Tannic acid as a multi-target regulator of intestinal barrier function in livestock

Abstract

The intestinal barrier serves as a critical defense system that prevents pathogen invasion and the translocation of toxins. A compromised barrier initiates a cascade of damage, including impaired mucus secretion, dysregulated inflammatory responses, reduced antioxidant capacity, and microbial dysbiosis. Emerging evidence has highlighted polyphenolic phytochemicals as promising candidates for restoring the barrier. Tannic acid (TA), a hydrolysable tannin, demonstrates multi-mechanistic potential to restore intestinal barrier integrity. This potential originates from its distinctive chemical structure, which functionally ensures the performance of these multiple biological roles. This review synthesizes current evidence on the mechanisms by which TA reinforces intestinal barrier function. Tannic acid remodels the gut microbiota to increase the production of beneficial metabolites, such as butyrate, which subsequently strengthens the physical barrier by upregulating tight junction proteins. In parallel, TA directly enhances the antioxidant defense via the Nrf2 pathway and modulates intestinal immune response by suppressing key pro-inflammatory signaling pathways, including NF-κB and NLRP3. However, the practical application of TA is limited by anti-nutritional effects, necessitating the development of mitigation strategies, such as microencapsulation or synergistic formulations. Overall, this review aims to provide insights into the potential applications of TA for the prevention and treatment of intestinal disorders in livestock and poultry.

1. Introduction

The intestine functions as a central organ in systemic metabolism, with its barrier integrity being fundamental to physiological homeostasis. This sophisticated barrier system consists of four interconnected components: the physical, chemical, biological, and immune barriers. These components operate in synergy to maintain nutrient absorption, exclude pathogens, facilitate immune surveillance, and preserve the stability of the intestinal microenvironment (Yu et al., 2025; Zhang et al., 2024a). However, in modern livestock and poultry production, this crucial intestinal homeostasis is frequently disrupted. Common challenges, such as weaning stress in piglets, enteric pathogen infections (e.g., Escherichia coli), and the overuse or withdrawal of antibiotics, can severely compromise barrier function (Choi et al., 2022a; Feng et al., 2019; Wijtten et al., 2011). This dysfunction manifests as inflammation, oxidative stress, dysbiosis, and increased permeability, leading to reduced growth performance, diarrhea, and heightened susceptibility to disease (Zhao et al., 2025). Consequently, there is an urgent need to identify effective, natural alternatives that can restore and strengthen intestinal barrier integrity to support animal health and sustainable production.

Tannic acid (TA), a hydrolysable tannin, has emerged as a promising candidate due to its multifunctional bioactivities, including anti-inflammatory, antioxidant, antimicrobial, and immunoregulatory properties (Huang et al., 2018; Kawano et al., 2020; Wu et al., 2023; Yesilkent and Ceylan, 2022). For instance, dietary TA enhances the expression of anti-inflammatory cytokine interleukin (IL)-10, while reducing the production of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), in the jejunum and ileum of lambs (Ma et al., 2024). Furthermore, TA activates the Nrf2 pathway in porcine intestinal epithelial cell line J2 (IPEC-J2), thereby boosting antioxidant capacity and alleviating oxidative damage (Wang et al., 2022). The full names of the abbreviations of all proteins can be found in Table S1. Tannic acid also exerts direct antibacterial effects, such as inhibiting Salmonella colonization in broilers and reducing associated intestinal damage (Choi et al., 2022b; Wu et al., 2025). These data indicate that TA holds significant potential for protecting intestinal health.

However, the application of TA is not without complexity. Its benefits exhibit a strong dose-dependency, where excessive doses can impair growth performance and nutrient digestibility. In broilers infected with Eimeria maxima, TA supplementation at doses up to 5000 mg/kg significantly impairs growth performance (Choi et al., 2022a). Similarly, in weaned piglets, dietary TA at 0.4% reduces crude protein digestibility and gross energy (Song et al., 2021). Furthermore, bioactivity varies with tannin type, as hydrolysable tannins like TA often demonstrate more favorable effects on gut health compared to some condensed tannins (Li et al., 2020a; Song et al., 2021). Therefore, identifying an optimal and context-specific application strategy is essential.

