiotic growth, metabolic activity, and EPS production, further supporting aggregate stability and competitive exclusion [ref. 154,ref. 333]. Specific probiotic cell wall proteins (e.g., postbiotics from L. acidophilus LA-5 and L. rhamnosus GG) and exopolysaccharides mediate this interaction and may be enhanced by plant-derived polysaccharides. Polyphenols, such as quercetin and p-coumaric acid, can enhance coaggregation and other probiotic properties, suggesting their potential for synbiotic applications [ref. 334,ref. 335].

5.3. Quorum-Sensing Disruption Reinforced by Mixed Biological Signals

Both probiotics and phytochemicals possess quorum-quenching properties; however, they operate via different mechanisms. While probiotics mainly contribute through enzymatic degradation of signaling molecules and microbial homeostasis, phytochemicals may interfere with QS by acting as signal mimics and inhibitors [ref. 336,ref. 337]. For example, quercetin combined with L. acidophilus LA5 enhanced probiotic autoaggregation and coaggregation with E. coli, reduced pathogen adhesion to differentiated Caco-2 cells, and improved epithelial barrier function by increasing TEER values and claudin-1 expression, while reducing pro-inflammatory COX-2 expression [ref. 334]. Similarly, the combination of L. fermentum ASBT-2 and oxyresveratrol suppressed the motility and virulence-associated traits of Salmonella enterica more effectively than either component alone, suggesting complementary anti-virulence activity [ref. 338].

These observations support the concept that probiotic–phytochemical combinations may reinforce pathogen colonization control and virulence attenuation, although direct QS interactions require further investigation [ref. 111,ref. 339,ref. 340,ref. 341,ref. 342,ref. 343].

5.4. Co-Modulation of the Host Immune System

The interaction between probiotics and phytochemicals extends beyond direct antibacterial action and may influence the host immune responses. In selected models, combined probiotic–phytochemical formulations, including those evaluated in atopic dermatitis, have shown stronger anti-inflammatory or microbiota-modulating effects than individual components by promoting beneficial bacteria (e.g., Bifidobacterium and Akkermansia), suppressing pathogens, and reducing inflammatory cytokines [ref. 292,ref. 344]. Together, these mechanisms may support a more resilient mucosal environment that limits pathogen invasion [ref. 345,ref. 346].

5.5. Biotransformation of Plant Compounds by Probiotic Strains

Probiotic microorganisms can biotransform complex phytochemicals into more bioavailable and biologically active metabolites. Probiotic bacteria, including strains such as L. brevis DSM 6235, L. plantarum DSM 20205, L. paracasei DSM 20312, and L. rhamnosus NCTC 10302, possess glycosyl hydrolases, such as β-glucosidases, that cleave sugar moieties from phytochemical glycosides, thereby releasing more bioavailable and biologically active aglycones. For example, citrus flavonoids, such as hesperidin and naringin, can be converted into hesperetin and naringenin, respectively, which often display enhanced antioxidant and anti-inflammatory activities compared with their parent compounds [ref. 347]. Microbial fermentation of Syzygium cumini kernels using curd and yogurt starter cultures also generates metabolites with antibacterial, antioxidant, and anti-inflammatory properties [ref. 348]. Such biotransformation processes may enhance the bioavailability, bioactivity, and pharmacological potential of plant-derived compounds, thereby increasing the functional value of phytochemicals in probiotic–phytochemical formulations.

Metabolic crosstalk with phytochemicals can potentiate these effects on the gut microbiota. Certain polyphenols such as catechins, anthocyanins, and proanthocyanidins upregulate probiotic metabolic pathways, boosting SCFA and bacteriocin production [ref. 349,ref. 350,ref. 351,ref. 352,ref. 353]. Selected probiotic strains of LAB, including L. plantarum, L. fermentum, and other Lactobacillus s.l. representatives, can biotransform plant polyphenols into bioactive derivatives, including aglycones and phenolic acids. For example, Wang et al. [ref. 354] investigated the probiotic transformation of fruit polyphenols, whereas LAB were shown to participate in the bidirectional metabolism of finger millet polyphenols [ref. 355]. In addition, bioconversion by probiotic bacteria such as L. reuteri DSM 20016, Enterococcus faecalis M74 and Bifidobacterium breve ATCC 15701 increased the antiradical activity of lotus seed epicarp polyphenols [ref. 356]. However, the conversion of ellagitannins into urolithins is mainly associated with specialized gut microbiota members (e.g., Gordonibacter urolithinfaciens, Gordonibacter pamelaeae, and Ellagibacter isourolithinifaciens) rather than classical probiotic strains; therefore, urolithin production should be discussed as a microbiota-dependent transformation rather than a general Lactobacillus/Bifidobacterium function [ref. 357].

