The effects of phenolic acid supplementation on intestinal barrier function: a review

Abstract

The intestinal barrier is critically implicated in the pathogenesis of diverse diseases, and its impairment constitutes a common pathological hallmark across numerous conditions. Therefore, restoring intestinal barrier function is a key therapeutic strategy for mitigating or treating associated diseases. Phenolic acid compounds, secondary metabolites derived from plants, exhibit diverse pharmacological properties, including anti-inflammatory, antioxidant, and antibacterial activities. This review summarizes the sources, absorption, and metabolic pathways of phenolic acids, delving into their mechanisms for maintaining intestinal barrier integrity. Key mechanisms encompass the upregulation of tight junction protein expression, modulation of mucus secretion, inhibition of oxidative stress and inflammatory responses, and regulation of gut microbiota composition. Furthermore, we summarize the therapeutic potential of phenolic acid compounds in treating diseases associated with intestinal barrier dysfunction, discuss their clinical applications and safety profiles, and critically evaluate challenges in clinical translation. This review aims to provide a scientific foundation for the potential therapeutic application of phenolic acid compounds. However, their definitive clinical value necessitates further validation through rigorous clinical trials.

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1. Introduction

Phenolic acids are widely distributed plant secondary metabolites. As dietary supplements, phenolic acids provide a broad spectrum of health benefits, for example, antioxidant, antimicrobial and anti-inflammatory effects.^1–3 In recent years, public research on phenolic acids has increased, especially in intestinal diseases. Currently, millions of people around the world suffer from intestinal diseases, including IBS,⁴ IBD⁵ and intestinal infections.⁶ The treatment of these intestinal diseases is limited to managing symptoms and they cannot be completely eradicated. Therefore, identifying the key pathogenic mechanisms of intestinal diseases is critical to overcoming this problem.

The intestinal barrier, the first line of defense between the gut and the external environment, plays a vital role in regulating the transport of nutrients, water, and waste while resisting pathogen invasion. Its integrity is closely associated with the development and progression of various intestinal diseases.^7,8 Therefore, preventing or repairing intestinal barrier damage may represent a promising approach for treating these conditions.⁹ Several phenolic acids, such as chlorogenic acid,¹⁰ gallic acid,¹¹ caffeic acid,¹² and ferulic acid,¹³ have been shown to repair damaged intestinal barriers by upregulating the expression of tight junction proteins. Protocatechuic acid,¹⁴ sinapic acid,¹⁵ and vanillic acid¹⁶ can also exert protective effects on the intestinal barrier through their anti-inflammatory and antioxidant properties. Similarly, studies have demonstrated the beneficial effects of phenolic acid rich foods on intestinal barrier integrity.^17,18

This review systematically synthesizes the molecular mechanisms through which phenolic acids protect the intestinal barrier, including increasing tight junction protein expression, regulating mucus secretion, reducing oxidative stress, modulating intestinal microbiota composition, and normalizing immune function. Furthermore, it evaluates their therapeutic potential and clinical translation barriers, providing a scientific foundation and future research directions for developing phenolic acid-based interventions targeting barrier repair.

2. Sources, dietary forms, and absorption and metabolism of phenolic acids

2.1 Sources of phenolic acid

Phenolic acids are ubiquitous in foods, including fruits (such as apples, lemons, grapes, pomegranates and strawberries), vegetables (such as peppers, onions, eggplants and coriander), beans (such as peas, mung beans and kidney beans), grains (such as barley, wheat, rye and millet), and oilseeds (such as flax, rapeseed and mustard seeds).¹⁹ Additionally, the gut microbiota can metabolize precursors such as cinnamic acid into a variety of phenolic acids via the shikimate and phenylpropanoid pathways, including salicylic acid,²⁰ chlorogenic acid,²¹ protocatechuic acid,²² gallic acid,²³ coumaric acid,²⁴ caffeic acid,²⁵ ferulic acid, and sinapic acid.²⁶ Dietary anthocyanins, procyanidins, and quercetin undergo biotransformation into chlorogenic acid,^27–29 while anthocyanin-3-glucoside (C3G) yields metabolites including protocatechuic acid, vanillic acid, ferulic acid and derivatives.³⁰ Similarly, flavanol compounds are metabolized by the gut microbiota to 15 phenolic acids, including caffeic acid and ferulic acid,³¹ all of which exhibit significant antioxidant and anti-inflammatory activities. Additionally, during the processes of absorption and metabolism, phenolic acids can undergo interconversion: hepatic metabolism converts ferulic acid to vanillic acid;³² the gut microbiota metabolizes protocatechuic acid to vanillic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, and 3-methoxybenzoic acid;³³ and colonic microorganisms degrade chlorogenic acid to caffeic acid.³⁴