Currently, while TA is known to modulate intestinal barrier function through multiple mechanisms, its efficacy is highly context-dependent, and the precise, integrated mechanisms underlying its restorative effects across the different barrier components remain incompletely elucidated (Choi et al., 2022a; Song et al., 2021). This gap hinders its rational and effective application. Here, this review examines the role of TA in restoring intestinal barrier integrity in livestock and poultry affected by intestinal damage. It begins by elucidating how its unique chemical architecture underpins its multifunctional bioactivity, then focuses on its multifaceted effects across the physical, chemical, biological, and immune barriers, with the aim of synthesizing a mechanistic framework to guide the development of TA as a targeted nutritional intervention for intestinal health.

2. The chemical architecture of TA as the source of its functional versatility

Tannic acid, a hydrolysable tannin, has garnered significant research interest across diverse fields. This broad applicability stems from its potent biological activities, including protein-binding affinity (Xie et al., 2017), antioxidant capacity (Lou et al., 2018), and antimicrobial effects (Cipriano-Salazar et al., 2018). These functions are directly attributable to the distinctive and complex molecular architecture of TA. Structurally, TA belongs to a large family of polyphenols composed of multiple polygalloyl glucose units, characterized by a central β-D-glucose core whose hydroxyl groups are extensively esterified with galloyl units. A key structural feature is the further interconnection of these galloyl moieties via ester linkages, forming a highly branched, high-molecular-weight polymer. This unique arrangement confers two critical topological properties: an exceptionally high density of phenolic hydroxyl groups and a flexible, three-dimensional conformation capable of multivalent interactions, which together form the physicochemical basis for its diverse bioactivities (Fig. 1).

Fig. 1.

The chemical structure and biological functions of tannic acid (TA). The dashed boxes highlight specific functional moieties: the top galloyl groups mediate metal ion chelation; the left-side phenolic-OH and aromatic rings drive protein binding; and the right-side counterparts confer antimicrobial activity.

2.1. Membrane disruption and antimicrobial activity

Tannic acid is a water-soluble polyphenolic compound whose structure comprises numerous phenolic hydroxyl groups together with aromatic rings capable of π–π interactions (Almaie and Vatanpour, 2026; Rodrigues et al., 2024). These structural features are consistent with its capacity to interact with and perturb bacterial membranes, as evidenced in Clostridium perfringens, where TA treatment significantly increased extracellular K⁺ and Mg²⁺ levels, indicative of membrane permeabilization and cytoplasmic leakage (Xu et al., 2025a), an effect that is particularly pronounced in synergistic antimicrobial systems. Research shows that TA-based hydrogels can cause severe membrane disruption in pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, resulting in effective bactericidal activity (Garg et al., 2024). This membrane-targeting property serves as a key defense mechanism contributing to intestinal health, enabling TA to selectively inhibit pathogenic bacteria. This function is likely to contribute significantly to the enhancement of intestinal epithelial integrity (Fig. 1).

2.2. The multifaceted capability of metal chelation

The metal-chelating capacity of TA is primarily attributed to the catechol groups within its galloyl units. For instance, TA acts as a natural reducing agent, converting Fe³⁺ to the more reactive Fe²⁺, thereby promoting the Fenton reaction, enhancing hydroxyl radical generation, and improving the efficacy of chemodynamic therapy against tumor cells (Zhu et al., 2020). Conversely, coordination with other metal ions can modulate the behavior of TA. Under physiological pH, TA forms a stable 3:1 complex with Cu²⁺, which, through steric hindrance and charge neutralization, attenuates its strong binding to human serum albumin (HSA), mitigates perturbation of HSA's secondary structure, and thus modulates its interaction with transport proteins, with implications for in vivo bioavailability (Guan et al., 2025). Furthermore, leveraging TA coordination with Zn²⁺ enables the construction of multifunctional nanoparticles that co-deliver antibiotics, target multiple pathogenic factors in sepsis, scavenge cell-free DNA and reactive oxygen species, and exert potent antimicrobial effects, showcasing great potential for multi-target synergistic therapy (Liu et al., 2021). These examples collectively underscore the multifaceted and tunable functionality of TA, which arises from its adaptable metal-chelating behavior (Fig. 1).