5.6. Reduced Antibiotic Requirement Through Potent Synergy

By simultaneously disrupting pathogen membranes, inhibiting quorum signaling, suppressing virulence, and supporting host defenses, probiotic–phytochemical combinations may reduce the minimum effective concentration of selected antibiotics [ref. 104,ref. 358]. This supports the development of antibiotic-sparing therapeutics, which is a critical approach for mitigating AMR.

5.7. Conceptual Model of Probiotic–Phytochemical Synergy

The emerging model suggests that synergy arises through the following:

1. Direct microbial antagonism (multi-target inhibition of pathogens);
2. Metabolic cooperation (biotransformation + enhanced probiotic metabolite production);
3. Immune co-modulation;
4. Ecological stabilization of the microbiota;
5. Barrier reinforcement;
6. Biofilm eradication.

This multifaceted cross-domain interaction underscores the translational potential of combined probiotic–phytochemical interventions (Table 3).

6. Methodological Approaches to Evaluate Probiotic–Phytochemical Interactions

A major methodological limitation in this field is the inconsistent application of the term “synergy.” In this review, quantitative synergy refers only to interactions confirmed by formal assays, such as checkerboard analysis with FICI calculation or time-kill experiments showing enhanced pathogen reduction compared with the most active single treatment [ref. 363]. In the absence of formal synergy testing, the combined effects are described as additive, complementary, or mechanistically plausible interactions. Because probiotic–phytochemical interactions may involve direct antimicrobial activity, biofilm modulation, metabolic crosstalk, epithelial barrier protection, and immune regulation, multiple endpoints are often necessary (Figure 3) [ref. 364,ref. 365]. However, methodological interpretation should remain conservative: growth inhibition, improved probiotic viability, altered cytokine production, or biofilm reduction alone should not be considered proof of synergy unless appropriate single-agent controls and quantitative interaction metrics are included. In biofilm-based models, complementary structural or molecular readouts may be useful because biofilm tolerance reflects multiple interacting processes, including diffusion, metabolism, gene expression, and physiological heterogeneity [ref. 130,ref. 366].

The principal methodological approaches and recommended endpoints are presented in Table 4.

7. Potential Clinical, Biotechnological, and Nutraceutical Applications

Emerging evidence suggests that the interactions between probiotics and plant-derived phytochemicals may be relevant to clinical medicine, biotechnology, and the rapidly growing nutraceutical sector [ref. 324,ref. 405,ref. 406]. These combined bio-interventions may provide multi-target antimicrobial action, immune modulation, and microbiota support, which aligns with current efforts to develop sustainable and biologically based strategies for gut health and antimicrobial protection [ref. 294,ref. 407]. However, most interactions between probiotics and plant-derived bioactives have been investigated in vitro or in animal models. Only a limited number of human studies have evaluated combined interventions involving probiotic strains and plant-derived bioactives (Table 5). These studies provide preliminary translational evidence; however, their interpretation remains limited by short intervention periods, heterogeneous formulations, small or disease-specific cohorts, and the frequent absence of formal synergy metrics.

Table 5 includes human studies evaluating combined interventions involving probiotic strains and plant-derived bioactive compounds; however, not all studies were specifically designed to quantify the synergy between both components.