2.2 Dietary forms of phenolic acid

In food matrices, hydroxycinnamic acids are commonly present as glycerides. For instance, ethyl p-coumarate has been identified in certain varieties of radish and tomato.³⁵ Chlorogenic acid exists as ethyl chlorogenic acid in unripe sunflower seeds,³⁶ while caffeic acid and monoglycerides of p-coumaric acid have been isolated from pineapple stems.³⁷ Hydroxybenzoic acids are predominantly present in foods as glycosides. Caffeic acid, protocatechuic acid, and chlorogenic acid are found in currants, blueberries, and gooseberries, respectively, in the form of 4-O-glycosidic bonds.³⁸ Para-hydroxybenzoic acid occurs as glycosides in star anise,³⁹ and glycoside forms of various phenolic acids, including salicylic acid, vanillic acid, and eugenic acid, have been detected in a wide range of fruits and vegetables such as onions, potatoes, and cherries.⁴⁰ In general, phenolic acids are predominantly found in foods as esters or glycosides, typically conjugated with natural compounds such as sterols, triterpenes, and lignans.

2.3 Absorption and metabolism of phenolic acids

Phenolic acids undergo dynamic processes of absorption, metabolic processing and excretion (Fig. 1), which determine their bioavailability. Free phenolic acids (such as caffeic acid) are partially absorbed in the stomach through passive diffusion, whereas conjugated phenolic acids require hydrolysis mediated by the colonic microbiota for biological activation. The metabolic processing of phenolic acids occurs in the colon and liver. Conjugated phenolic acids and macromolecular phenolic acids are initially metabolized in the colon and then reach the liver through the hepatic portal vein for further metabolism, where they undergo phase I metabolic reactions in the liver through structural modifications (hydroxylation, decarboxylation, and thiolation) followed by phase II binding reactions (glucuronidation, methylation, and sulfation). Structural modifications in phase I metabolism can activate or enhance the pharmacological activities of certain phenolic acids. Phase II binding reactions reduce the potential toxicity of phenolic acids and increase their hydrophilicity, promoting the excretion of water-soluble metabolites in bile or urine.⁴¹ Bulky conjugated metabolites are eliminated in bile, whereas smaller conjugated metabolites, such as monosulfate derivatives, are excreted in urine.⁴²

Fig. 1 Absorption and metabolism of phenolic acids. Drawn using Figdraw. https://www.figdraw.com.

Evidence indicates significant inter-compound variation in the absorption, metabolism, and excretion profiles of different phenolic acids. Following jejunal perfusion, ferulic acid demonstrates an absorption rate of approximately 56%.⁴³ Subsequent metabolism within colonic epithelial cells yields feruloyl glucuronide, sulfate conjugates, and dihydroferulic acid.⁴⁴ Post-absorption, the majority of ferulic acid undergoes urinary excretion as glucuronide conjugates, while the free acid fraction enters the liver via the portal circulation for further biotransformation.⁴⁵ Conjugated derivatives, specifically sulfoglucuronide forms, constitute up to 84% of the total urinary ferulic acid metabolites.⁴⁶ Notably, fecal excretion of ferulic acid remains negligible irrespective of the administered dose.⁴⁵ Protocatechuic acid is predominantly absorbed in the intestine⁴⁷ and undergoes metabolism in both the liver and colon;⁴⁸ its absorption across the gastric mucosa remains poorly characterized. Post-metabolism, protocatechuic acid and its metabolites—including the free acid, glucuronide, sulfate, and methylated conjugates—are excreted via both urinary and fecal routes in rodent and human models.^49–51 Caffeic acid undergoes rapid systemic absorption. Detection of free caffeic acid in gastric effluent within 5 minutes following intraportal administration, reaching levels equivalent to 89.7% of the administered dose, indicates efficient absorption via this route.⁵² Conversely, perfusion studies revealed substantially lower intestinal absorption rates: 12.4% in the duodenum and 19.5% in the jejunoileum, respectively.^53,54 Caffeic acid is subject to extensive hepatic metabolism.^55–57 Within 72 hours post-administration, urinary excretion accounts for up to 68% of ingested caffeic acid derivatives, markedly exceeding the 4.6% recovered in feces.⁵⁶ Human data indicate that only approximately 11% of the ingested dose is excreted renally as the unmetabolized parent compound.⁵⁸ This suggests that the remainder undergoes elimination as conjugated or oxidized metabolites, potentially over a prolonged elimination phase.