2.3. Hydrogen bonding, hydrophobic interactions, and protein binding

The phenolic hydroxyls serve as potent hydrogen bond donors, while the galloyl aromatic rings contribute hydrophobic interactions (He, 2022). During protein complexation, these structural features act cooperatively: hydrogen bonding and hydrophobic association together drive the formation of stable TA–protein complexes (He et al., 2006). Indeed, this hydrogen bond-driven assembly has been directly demonstrated in food systems, where TA acts as a crosslinker through its phenolic hydroxyls to form dense, protective shells around soy protein microgel emulsions (Wu et al., 2022). The protein-binding ability of TA exemplifies how this compound, through its unique chemical architecture, achieves its broad-spectrum biological functions through concerted molecular interactions. For instance, TA has been shown to alleviate hepatic oxidative stress induced by arsenic trioxide poisoning in rats through activation of the Keap1-Nrf2/ARE signaling pathway (Li et al., 2020b). However, how specific structural features of TA activate these intracellular antioxidant pathways remains unclear.

In summary, the molecular structure of TA is not merely a static entity but a dynamic blueprint for function. The central glucose core, densely functionalized with a complex network of galloyl units, forms a molecular platform that engages with diverse biological targets through a repertoire of interactions. It is precisely this chemically grounded versatility that empowers TA to underpin its multifaceted biological roles.

3. Tannic acid-mediated restoration of intestinal barrier function

The intestinal barrier is a multi-layered defense system, the dysfunction of which underlies many enteric disorders in animal production. Tannic acid demonstrates a remarkable, multi-target capacity to restore its integrity. Its effects are not isolated to a single component but operate through an interconnected cascade: TA directly remodels the gut microbiota and its metabolic output, which in turn provides key signals for the repair of the physical barrier. Concurrently, TA also exerts direct effects on epithelial and immune cells. This coordinated action leads to conserved effects across livestock and poultry species (Table S2).

3.1. Remodeling of the gut microbiota and metabolite profile

The gut microbiota constitutes a critical biological barrier, and its metabolites are fundamental regulators of intestinal homeostasis (Ducarmon et al., 2019; Horrocks et al., 2023). In weaned piglets, disruption of this microbial equilibrium can lead to various pathological conditions, including diarrhea-associated diseases (Gresse et al., 2017). Tannic acid directly shapes this ecological community, inhibiting pathogens while fostering beneficial symbionts and their metabolites. Dietary TA (0.10% and 0.15%) suppresses the proliferation of pathogens such as E. coli and Bilophila, while promoting beneficial taxa including Bacillus and butyrate-producing bacteria in weaned piglets (Song et al., 2021; Xu et al., 2022). Of particular interest, TA increases the abundance of Lactobacillus amylovorus (Sun et al., 2021), a bacterial species implicated in promoting epithelial repair through activation of the Wnt/β-catenin pathway (Wu et al., 2024). This regulatory effect extends to poultry (Zou et al., 2024). Tannic acid enriches beneficial families like Lactobacillaceae while suppressing pro-inflammatory Proteobacteria (Xu et al., 2025b). Under pathogenic challenge, this activity becomes clinically significant: in broilers with necrotic enteritis, TA supplementation (750 mg/kg) effectively reduces cecal C. perfringens load (Xu et al., 2023a). During Salmonella infection, TA optimizes microbial structure through multifaceted mechanisms. It inhibits the colonization of pathogenic taxa, including Proteobacteria, Desulfobacterota, and Escherichia-Shigella, while simultaneously enriching functional bacteria such as Bacteroides fragilis within Bacteroidetes, thereby mitigating inflammation and dysbiosis in broilers (Wu et al., 2025). These data collectively indicate that TA acts as a critical regulator of the gut microbiota, remodeling the gut community toward a symbiotic state that is essential for robust barrier function.