7.1. Potential Clinical Applications

7.1.1. Potential Support in Gastrointestinal Infection Management

Probiotic–phytochemical combinations represent promising alternatives or adjuncts to antibiotic therapy for GI infections caused by C. difficile, Salmonella, E. coli, S. aureus, and other pathogens [ref. 108,ref. 414]. Their benefits arise from the restoration of healthy microbiota balance, suppression of pathogen growth via multi-target inhibition, reinforcement of epithelial barrier integrity, and reduction of inflammation and toxin-mediated damage. Such formulations may potentially reduce relapse risk and lessen the need for broad-spectrum antibiotics, thereby mitigating dysbiosis and slowing the emergence of resistance [ref. 407,ref. 415].

7.1.2. Management of Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)

Phytochemicals with anti-inflammatory and antioxidant activities (e.g., curcumin, resveratrol, and quercetin) combined with probiotic strains (Lactobacillus s.l., Bifidobacterium, and Bacillus) can modulate cytokine profiles, improve mucosal healing, and restore gut barrier function. Combined interventions may reduce oxidative stress and mucosal damage, increase SCFA production, and promote the normalization of dysregulated immune response. Such combinations have shown encouraging results in preclinical models, paving the way for future clinical trials [ref. 416,ref. 417,ref. 418,ref. 419].

7.1.3. Potential Support in Oral and Dermal Infection Prevention

Topical and oral formulations combining probiotics and plant extracts have shown promising activity in preliminary studies against opportunistic pathogens in the oral cavity (Candida spp. and Streptococcus mutans) and skin (S. aureus and P. aeruginosa). Benefits include inhibition of biofilm formation, suppression of virulence factors, reduced pathogen adhesion, and enhancement of local immune defenses. The generally favorable safety profiles support further evaluation of preventive care formulations [ref. 420,ref. 421,ref. 422,ref. 423].

7.1.4. Antibiotic-Sparing Therapeutics

A potential clinical advantage of probiotic–phytochemical combinations is their capacity to reduce the required antibiotic dosage while maintaining beneficial antimicrobial effects. This approach decreases selective pressure for resistant strains, preserves commensal microbiota, and lowers the risk of adverse drug effects. These combinations align with global antimicrobial stewardship efforts. Moreover, combining plant extracts with antibiotics or probiotics has been reported to reduce the minimum inhibitory concentration (MIC) of antibiotics in selected experimental models, lowering the required dosage and minimizing side effects [ref. 424,ref. 425].

7.2. Biotechnological Applications

7.2.1. Development of Synbiotic Formulations

Documented or proposed probiotic–phytochemical interactions may support the development of microbiota-targeted synbiotic formulations, in which plant-derived bioactives function not only as prebiotic substrates but also as antimicrobial and immunomodulatory co-effectors in the gut. This new class integrates probiotics with proven antagonistic activity, phytochemicals that enhance metabolite production, and formulations optimized using metabolomic and transcriptomic profiling [ref. 4,ref. 426,ref. 427,ref. 428,ref. 429].

7.2.2. Fermentation Technology and Metabolite Bioengineering

Probiotic fermentation of phytochemicals generates more bioactive metabolites such as hydroxycinnamic acid derivatives and activated flavonoids. Industrial applications include the biotechnological production of health-promoting compounds, natural antimicrobial preservatives, and valorization of plant waste streams [ref. 430,ref. 431,ref. 432,ref. 433].

7.2.3. Biocontrol in Agriculture and Food Safety

Probiotic–phytochemical combinations can be integrated into biocontrol strategies to reduce bacterial contamination in agriculture [ref. 434,ref. 435], aquaculture [ref. 436,ref. 437], and food processing [ref. 438]. The potential advantages of this approach include an environmentally friendly profile, multi-target pathogen suppression, and compatibility with organic farming practices. This reduces reliance on chemical antibiotics in livestock and crop protection [ref. 439,ref. 440].

7.3. Nutraceutical and Functional Food Applications

7.3.1. Functional Foods with Enhanced Antimicrobial and Immunomodulatory Activity

There is an increasing demand for foods enriched with probiotics and phytochemicals to support gut health, immunity, and microbiota balance. The food matrices used include yogurt and fermented dairy, kombucha and fermented beverages, plant-based fermented foods, and encapsulated-supplement formats. Combined probiotic–phytochemical formulations may offer additional health benefits compared to traditional single-component products, although further clinical validation is required [ref. 294,ref. 441,ref. 442,ref. 443].