3. Protective effects of phenolic acids on intestinal barrier function

The four major functional units of the intestinal mucosal barrier are biological barrier, chemical barriers, epithelial barrier and immune barriers. Studies have shown that phenolic acids and their derivatives play a protective role in intestinal barrier function. Specifically, phenolic acids increase the expression of tight junction proteins, thereby reducing intestinal permeability, promoting the secretion of intestinal mucus and serving as a “physical barrier” to prevent the invasion of pathogens. In addition, the antioxidant properties of phenolic acids help prevent further deterioration of the damaged intestinal barrier; at the same time, phenolic acids regulate the intestinal microbiota and immune response, jointly maintaining the integrity of the intestinal barrier. Their multifaceted effects highlight the potential of phenolic acids as therapeutic agents to maintain intestinal health (Table 1).

Table 1 The role and mechanism of phenolic acids in protecting the intestinal barrier

Phenolic acid	Structural formula	Model	Dose	Effect	Ref.
Chlorogenic acid		ICR mice treated with 3% DSS for 7 days	250, 500 mg kg^−1	Increased expression of tight junction protein mRNA; reduced oxidative stress; inhibited release of inflammatory factors	10
		BALB/c mice treated with 3% DSS for 7 days	20, 40 mg kg^−1	Relieved colitis and inhibited IL-1β	59
		C57BL/6 mice treated with 3% DSS for 5 days	50 mg kg^−1	Reduced the polarization of M1 macrophages; reduced colon inflammation	60
		C57BL/6 mice treated with 3% DSS for 8 days	1000 μM	Significantly inhibited mRNA expression IL-1β	61
		C57BL/6 mice treated with 2.5% DSS for 7 days	1000 μM	Improved infiltration of T cells, neutrophils, and macrophages by inhibiting NF-κB signaling	62
		C57BL/6 mice treated with 5% DSS for 7 days	30, 60 and 120 mg/kg	Relieved oxidative stress; reduced the release of pro-inflammatory factors IL-1 and IL-6	63
		BALB/c mice treated with 40 mg mL^−1 TNBS for 7 days	20 mg kg^−1	Reduced neutrophil infiltration	64
		C57BL/6 mice treated with high-fat chow for 12 weeks	60 mg kg^−1	Increased expression of tight junction proteins; reduced abundance of harmful bacteria	65
		Mice treated with white wine for 21 days	60 mg kg^−1	Increased expression of tight junction proteins; regulated intestinal flora	66
		Restraint stress stimulation rats, 21 days	100 mg kg^−1	Increased tight junction protein expression; down-regulated TNF-α gene expression	67
		C57BL/6 mice treated with 10 mg kg^−1 SD	30 and 60 mg kg^−1	The expression of tight junction proteins ZO-1 and occludin is up-regulated	68
		BALB/c mice treated with IL-10 KO	1, 3 and 50 mg kg^−1	Increased ratio of CD4+/CD8+ T cell subsets, prevented inflammation	69
		LPS treatment of Caco-2 cells, 24 h	35.28, 70.56 and 141.12 μM	Increased expression of tight junction protein, down-regulated expression of pro-inflammatory factors	70
		50 ng mL^−1 LPS and 10 ng mL^−1 IFN-γ were co-incubated with Caco-2 cells for 24 h	100 μM	Inflammatory factors TNF-α, IL-8 and IL-6 are down-regulated	71
		2 mM H2O2 and 10 ng mL^−1 TNF-α coincubation of Caco-2 cells	500, 1000 and 2000 μM	Inhibited IL-8 secretion	72
Gallic acid		Mice treated with 2.5% DSS for 10 days	20, 100 and 500 mg kg^−1	Increased abundance of beneficial bacteria; increased secretion of anti-inflammatory factors; reduced secretion of pro-inflammatory factors	73