The restructuring of the microbiota drives a beneficial shift in the metabolite landscape, which mediates many downstream effects of TA. Dietary supplementation with TA positively modulates microbial metabolite profiles, including enhancing short-chain fatty acid (SCFA) levels in the large intestine of piglets. Of note, the effects of TA on SCFAs are source-dependent: gallnut TA significantly elevates butyric acid in weaned piglets, whereas chestnut TA preferentially enhances isobutyric acid production (Song et al., 2021; Zhang et al., 2025). Butyrate, a key SCFA, enhances the intestinal barrier by downregulating the pro-leakage protein CLDN-2 and upregulating sealing proteins, including OCLN, ZO-1, and ZO-2 (Ploger et al., 2012; Wang et al., 2012); this effect is potentially mediated through the inhibition of TLR4 signaling (Huangfu et al., 2024). Beyond this, microbial metabolites extend beyond SCFAs. Folate, another key metabolite (Malinowska et al., 2022), is increased by TA in the colon, ameliorating colitis through regulation of methylation processes (Wang et al., 2024). This elevation in folate may be linked to TA-induced modulation of microbial community structure and function (Wang et al., 2024). Collectively, TA directly shapes microbial composition and indirectly reinforces the intestinal barrier via these metabolite-mediated mechanisms (Fig. 2).

Fig. 2.

Tannic acid (TA) mitigates intestinal injury via regulating antioxidant, inflammatory response and microbial barrier function. Under TA intervention, the intestine presents intact barrier function, accompanied by upregulated antioxidant enzymes, enriched beneficial bacteria and elevated short-chain fatty acids (SCFAs) levels, as well as attenuated interferon-γ (IFN-γ) and interleukin (IL)-1β and increased IL-10 (left panel). In contrast, the impaired barrier state is featured by decreased antioxidant enzymes, gut dysbiosis, higher epithelial permeability, and aggravated bacterial translocation; activated immune cells secrete excessive IFN-γ and IL-1β, whereas IL-10 production is suppressed (right panel). The central inset summarizes the key signaling pathways of TA: inflammatory inhibition (TLR4/MyD88/NF-κB, IL-17, and NLRP3) and antioxidant enhancement (p62/Keap1/Nrf2). Vertical arrows represent increased and decreased molecular levels, respectively. Solid arrows indicate activation; bar-headed lines represent inhibitory effects; hollow arrows stand for the regulatory effects of TA; dashed arrows indicate cytokine secretion. The full names of the abbreviations of all proteins can be found in Table S1.

3.2. Reinforcement of the physical barrier

The intestinal epithelial physical barrier, comprising tight junctions and the mucus layer, is the ultimate gatekeeper against luminal threats (Cornick et al., 2015; Suzuki, 2020). Nevertheless, this critical barrier is vulnerable to disruption by prevalent husbandry challenges such as weaning stress, enteric infections, and antibiotic misuse, all of which may compromise its integrity (Choi et al., 2022a; Feng et al., 2019; Wijtten et al., 2011). Tannic acid strengthens this barrier through both direct cellular effects and indirect, microbiota-mediated pathways. For instance, weaning stress in piglets induces intestinal damage and disrupts tight junction protein expression; of note, dietary supplementation with TA coating (0.15%) enhances the expression of tight junction proteins (Xu et al., 2022) an effect that may be associated with elevated butyric acid levels (Wang et al., 2012). As outlined in the previous section, TA promotes the abundance of butyrate-producing bacteria. Butyrate is known to enhance CLDN-1 expression by facilitating the interaction between transcription factor SP1 and specific promoter sequences of CLDN-1 (Wang et al., 2012). This mechanism underscores the indirect pathway through which TA strengthens the physical barrier.