7.3.2. Encapsulation and Controlled-Release Technologies

Advanced encapsulation techniques (e.g., alginate beads, microcapsules, and biopolymer composites) can co-deliver probiotics and phytochemicals to the gut. Their benefits include targeted release in the intestine, enhanced viability of probiotics, protection of sensitive phytochemicals from degradation, and controlled modulation of the microbiota composition [ref. 444,ref. 445,ref. 446,ref. 447].

7.3.3. Personalized Nutrition and Microbiome-Targeted Products

The integration of metagenomics and personalized nutrition trends has led to the development of microbiota-tailored nutraceuticals. Probiotic–phytochemical combinations fit this paradigm by offering formulations that are tuned to individual microbial profiles, optimized for immune or metabolic outcomes, and adaptable to specific populations (elderly, athletes, IBS patients, etc.) [ref. 448,ref. 449,ref. 450,ref. 451].

8. Regulatory and Safety Considerations

Although probiotics and plant-derived bioactives are generally considered safe when used individually, their combined use in concentrated formulations necessitates thorough safety and regulatory evaluations. First, plant-derived bioactives may exert dose-dependent effects; compounds that are beneficial at nutritional levels may become cytotoxic, pro-oxidant, hepatotoxic, or irritant at high concentrations or after prolonged exposure. Therefore, concentrated extracts should be chemically standardized and evaluated for toxicity, acceptable daily intake, contaminants, solvent residues, and potential interactions with drugs or host metabolism [ref. 452,ref. 453,ref. 454].

Second, phytochemicals may negatively affect the viability of probiotics. Some phenolics, essential oils, alkaloids, and tannins can inhibit bacterial growth, disrupt membranes, or reduce metabolic activity, which may compromise the survival of probiotic strains during manufacturing, storage, GI transit, and co-delivery. Therefore, compatibility testing between each probiotic strain and plant-derived bioactives should be performed before formulation, including viability assays, stress tolerance tests, and stability studies under relevant pH, oxygen, temperature, and storage conditions [ref. 455,ref. 456].

Third, strain safety is essential. Probiotic candidates should be identified at the strain level, preferably using whole-genome sequencing, and screened for virulence factors, transferable antibiotic resistance genes, toxin production, hemolytic activity, and undesirable metabolic traits. This is particularly important for non-LAB probiotics and spore-forming bacteria, for which safety cannot be inferred from the species name alone [ref. 453,ref. 455].

Fourth, microbiome-related risks should be considered in future studies. Probiotic–phytochemical combinations may have off-target effects on commensal microorganisms, alter microbial diversity, or shift metabolic outputs in a host-dependent manner [ref. 171,ref. 457]. These effects may be beneficial in some contexts but undesirable in others, especially in vulnerable populations, including immunocompromised individuals, infants, older adults, and patients with severe dysbiosis [ref. 171,ref. 458]. Interindividual variability in phytochemical metabolism and gut microbial metabotypes may further influence biological responses to these interventions [ref. 185,ref. 186]. Therefore, it is important to monitor the microbiome and include metabolomic endpoints to determine the intended and unintended ecological effects in future studies [ref. 459].

Finally, formulation-related risks must be considered. Co-formulation may modify the stability, bioavailability, release kinetics, and biological activity of probiotics and phytochemicals [ref. 460,ref. 461]. Encapsulation, microencapsulation, and controlled-release systems can improve probiotic survival and targeted delivery. Nonetheless, these methods may modify dose exposure, elevate production expenses, and necessitate further validation for safety and stability [ref. 461,ref. 462,ref. 463]. Regulatory classification remains challenging because probiotic–phytochemical products may fall between functional foods, dietary supplements, nutraceuticals, and therapeutic products [ref. 463,ref. 464,ref. 465]. Consequently, transparent reporting of strain identity, phytochemical composition, dosage, formulation matrix, viability, stability, and intended use is essential for the reproducibility, consumer safety, and regulatory evaluation of probiotic and plant-derived bioactive formulations [ref. 464,ref. 466].