		Mice treated with 3.5% DSS for 10 days	40, 80 and 120 mg kg^−1	Inhibited inflammatory body stimulation activation; reduced the expression of inflammatory factors	74
		BALB/c mice treated with TNBS	20, 40 and 60 mg kg^−1	Inhibited the NF-κB pathway; inhibited expression of inflammatory factors IL-1, IL-4, IL-6, etc.	11
		SD rats fed a HFD for 112 days	100 mg kg^−1	Increased tight junction protein expression; restored intestinal microbial diversity	75
		Wistar rats treated with 40 mg kg^−1 DMH for 14 days	25 mg kg^−1	Reduced goblet cell damage; increased mucin secretion	76
		Albino Wistar rats treated with 20 mg kg^−1 DMH for 30 weeks	50 mg kg^−1	Maintained antioxidant factor activity	77
		50 ng mL^−1 LPS + 10 ng mL^−1 IFN-γ-treated Caco-2 cell and RAW 264.7 cell co-culture model	100 μM	Enhanced tight junction protein; reduced the expression of inflammatory factors	78
		10 μg mL^−1 LPS treatment of Caco-2 cells	5.88, 29.41 and 58.82 μM	Reduced oxidative stress; reduced inflammation	79
		25 ng mL^−1 IL-1b or 50 ng ml^−1 TNF-α or 10 mg mL^−1 LPS treatment of Caco-2 cells for 24 h	50 μM	Decreased NF-κB; reduced inflammation	80
		Calcium ion depletion treatment of T84 cells	200 µM	Promoted recombination of tight junction proteins ZO-1 and occludin	81
		BALB/c mice treated with 2.5% DSS for 7 days	10 mg kg^−1	Reduced oxidative stress; inhibited IL-21 and IL-23 expression	82
Caffeic acid		ICR mice treated with 3% DSS for 7 days	251 mg kg^−1	Suppressed inflammation; increased expression of antioxidant factors	12
		Piglets treated with 80 μg kg^−1 LPS for 7 days	500 mg kg^−1	Increased expression of tight junction protein mRNA; modulated intestinal microbial composition	83
		PA treatment of LS174T cells	500 µM	Increased the level of MUC2	84
Ferulic acid		Piglets treated with 10 mg kg^−1 LPS for 2 days	4000 mg kg^−1	Increased expression of tight junction protein mRNA; altered gut microbial composition; reduced expression of inflammatory factors	16
		Sprague Dawley rats treated with 100 mg kg^−1 TNBS for 1 day	10, 20 and 40 mg kg^−1	Decreased MDA and NO levels; increased antioxidant enzyme activity	13
		Mice treated with 15 mg/LNaAsO2 for 1 day	100 mg kg^−1	Reduced oxidative stress by activation of the Nrf2/HO-1 pathway; increased expression of tight junction proteins	85
		C57BL/6 mice fed high-fat chow for 8 weeks	50 mg kg^−1	Upregulated MUC2 mRNA expression	86
		Wistar rats treated with 7% acetic acid	20, 40 and 60 mg kg^−1	Decreased expression of inflammatory factors	87
		SD rats treated with 100 mg kg^−1 TNBS for 14 days	10, 20 and 250 mg kg^−1	Inhibited the TXNIP/NLRP3 pathway; reduced expression of inflammatory factors	88
		Heat stress treatment of IEC-6 cells for 6 hours	5, 10 and 20 μM	Intercellular gaps became smaller, increased expression of tight junction proteins	89
		PA treatment of LS174T cells	500 µM	Increased the level of MUC2	90
		50 ng mL^−1 TNFα + 50 ng mL^−1 IFNγ + 25 ng mL^−1 IL- 1β + 10 µg mL^−1 LPS mixed treatment of Caco-2 cells for 24 h	50 μM	Attenuated pro-inflammatory responses in polarized intestinal epithelial cells via IRE1a and PERK pathways; reduced NO levels	91
		10 ng mL^−1 TNF-α treated HIMECs	125, 250 and 500 µM	Reduced expression of inflammatory factors	92