Tannic acid also directly contributes to mucosal integrity. Serum diamine oxidase (DAO) and D-lactate are well-established biomarkers of mucosal integrity (Guo et al., 2010; Zhang et al., 2022a), with elevated levels reflecting epithelial damage such as that induced by weaning stress in piglets (Huangfu et al., 2024). Tannic acid supplementation (0.2% or 1.0%) reduces serum DAO levels in weaned piglets (Yu et al., 2020), and this effect is conserved in broilers, where TA also modulates tight junction protein expression and lowers intestinal DAO levels (Jing et al., 2022). This conserved response is accompanied by a significant increase in intestinal mucin secretion, further supporting the role of TA in enhancing barrier function across species.

Furthermore, TA consistently improves overall intestinal morphology, a prerequisite for optimal barrier function and nutrient absorption. In Salmonella-infected broilers, dietary TA (0.1%–0.3%) enhances intestinal integrity and increases villus height (VH) (Zou et al., 2024). Similarly, in weaned piglets, TA supplementation (0.3%) elevates VH, reduces crypt depth (CD), and improves the VH/CD ratio, thereby enhancing digestive and absorptive capacity (Ma et al., 2021). This improvement in mucosal architecture is also a key mechanism by which TA ameliorates necrotic enteritis in poultry, preserving digestive function and pathogen resistance (Xu et al., 2023a) (Fig. 3).

Fig. 3.

Tannic acid (TA) promotes intestinal physical barrier recovery. Under TA supplementation, the intestine shows an intact mucus layer, restored tight junctions, balanced microbiota, and reduced circulating diamine oxidase (DAO) and D-lactate levels (left panel). In contrast, the injured state displays mucus thinning, epithelial damage, pathogenic bacterial translocation, disrupted tight junctions with enlarged paracellular pores, and elevated DAO and D-lactate (right panel).

3.3. Augmentation of antioxidant defenses and attenuation of inflammation

The intestinal chemical and immune barriers are closely intertwined and are often simultaneously compromised. Tannic acid addresses both through a dual strategy: directly boosting endogenous antioxidant systems and suppressing disproportionate inflammatory signaling (Wang et al., 2022) (Fig. 2).

3.3.1. Enhancement of antioxidant defenses

The chemical barrier function of the intestine relies on robust antioxidant systems to neutralize oxidative damage. Tannic acid has been demonstrated to significantly boost this defense mechanism both in vitro and in vivo. In porcine IPEC-J2, TA treatment (2.5-5.0 µmol/L) increases the total antioxidant capacity (T-AOC) and stimulates the synthesis of glutathione (GSH), a key intracellular antioxidant (Wang et al., 2022). This cell-level finding is consistently corroborated in animal models. In weaned piglets, dietary TA (1000 mg/kg) enhances glutathione peroxidase (GSH-Px) activity in the ileum and serum, and increases serum catalase (CAT) activity, while concurrently reducing the level of ileal malondialdehyde (MDA), a marker of lipid peroxidation (Liu et al., 2020; Wang et al., 2022). Similarly, in broilers, TA administration (600, 100, and 250 mg/kg) elevates plasma activities of CAT, GSH-Px, and glutathione S-transferase (GST), and boosts jejunal total-SOD (T-SOD) activity, all while decreasing circulating MDA concentrations (Liu et al., 2023; Tong et al., 2021; Xi et al., 2022). This effect is further reflected in the jejunum, where TA supplementation significantly elevates T-SOD activity (Xi et al., 2022). Consistent with these findings, partial substitution of dietary corn with low-TA sorghum also improves antioxidant status in broilers (Saleh et al., 2019). Moreover, under pathogenic conditions such as aflatoxin B₁ challenge, TA (250 or 500 mg/kg) effectively boosts serum antioxidant enzyme activities (Xi et al., 2022; Zhang et al., 2022b). The molecular mechanism underlying this broad-spectrum antioxidant effect involves the activation of the Nrf2 pathway. Tannic acid upregulates the expression of p62, which competitively binds to Keap1, thereby relieving Keap1-mediated inhibition of Nrf2 and facilitating the nuclear translocation of Nrf2. This, in turn, initiates the transcription of a suite of cytoprotective and antioxidant genes (Liu and Guo, 2024).