Briefly, phytoprobiotic formulations require the following [ref. 452,ref. 453,ref. 454,ref. 455,ref. 456]:

• toxicity testing of concentrated phytochemicals;
• stability and viability assessment of the final formulation;
• clear documentation of genomically verified probiotic strain identity;
• compliance with the European Food Safety Authority (EFSA) and Food and Drug Administration (FDA) guidelines for probiotics and botanical supplements.

The regulatory landscape is evolving to accommodate potential synergistic bioactive combinations in functional foods and dietary supplements.

9. Limitations, Challenges, and Future Perspectives

Despite the growing interest in the synergistic interactions between probiotics and plant-derived phytochemicals, several conceptual, methodological, and translational challenges remain. Addressing these limitations is essential for advancing the field toward clinically validated, standardized, and commercially viable therapeutic strategies [ref. 467].

9.1. Limitations and Current Challenges

9.1.1. Variability in the Composition of Plant Extracts

Plant extracts are inherently heterogeneous, and their chemical composition is influenced by factors such as cultivation conditions, plant age, extraction methods, and storage. This variability creates challenges in terms of reproducibility across studies, standardization of doses, regulatory approval, and consistency of clinical outcomes. Phytochemical fingerprinting (untargeted LC-MS/MS, NMR) is often required but not always performed in probiotic–phytochemical studies [ref. 468,ref. 469].

9.1.2. Strain-Specific Response of Probiotics

• Probiotic responses to plant-derived bioactives are strongly strain-specific and cannot be reliably inferred from species-level taxonomy alone [ref. 466,ref. 470]. Strains belonging to the same species may differ in membrane composition, stress response systems, carbohydrate utilization pathways, bile and acid tolerance, adhesion capacity, bacteriocin production, and enzymatic machinery involved in phytochemical biotransformation [ref. 192,ref. 466,ref. 471]. These differences determine whether a given plant extract stimulates, has no measurable effect on, or inhibits probiotic growth [ref. 95,ref. 144]. For example, polyphenol-rich extracts may support selected Lactobacillus or Bifidobacterium strains by acting as fermentable substrates or metabolic modulators, whereas the same extracts may suppress other strains because of the presence of membrane-active phenolics, tannins, or essential oil constituents [ref. 95,ref. 144,ref. 192]. Therefore, probiotic–phytochemical combinations should be designed and tested at the strain level, with viability, metabolic activity, adhesion properties, and phytochemical biotransformation capacity assessed under formulation-relevant and GI conditions [ref. 172,ref. 466,ref. 472]. This strain-level variability is one of the main reasons why results obtained for one probiotic strain cannot be generalized to other strains, even within the same species [ref. 171,ref. 466].

9.1.3. Lack of Standardized Synergy Definitions and Protocols

Although checkerboard and time-kill assays are common, there is no universal standard for defining synergy between biological agents. The differences across laboratories include the following [ref. 468,ref. 473,ref. 474]:

• Inoculum sizes;
• Extraction solvents;
• Culture media;
• Endpoints used to define inhibition;
• Interpretation thresholds.

This lack of harmonization hinders cross-study comparisons and meta-analyses.

9.1.4. Limited in Vivo and Clinical Evidence

Most synergy research remains at the in vitro level. Challenges include differences in the in vivo bioavailability of phytochemicals, survival and colonization of probiotics in the gut, rapid metabolism of plant compounds, and host-specific microbiota response. Only a few studies have validated the synergistic effects in animal models, and even fewer have extended this validation to humans [ref. 107,ref. 468,ref. 473,ref. 475].

9.1.5. Challenges in Co-Formulation and Stability

The combination of probiotics and plant extracts introduces significant formulation issues, including the sensitivity of probiotics to pH, oxygen, heat, and solvents; instability of polyphenols during processing; antagonism between certain strains and compounds; and difficulty in synchronizing their release profiles. Advanced encapsulation technologies can mitigate these problems; however, they also increase production costs [ref. 476,ref. 477].

9.1.6. Regulatory Ambiguity

Current regulatory frameworks for probiotics and botanical supplements are not fully adapted to combined biological therapies. Regulators often lack clear categories for synbiotic formulations with therapeutic claims, probiotic–phytochemical medicinal products, and biotransformed phytochemicals produced during fermentation. This regulatory gap complicates commercialization and clinical trial designs [ref. 469,ref. 475].