Protocatechuic acid		Piglets treated with 10 μg kg^−1 LPS for 21 days	4000 mg kg^−1	Upregulated tight junction protein mRNA expression; restored gut microbial diversity	14
		Wistar rats treated with 5% DSS for 5 days	10 mg kg^−1	Reduced oxidative stress; inhibited plasma inflammatory factor expression; inhibited elevated colonic myeloperoxidase activity	93
		C57BL/6 mice treated with 3.5% DSS for 7 days	5, 10 and 20 mg kg^−1	Inhibited inflammatory factor expression; increased expression of tight junction proteins; restored the relative abundance of intestinal flora; reduced oxidative stress	94
		BALB/c mice treated with 20 mg mL^−1 TNBS for 1 day	30 and 60 mg kg^−1	Reduced oxidative stress; increased expression of antioxidant enzymes SOD, CAT; reduced expression of inflammatory factors	95
		ETEC K88 infected IPEC-1 cell	40 μM	Increased expression of tight junction proteins; downregulated inflammatory factor mRNA levels	96
Vanillic acid		Piglets treated with 10 mg kg^−1 LPS for 2 days	4000 mg kg^−1	Reduced inflammation; restored intestinal flora diversity; enhanced tight junction protein mRNA expression	97
		BALB/c mice treated with 5% DSS for 7 days	200 mg kg^−1	Decreased IL-6 levels; inhibited NF-κB activation	98
		PA treatment of LS174T cells	500 µM	Increased the level of MUC2	99
Sinapic acid		Kunming mice treated with 2% DSS for 7 days	10 and 50 mg kg^−1	Reduced oxidative stress; reduced expression of inflammatory factors; reduced inflammatory vesicle expression	15
		BALB/c mice treated with 30 mg kg^−1 TNBS for 1 day	10, 30 and 100 mg kg^−1	Decreased MPO activity and reduced MDA levels	100
		10 μmol mL^−1 LPS treatment of Caco-2 cells	5, 10 and 15 μM	Enhanced tight junction protein expression and redistribution of injured tight junction proteins	101
		20 μg mL^−1 LPS and 20 ng mL^−1 TNF-α mixed treatment of Caco-2 cells for 24 h	12.5, 25 and 50 μM	Inhibited inflammatory factor expression; inhibited tight junction protein delocalization	102
p-Coumaric acid		c57 mice treated with high-fat chow + STZ for 8 weeks	200 mg kg^−1	Promoted mucus secretion; enhanced tight junction protein expression	103
		PA treatment of LS174T cells	500 µM	Increased the level of MUC2	104
Rosmarinic acid		Mice treated with 4% DSS for 7 days	5, 10 and 20 mg kg^−1	Increased cuprocytes, increased mucus secretion; inhibited inflammatory factor expression	105
		Mice treated with 5% DSS for 7 days	100 mg kg^−1	Regulated the composition of intestinal flora; suppressed inflammation	106
Coumaric acid		Wistar rats treated with 7% acetic acid for 1 day	50, 100 and 150 mg kg^−1	Inhibited NF-κB expression; reduced inflammation	107
		Wistar rats treated with 7% acetic acid for 1 day	100 and 150 mg kg^−1	Reduced oxidative stress	108
Syringic acid		C57BL/6 mice treated with 2.5% DSS for 7 days	50 mg kg^−1	Up-regulated antioxidant indicator expression; increased abundance of intestinal flora	109
		Wistar rats treated with 7% acetic acid for 1 day	10, 25 and 50 mg kg^−1	Reduced oxidative stress	108
4-Hydroxybenzoic acid		C57BL/6 mice treated with 2.5% DSS for 7 days	100 mg kg^−1	Promoted mucus secretion	110
		PA treatment of LS174T cells	500 µM	Increased the level of MUC2	104
Chicory root phenolic acid		Mice treated with 2.5% DSS	100 and 200 mg kg^−1	Restored intestinal flora composition; reduced expression of inflammatory factors	111
Salvinorin		C57BL/6 mice treated with 2% DSS for 7 days	100 and 200 mg kg^−1	Suppressed inflammatory response	112