3.3.2. Suppression of inflammation pathways

Concurrent with its antioxidant action, TA directly targets and dampens the activation of the intestinal immune barrier, preventing a disproportionate inflammatory response (Miguel Libanori et al., 2025). Evidence from immunocyte models shows that TA balances T-helper cell polarization: it suppresses the production of pro-inflammatory cytokines (e.g., interferon-γ [IFN-γ], IL-17) and enhances the secretion of the anti-inflammatory cytokine IL-10 in anti-CD3/CD28 antibody-stimulated splenocytes. Additionally, TA regulates innate immune responses by reducing IFN-γ and IL-1β secretion in lipopolysaccharide (LPS)-stimulated splenocytes (predominantly macrophages) (Kawano et al., 2020). This immunomodulatory profile is conserved in production animals. In piglets, TA initially elevates IL-6 to mount an early defense, then facilitates its normalization to prevent chronic inflammation (Tan et al., 2023). Tannic acid also attenuates key inflammatory markers, including CRP and MPO, which serve as broad-spectrum indicators of systemic and local inflammatory markers of neutrophil infiltration, respectively (Cheng et al., 2019; Sproston and Ashworth, 2018; Xu et al., 2023a). In broilers suffering from necrotic enteritis, TA supplementation reduces ileal levels of TNF-α, serum CRP, and MPO, while promoting the expression of anti-inflammatory cytokines like IL-4 and IL-10 during the later stages of inflammation (Xu et al., 2023a,b). Furthermore, in an LPS-induced liver injury model, TA (300 mg/kg) enhances immune function (Yuan et al., 2023). Upon Salmonella infection, TA promotes M2 macrophage polarization, thereby suppressing excessive inflammation (Wu et al., 2025). These findings indicate that TA may modulate intestinal immunity by regulating inflammation-related signaling molecules.

The molecular basis underlying these anti-inflammatory effects involves the inhibition of key signaling hubs by TA. It suppresses the classical TLR4/MyD88/NF-κB pathway and inhibits the activation of the NLRP3 inflammasome, leading to downregulation of associated molecules (TLR4, MyD88, NF-κB, and NLRP3) and blockade of pro-inflammatory cytokine release (e.g., IL-1β) (Jin et al., 2020; Liu and Guo, 2024; Wang et al., 2024). Additionally, TA (3 mg/mL) can inhibit IL-17 signal transduction, reducing NF-κB p65 nuclear translocation and alleviating colitis (Wang et al., 2024), a conserved effect also observed in neuroinflammation models (Azimullah et al., 2023). The varied immunomodulatory phenotypes, including cytokine regulation and macrophage polarization, underscore the role of TA as a sophisticated modulator capable of adapting its response to different pathological contexts, all grounded in the suppression of overarching inflammatory signaling axes.

4. Practical applications and limitations

The wealth of evidence detailing the action mechanisms of TA naturally leads to an evaluation of its practical application. This section synthesizes the validated efficacy of TA in animal production and critically examines the factors limiting its practical use.

4.1. Validation of efficacy in livestock and poultry production

Substantial research in swine and poultry provides compelling in vivo validation for the multi-target mechanisms of TA. In weaned piglets, dietary TA supplementation consistently improves gut health and performance. Benefits include enhanced intestinal morphology (increased VH and reduced CD) (Ma et al., 2021), upregulated expression of tight junction proteins (Xu et al., 2022), improved nutrient digestibility linked to increased digestive enzyme activity (Xu et al., 2022), and a beneficial remodeling of the gut microbiota (Sun et al., 2021). These changes collectively contribute to a significant reduction in diarrhea incidence and modulation of immune markers, positioning TA as a viable alternative to traditional growth-promoting antibiotics (Tan et al., 2023; Table S2).