The major limitations and corresponding technological priorities for advancing probiotic–phytochemical strategies are summarized in Table 6.

Together, these challenges highlight the need for integrated, standardized, and multilevel approaches to fully realize the therapeutic potential of probiotic–phytochemical synergy.

9.2. Future Perspectives

9.2.1. Precision Synbiotics and Personalized Microbiome Interventions

One of the most promising future directions is the development of precision synbiotics, defined as rationally selected combinations of probiotic strains and plant-derived bioactives tailored to the microbiome composition, metabolic capacity, and clinical or nutritional context [ref. 305,ref. 494]. This approach is particularly relevant because probiotic effects are strain-specific, whereas phytochemical metabolism strongly depends on the functional capacity of the resident gut microbiota [ref. 190,ref. 466]. For example, interindividual differences in microbial metabotypes may determine whether dietary ellagitannins are efficiently converted into urolithins, thereby influencing the biological response to pomegranate and berry-derived polyphenols [ref. 185,ref. 190]. Therefore, the successful implementation of probiotic–phytochemical interventions will depend not only on the botanical source or probiotic species but also on strain-level functionality and phytochemical biotransformation capacity [ref. 192,ref. 466].

Future advances in this area are likely to incorporate metagenomic diagnostics, metabolomic profiling, machine-learning prediction of promising probiotic–phytochemical pairs, and microbiome-based participant stratification [ref. 491,ref. 495,ref. 496]. However, precision synbiotic design will require standardized reporting of probiotic strain identity, phytochemical composition, dose, formulation, viability, and stability to ensure reproducibility and facilitate validation across studies [ref. 172,ref. 466]. Currently, personalized probiotic–phytochemical approaches remain an emerging area of research rather than an established clinical tool, and their translation into practice will require robust human validation studies, reproducible biomarkers of response, and clinically meaningful outcomes [ref. 171,ref. 172].

9.2.2. Translational Challenges

Several additional factors complicate the translational development of probiotic–phytochemical combinations. Pharmacokinetic and pharmacodynamic challenges arise because many phytochemicals exhibit limited oral bioavailability, rapid metabolism, chemical instability, and significant interindividual variability in absorption and microbial biotransformation [ref. 497]. In parallel, probiotic viability, colonization efficiency, and metabolite production are strongly influenced by the formulation, gastrointestinal conditions, and host microbiota composition [ref. 498]. Clinical trial design is further complicated by differences in probiotic strains, phytochemical preparations, dosages, treatment duration, dietary backgrounds, and outcome measures [ref. 499]. Variability in the host microbiota and responder phenotypes may also contribute to heterogeneous clinical responses. Consequently, standardized formulations, validated biomarkers, and adequately powered randomized controlled trials are required to facilitate the successful translation of these findings into clinical practice [ref. 499,ref. 500].

9.2.3. Multi-Omics Integration

A robust understanding of probiotic–phytochemical interactions requires the integration of multiple omics technologies, as no single analytical approach can fully capture the complexity of microbial metabolism, host responses, and microbiota-mediated effects [ref. 459,ref. 493]. Metabolomics can identify changes in SCFA production, phytochemical biotransformation products, and other microbiota-derived metabolites, whereas genomics, transcriptomics, and proteomics provide complementary information on strain functionality, gene expression, metabolic pathways, and host–microbe interactions [ref. 171,ref. 172,ref. 459,ref. 466,ref. 493].

Integrated multi-omics approaches may help distinguish direct antimicrobial effects from indirect microbiota- or host-mediated responses and facilitate the identification of biomarkers associated with treatment responsiveness and microbial resilience [ref. 67,ref. 185,ref. 186]. However, the meaningful integration of multi-omics datasets remains challenging because of differences in analytical platforms, bioinformatic pipelines, and reporting standards [ref. 459]. The generation of consistent and biologically meaningful mechanistic insights will require standardized experimental frameworks combined with comprehensive microbiome and multi-omics analyses [ref. 171,ref. 172].