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3.1 Increased tight junction protein expression

3.1.1 Tight junction proteins and the intestinal barrier. Tight junction proteins are located in the top region of intestinal epithelial cells and strictly regulate the transport of molecules through epithelial cell pathways. They are key factors determining the permeability of the intestinal barrier. Freeze-rupture electron microscopy clearly revealed that tight junctions consist of a series of anastomosed chains.^113,114 Tight junction proteins can be roughly divided into transmembrane proteins and scaffold proteins. The transmembrane proteins include junction adhesion molecules (JAMs), vascular epicardial material (BVES), claudins, occludin and tricellulin. Studies have shown that mice with damaged or deficient transmembrane proteins have increased epithelial permeability in the intestine,^115–119 indicating that increased expression of tight junction proteins helps maintain gut barrier function.

3.1.2 Phenolic acids increase tight junction protein expression. Phenolic acids can enhance intestinal barrier function by regulating the expression of tight junction proteins. Hongkang Zhu et al. found that in individuals with alcohol-induced inflammatory bowel disease, chlorogenic acid reduced colonic mucosal damage by increasing the expression of the tight junction protein occludin.⁶⁶ In an arsenic-induced intestinal barrier damage model, ferulic acid reversed the downregulation of claudin-1, occludin and ZO-1 in the colon tissue of arsenic-exposed mice, thereby alleviating intestinal barrier dysfunction.⁸⁵ Shasha He et al. observed that ferulic acid reversed the heat stress-induced reductions in occludin, ZO-1 and E-cadherin levels in rats and restored the shape and localization of these proteins.⁸⁹ In LPS-induced intestinal injury in piglets, protocatechuic acid increased the expression of ZO-1 and claudin-1 in the ileal mucosa.¹⁴ Similarly, caffeic acid reversed the LPS-induced downregulation of ZO-1 and claudin-1 mRNA expression;⁸³ and both ferulic acid and vanillic acid increased the expression of ZO-1, occludin and claudin-1 in the small intestine of piglets, with ferulic acid being more effective.⁹⁷ In a mouse model of DSS-induced colitis, chlorogenic acid upregulated the expression of occludin and ZO-1 in the colon tissue,¹⁰ whereas caffeic acid significantly increased the expression levels of ZO-1 and occludin.¹²In vitro studies have also confirmed the positive effects of phenolic acids on tight junction protein expression. In the LPS-damaged Caco-2 cell model, caffeic acid, chlorogenic acid, 5-caffeoylquinic acid, gallic acid and ferulic acid reversed the downregulation and structural destruction of tight junction proteins such as claudin-1, ZO-1 and occludin.^78,104 Chlorogenic acid reversed the LPS-induced decreases in the expression of occludin and ZO-1. The optimal effect was observed at a concentration of 100 µg mL⁻¹.⁷⁰ Sinapic acid increased the mRNA and protein expression levels of ZO-1, claudin-1 and occludin, and promoted the reorganization of damaged tight junction proteins.¹⁰¹ In a high-fat diet (HFD)-induced intestinal barrier damage model, coumaric acid reduced HFD-induced intestinal barrier damage by increasing the expression of the ZO-1 and occludin proteins.¹⁰³ Furthermore, chlorogenic acid increased the expression of the tight junction proteins occludin and ZO-1.⁶⁵ Similarly, gallic acid upregulated the expression of occludin, claudin-3 and claudin-1 in jejunal tissue.¹²⁰ In addition, chlorogenic acid inhibits intestinal barrier dysfunction associated with cognitive impairment by increasing the expression of the ZO-1 and occludin proteins,⁶⁸ and CGA also reverses the significant chronic stress-induced downregulation of occludin, ZO-1 and claudin-3.⁶⁷ In ETECK88-infected IPEC-1 cells, protocatechuic acid increased the expression of the tight junction proteins occludin, claudin-1 and ZO-1.⁹⁶ In a model of intestinal barrier damage induced by Ca²⁺ depletion in T84 cells, gallic acid promoted the expression and reorganization of ZO-1 and occludin after destruction.¹²¹ Collectively, these findings demonstrate that phenolic acids exert intestinal barrier-protective effects in both in vivo animal models and in vitro cellular systems, mediated through enhanced tight junction protein expression.