Similarly, in broilers facing pathogenic challenges such as Salmonella or C. perfringens infections, TA demonstrates protective efficacy. It reduces pathogen load and intestinal inflammation, thereby mitigating infection-specific damage (Xu et al., 2023a; Zou et al., 2024). Concurrently, it maintains core indicators of barrier integrity, including villus architecture and serum markers of epithelial permeability (e.g., DAO and D-lactate) (Jing et al., 2022). The convergence of these phenotypic outcomes, such as structural repair, enhanced antioxidant status, and anti-inflammatory effects, and microbial eubiosis across distinct species and challenges directly mirrors the molecular pathways detailed previously. This consistency confirms the role of TA as a broad-spectrum bioregulator of intestinal homeostasis and strengthens translational confidence for its use in animal production.

4.2. Major challenges and limitations for the application

Despite TA demonstrating promising potential, several intrinsic and practical limitations constrain the widespread application of TA in animal feeds. The foremost challenge is its anti-nutritional property. Its high affinity for nonselective binding to dietary proteins (e.g., proline-rich proteins), digestive enzymes (e.g., trypsin), and essential minerals can significantly impair nutrient digestibility, bioavailability, and animal growth performance, especially at higher doses (Choi et al., 2022a; Kheto et al., 2025; Smeriglio et al., 2017; Song et al., 2021).

Furthermore, the biological effects of TA are highly context-dependent, creating challenges for its practical application. Efficacy and safety vary significantly with dosage, animal species, health status, and, critically, the botanical source and specific chemical profile of the tannin. For instance, while both chestnut- and quebracho-derived TA can improve ileal morphology in weaned piglets, their effects on VH and CD differ, underscoring that not all TA are functionally equivalent (Ma et al., 2021; Zhang et al., 2025). Crucially, high doses of condensed tannins, in contrast to hydrolysable TA like that from chestnut, can exacerbate intestinal inflammation, as observed in grass carp enteritis models, highlighting the dose-specific and structure-dependent duality of tannin actions (Li et al., 2020a). Additionally, a significant knowledge gap exists regarding the effects of TA in ruminants, where complex ruminal fermentation is likely to modulate its biological impact, leaving its influence on the ruminant intestinal barrier poorly understood, despite preliminary evidence suggesting effects on product quality (Santillo et al., 2022).

5. Perspectives

5.1. Engineering strategies to overcome intrinsic limitations

Advanced formulation technologies are central to mitigating the anti-nutritional drawbacks of TA while enabling targeted delivery. Microencapsulation or coating (e.g., with lipids or polymers) masks the astringency of TA, improves feed palatability, and permits controlled release in the intestinal tract, thereby minimizing gastric irritation and maximizing local action at the barrier site. Consistent with this rationale, microencapsulated TA improves intestinal morphology and nutrient transporter expression in weaned piglets more effectively than the free form (Liang et al., 2021; Wang et al., 2020). Developing defined TA-mineral complexes (e.g., Zn-TA nanoparticles) is another promising approach in vitro. This strategy preemptively addresses the mineral-chelating issue and can create novel multifunctional entities with enhanced anti-inflammatory and antioxidant properties, as demonstrated in inflammatory bowel disease (IBD) models (Zhang et al., 2024b). Beyond formulation, the adaptability of the host gut microbiota is itself a determinant of TA efficacy and therefore a tractable engineering target. In weevils feeding on TA-rich oak, members of the genus Bacillus facilitate tannin utilization (Wang et al., 2025), suggesting that targeted supplementation with tannin-metabolizing bacteria may attenuate the anti-nutritional effects of TA and widen its effective dose window.

5.2. Unresolved mechanistic questions

Tannic acid enhances barrier integrity by upregulating tight junction proteins, improving villus-crypt architecture, and reducing epithelial permeability. Nevertheless, key mechanistic aspects remain unresolved, including how TA precisely regulates VH/CD and mucin synthesis. Tannic acid also activates the Nrf2 pathway to strengthen antioxidant defenses and enriches butyrate-producing microbiota. However, the spectrum of gut microbiota-derived metabolites extends beyond SCFAs, and the influence of TA on other bioactive metabolites (e.g., indole compounds) remains an important area for future investigation. Concurrently, TA suppresses pro-inflammatory pathways (e.g., TLR4/NF-κB), inhibits pathogens such as C. perfringens, and promotes an anti-inflammatory cytokine milieu. Still, other inflammatory signaling (e.g., MAPK signaling) remains unexplored in the context of TA supplementation. Elucidating these mechanisms will enable more precise and context-specific application of TA in livestock production.