9.2.4. High-Throughput Screening Platforms

The identification of effective probiotic–phytochemical combinations is challenging because of the large number of possible interactions among probiotic strains, phytochemicals, doses, formulations, and target microorganisms. Therefore, automated and miniaturized screening platforms may become increasingly important for prioritizing promising combinations for mechanistic validation [ref. 501,ref. 502]. Microfluidic and other miniaturized assay systems enable efficient testing of microbial growth, viability, antimicrobial activity, and dose–response relationships while reducing reagent consumption and experimental time [ref. 503,ref. 504,ref. 505]. Such platforms can be adapted to evaluate probiotic strain collections, plant-derived compounds, and complex microbial community models of the gut. However, preliminary screening results do not constitute evidence of synergy unless confirmed by quantitative methods, such as checkerboard, FICI, or time-kill assays.

Artificial intelligence and machine-learning approaches may further support this process by prioritizing combinations with a higher probability of functional compatibility or antimicrobial synergy [ref. 506,ref. 507,ref. 508]. Nevertheless, these tools are primarily hypothesis-generating rather than confirmatory, as predicted interactions still require experimental validation in microbiological, biofilm-, microbiome-based, and ultimately, clinical models.

9.2.5. Next-Generation Delivery Systems

The development of advanced delivery technologies will be crucial, including microencapsulation (alginate, chitosan, lipid-based systems), layered microgels with dual-release kinetics, targeting ligands for colon-specific release, and encapsulated probiotics co-formulated with stabilized phytochemicals. These systems can improve viability, absorption, and target activity [ref. 509,ref. 510,ref. 511].

The successful implementation of probiotic–phytochemical formulations will depend on delivery systems capable of improving probiotic survival and targeted delivery while maintaining compatibility between probiotics and phytochemicals throughout storage and gastrointestinal transit [ref. 172,ref. 325]. Factors such as release kinetics, matrix composition, moisture sensitivity, oxygen exposure, and phytochemical–microbe interactions may substantially influence the performance of the formulation [ref. 325,ref. 472]. Advanced encapsulation and controlled-release technologies may protect probiotic cells from acid, bile, oxygen, and processing stress, while also stabilizing sensitive phytochemicals against oxidation or degradation [ref. 38,ref. 325]. Ensuring consistent biological activity and reproducible results will require viability testing, stability evaluation, dose-exposure analysis, characterization of release profiles, and safety validation [ref. 171,ref. 172].

9.2.6. Eco-Friendly Biocontrol and Agricultural Applications

As concerns regarding antibiotic use in agriculture grow, probiotic–phytochemical combinations may represent eco-friendly candidates for future prevention-oriented strategies in crop pathogen management, livestock health support, and aquaculture microbiome modulation, although further validation under field conditions is required to confirm their efficacy. These applications may be particularly relevant for sustainable agriculture and food safety [ref. 512,ref. 513,ref. 514].

The translation of probiotic–phytochemical strategies to agriculture, aquaculture, and livestock production will require validation under realistic production conditions [ref. 11,ref. 515]. The successful implementation of probiotic–phytochemical strategies in agricultural settings will require long-term field studies evaluating not only pathogen suppression but also formulation persistence, probiotic survival, phytochemical stability, and consistency of performance across different environmental settings [ref. 172,ref. 325]. In aquaculture and animal production models, probiotic and plant-derived interventions may influence immune gene expression, intestinal microbiota composition, and disease resistance; however, these effects remain strongly dependent on host species, diet, formulation, and environmental conditions [ref. 10,ref. 515]. Assessment of potential unintended impacts on native microbial populations, ecosystem functions, and non-target organisms, including beneficial insects, soil microbes, and aquatic microorganisms, is also necessary [ref. 171,ref. 186]. Such data are essential for establishing the ecological safety, sustainability, and practical applicability of probiotic–phytochemical formulations as environmentally friendly alternatives or complements to conventional antimicrobial interventions [ref. 10,ref. 172].