3.1.3 Possible mechanisms involved. Activation of the ROCK/MLCK signaling pathway mediates actomyosin contraction through myosin light chain (MLC-2) phosphorylation, resulting in downregulation and mislocalization of tight junction (TJ) proteins, and consequently, increased intestinal barrier permeability.¹²² Inhibition of this pathway conversely restores TJ integrity. In vitro studies utilizing the Caco-2 intestinal epithelial model demonstrate that lipopolysaccharide (LPS) robustly induces the expression of p-MYPT1, p-MLC, MLCK, and ROCK1, concomitant with the downregulation of the key TJ proteins occludin, claudin-1, and ZO-1. Chlorogenic acid treatment effectively counteracts these LPS-induced alterations, significantly suppressing p-MYPT1, p-MLC, MLCK, and ROCK1 levels while elevating TJ protein expression. These data indicate that chlorogenic acid enhances TJ expression via targeted inhibition of the ROCK/MLCK pathway.⁸⁴ Similarly, sinapic acid potently enhances both transcript and protein abundance of ZO-1, claudin-1, and occludin and facilitates the redistribution and correct relocalization of compromised TJ proteins, primarily through suppression of the MLCK/MLC axis.¹⁰² Furthermore, CaMKK-induced AMPK activation promotes intestinal TJ assembly.¹²³ Gallic acid rescues calcium depletion-induced barrier dysfunction in T84 colonic epithelial cells by activating a CaMKKβ/AMPK/SIRT-1/ERK signaling cascade.⁸¹ Critically, activation of inflammatory or oxidative stress pathways (e.g., TLR4/NF-κB, p38 MAPK/NF-κB, NF-κB/NLRP3, Nrf2–Keap1, and Nrf-2/HO-1) similarly downregulates TJ proteins and compromises gut barrier integrity.¹²⁴ Substantial evidence confirms that phenolic acids mitigate TJ protein damage and enhance their expression through suppressing these pro-inflammatory cascades and activating cytoprotective antioxidant pathways.^{59,65,67,71,85} In summary, phenolic acids enhance TJ protein expression primarily through two distinct mechanisms: (1) direct targeting of the ROCK/MLCK signaling axis to modulate TJ protein synthesis, localization, and barrier competence and (2) through suppression of pro-inflammatory signaling or activation of antioxidant defense pathways, phenolic acids attenuate inflammatory or oxidative damage, thereby indirectly augmenting tight junction protein expression. The mechanism by which phenolic acids regulate tight junction protein expression is shown in Fig. 2.

Fig. 2 Mechanism of phenolic acid regulation of tight junction proteins. CaMkkβ, calcium/calmodulin-dependent protein kinase kinase beta; AMPK, adenosine monophosphate-activated protein kinase; SIRT-1, sirtuin 1; ERK, extracellular signal-regulated kinase; ZO-1, zonula occludens-1; MLCK, myosin light chain kinase; MLC, myosin light chain; ROCK, Rho-associated coiled-coil containing protein kinase; MYPT1, myosin phosphatase target subunit 1; ROS, reactive oxygen species.

3.2 Regulating intestinal mucus secretion

3.2.1 Mucus and the intestinal barrier. Mucus is the first line of defence of the intestinal barrier. It not only nourishes symbiotic bacteria to maintain the steady state of the intestinal flora but also limits contact between epithelial cells and the flora, thereby protecting the intestinal epithelium from invasion by pathogens. First, the intestinal mucus provides many binding sites that promote specific and nonspecific interactions between mucus and other molecules and bacteria.¹²⁵ Second, when the intestinal mucus renews outwards from the upper epidermal surface, the inner mucus can further expel bacteria outwards, forming a bacteria-restricted or sterile area on the epithelial surface.¹²⁶ Finally, mucin and the loose outer layer of mucus provide a nutrient source and a comfortable living environment for symbiotic bacteria. This nutritional support is highly important for maintaining the intestinal microecological balance and host health. The intestinal mucus consists of mucins and antibacterial peptides. In summary, regulating intestinal mucus secretion has a positive effect on intestinal barrier protection.