5.3. Expanding applications in intestinal health and disease

The foundational mechanisms of TA invite its exploration for the management of specific intestinal disorders. In biomedical models, TA shows direct efficacy against IBD (Zhang et al., 2024b), alleviating colitis by inhibiting IL-17/NF-κB signaling, modulating epigenetic methylation, and restoring oxidant–antioxidant balance (Wang et al., 2024). Engineered probiotic systems coated with TA polymers (e.g., EcN@SA-pBDT-TA, E. coli Nissle 1917 coated sequentially with sodium alginate and self-polymerizable aromatic dithiol/TA nanoparticles) have been designed for targeted IBD therapy, showcasing enhanced barrier repair and anti-inflammatory effects (Hu et al., 2024). In addition to binding with probiotics, chelation of TA with metals can also alleviate IBD. For example, Zn-TA nanoparticles with fine hollow microstructure can clear colon reactive oxygen and nitrogen species, reduce pro-inflammatory cytokine levels, upregulate ZO-1 and CLDN-1 expression, and reduce the occurrence of colitis in mice (Zhang et al., 2024b).

Intestinal disorders are closely associated with alterations in gut microbiota and metabolites. A starch–TA complex markedly promoted propionate production during in vitro fermentation with human fecal microbiota, an effect associated with decreased abundances of Segatella, Eubacterium_rectale_ATCC_33656, and CAG-352, all negatively correlated with propionate, indicating that the starch-TA complex holds practical potential for targeting specific gut bacteria to enhance propionate synthesis and thereby support host health (Duan et al., 2025); a similar effect was confirmed in colitis mice (Liu et al., 2024). Tannic acid additionally shows promise against infectious diarrheal disease, inhibiting sporulation, toxin production, and biofilm formation in Clostridioides difficile and improving survival in infected mice (Wang et al., 2023). Collectively, these emerging applications underscore the versatility of TA. Bridging the fields of animal nutrition, food science, and biomaterial engineering will be crucial to develop TA-based, multi-target interventions for intestinal health across species.

6. Conclusions

Emerging evidence indicates that TA modulates intestinal barrier function through multiple interconnected mechanisms. It remodels the gut microbiota toward a butyrate-producing state, upregulates tight junction protein expression and improves villus-crypt architecture, engages Nrf2-dependent antioxidant defenses, and attenuates TLR4/NF-κB-driven inflammation. At appropriate dietary doses, TA lowers diarrhea incidence in weaned piglets, improves feed conversion efficiency, and preserves body weight gain in broilers challenged with Salmonella, C. perfringens, or aflatoxin B₁, positioning TA as a practical antibiotic alternative for supporting gut health in swine and poultry production. Its benefits are nevertheless confined to a defined dose window and are further shaped by tannin source, animal species, and health status. Tannic acid is therefore best regarded not as a uniform additive but as a context-dependent bioregulator, whose value in practice depends on matching dose, source, and formulation to the specific physiological challenge.

Credit Author Statement

Lingyang Zhao: Writing – original draft, Conceptualization. Jia Huang: Writing – original draft. Zhihua Liu: Formal analysis. Peng Bin: Writing – review & editing. Wenjie Tang: Writing – review & editing. Peng He: Writing – review & editing. Xianfeng Peng: Writing – review & editing, Resources, Conceptualization. Shuo Li: Writing – review & editing, Supervision, Conceptualization.

Declaration of competing interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, and there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the content of this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wenjie Tang and Peng He are currently employed by Sichuan Animtech Group Co., Ltd. (Chengdu, Sichuan, China), Xianfeng Peng is currently employed by Guangzhou Insighter Biotechnology Co., Ltd. (Guangzhou, Guangdong, China).

Appendix A. Supplementary data

The following is the Supplementary data to this article.