9.2.7. Clinical Translation and Therapeutic Validation

Although numerous in vitro and preclinical studies suggest beneficial interactions between probiotics and phytochemicals, their clinical translation remains limited [ref. 171,ref. 172]. Clinical translation will require well-designed RCTs capable of distinguishing the individual and combined contributions of probiotic and phytochemical components. Factorial trial designs incorporating probiotic-only, phytochemical-only, combination, and placebo groups would provide a more rigorous assessment of the additive, complementary, or potentially synergistic effects under clinical conditions [ref. 171]. There is also a need for pharmacokinetic and pharmacodynamic studies of phytochemical–probiotic interactions, exploration of synergy in chronic inflammatory conditions, and evaluation of post-antibiotic microbiome restoration [ref. 516,ref. 517].

Clinical translation will require the integration of conventional clinical outcomes with microbiome-related, metabolomic, and inflammatory endpoints to improve mechanistic understanding and facilitate biomarker identification [ref. 185,ref. 186,ref. 459]. Greater consideration of dose optimization, treatment duration, formulation characteristics, and interindividual variability will also be necessary, as these factors may substantially influence treatment outcomes [ref. 185,ref. 190].

Long-term safety monitoring remains an essential component of clinical evaluation. A comprehensive assessment of both efficacy and safety is necessary to identify potential adverse effects, including microbiome disturbances, unintended metabolic consequences, and risks associated with prolonged exposure to concentrated phytochemicals or complex formulations, particularly in vulnerable populations [ref. 171,ref. 172]. Ultimately, successful clinical translation will require robust human validation studies, harmonized trial designs, and comprehensive integration of clinical, microbiological, metabolomic, and safety data [ref. 171,ref. 172,ref. 466].

9.2.8. Phage-Based Strategies as Complementary Approaches to Probiotic–Phytochemical Interventions

Phage-based strategies may represent a complementary future direction rather than being a central component of probiotic–phytochemical formulations. Bacteriophages specifically target bacterial hosts and are increasingly considered adjunctive tools against MDR and biofilm-associated infections [ref. 518,ref. 519,ref. 520]. However, phage–phytochemical combinations cannot be assumed to be intrinsically synergistic because plant-derived compounds may either reduce or enhance phage stability, infectivity, and antibacterial efficacy depending on the extract composition, phage type, formulation matrix, and environmental conditions [ref. 521,ref. 522,ref. 523,ref. 524]. Therefore, the successful implementation of phage-based multi-component antimicrobial strategies will depend on compatibility testing, formulation optimization, microbiome safety assessment, and clinical validation.

10. Conclusions

The combination of probiotics and plant-derived bioactives may represent a promising multi-target strategy for addressing the escalating challenges of AMR, dysbiosis, and chronic inflammatory conditions. While both probiotics and phytochemicals individually possess well-established antimicrobial, immunomodulatory, and barrier-protective properties, their combination may offer enhanced efficacy through complementary mechanisms of action. These include disruption of pathogen membranes, interference with QS, inhibition of virulence factors, reinforcement of epithelial integrity, modulation of host immunity, and metabolic biotransformation of phytochemicals into more active derivatives.

Despite their substantial potential, significant challenges remain, including variability in plant extract composition, strain-specific probiotic responses, lack of standardized synergy protocols, and limited translational evidence, all of which hinder their clinical integration. In addition, the clinical translation of probiotic–phytochemical interventions is complicated by the limited bioavailability and extensive metabolism of many phytochemicals, variability in probiotic survival and colonization, interindividual differences in host microbiota composition, and the complexity of designing and conducting standardized clinical trials. Addressing these pharmacokinetic, pharmacodynamic, and methodological challenges will be essential for developing evidence-based microbiota-targeted interventions. Nevertheless, advances in multi-omics, computational modeling, precision microbiome profiling, and advanced delivery systems are facilitating the rational design and evaluation of probiotic–phytochemical combinations.

As research continues to uncover the mechanistic basis and translational relevance of these synergistic interactions, probiotic–phytochemical combinations could become useful resources in clinical and applied microbiome studies, biotechnology, and personalized nutrition. Their capacity to combine antimicrobial-supportive activity with microbiota and host-health support highlights their potential as microbiota-targeted antimicrobial and immunomodulatory interventions in the post-antibiotic era.

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