3.2.2 Phenolic acids increase the expression of mucins. Phenolic acids protect the intestinal barrier by regulating mucus synthesis and secretion. In Caco-2 cells, palmitic acid (PA) significantly reduced the expression of the secreted proteins MUC2 and MUC5AC and the secreted factor TFF3, whereas the addition of chlorogenic acid increased the expression of these three proteins in a dose-dependent manner. Similarly, in LS174T cells, treatment with protocatechuic acid (PCA), 5-caffeoylquinic acid (5-CQA) and caffeic acid (CA) increased MUC2 levels by 12.1%, 13.6% and 15.2%, respectively, compared with those in the model group.⁹⁹ In a DSS-induced colitis mouse model, para-hydroxybenzoic acid (HA) completely reversed the downregulation of mucin (MUC) mRNA expression, including MUC1, MUC2 and MUC3. In addition, HA significantly increased the expression of the MUC2 protein in colon tissue.¹¹⁰ Rosmarinic acid (RA) reversed the DSS-induced decrease in mucin secretion in mice,¹⁰⁵ and gallic acid protected goblet cells and mucins in the colons of Wistar rats.⁷⁶ Hye-Jeong Hwang et al. found that feeding animals ferulic acid upregulated the expression of the MUC2 mRNA throughout the small intestine, thereby increasing the protective mucus layer located outside the intestinal epithelium.⁸⁶ In addition, in a high-fat model, supplementation with p-coumaric acid can increase mucin secretion by increasing goblet cell proliferation and ameliorating mucus layer damage caused by a high-fat diet.¹⁰³ Under pathological conditions characterized by diminished mucus secretion, phenolic acids stimulate mucus secretion from goblet cells and upregulate the expression of key mucins, thereby enhancing mucosal barrier integrity.

3.2.3 Possible mechanisms involved. KLF4, a key transcription factor abundantly expressed in goblet cells (GCs) of the intestinal crypts and colonic epithelium, regulates GC terminal differentiation. It drives the expression of genes such as MUC2, facilitating the formation and homeostatic maintenance of the intestinal mucus barrier.¹²⁷ Studies demonstrate that activation of the BMP4/Smad pathway induces transcriptional activation of KLF4 through Cdx2 regulation, thereby stimulating MUC2 secretion.¹²⁸ Furthermore, Wnt3a enhances GC differentiation and mucus secretion, whereas increased BMP2 expression upregulates Wnt3a expression.¹²⁹ In mouse models fed a high-fat diet, supplementation with p-coumaric acid significantly upregulated the gene and protein expression levels of BMP2, Wnt3a, BMP4, Klf4, Cdx2, Smad1, Smad5, and Smad8. These findings indicate that p-coumaric acid activates both the BMP4/Smad and BMP2/Wnt3a signaling pathways, thereby promoting GC proliferation, augmenting mucin secretion, and consequently restoring mucus layer homeostasis.¹⁰³ Although oxidative stress and inflammatory cytokines can stimulate mucus secretion, excessive reactive oxygen species (ROS) in inflammatory settings induce mucin hypersecretion; this results in excessive cross-linking of mucin polymers, leading to the formation of a dense gel, compromising its normal clearance capacity.¹³⁰ Therefore, suppression of intestinal oxidative stress represents a crucial strategy for preserving the mucus barrier. Rosmarinic acid facilitates mucus layer repair under inflammatory conditions via activation of the Nrf2/HO-1 signaling pathway and inhibition of inflammatory cytokine expression.⁷⁵ Within the endoplasmic reticulum (ER), mucins are synthesized and undergo initial post-translational modifications, primarily N-glycosylation and O-glycosylation. These glycosylation events are essential for establishing the structural integrity, functional properties, and interactions with microorganisms characteristic of mucins.¹³¹ Therefore, endoplasmic reticulum (ER) stress leads to decreased mucus secretion. Experimental studies demonstrate that protocatechuic acid, chlorogenic acid, 5-caffeoylquinic acid, and caffeic acid enhance the expression of mucins Muc2 and MUC5AC by attenuating intracellular ERS.⁸⁴ Similarly, ferulic acid has been demonstrated to increase mucus secretion through the mitigation of ERS in intestinal epithelial cells.⁸⁶Akkermansia muciniphila (A. muciniphila) is a predominant mucin-degrading commensal bacterium in the human gut. Through degradation of the outer, loose mucus layer, it stimulates GCs to synthesize new mucus, thereby preventing dysbiosis associated with excessive mucus accumulation.¹³¹ Studies demonstrate that intervention with p-hydroxybenzoic acid enhances intestinal chemical barrier function by increasing A. muciniphila abundance, which subsequently promotes GC mucus secretion.¹¹⁰ In summary, phenolic acids preserve intestinal mucus barrier homeostasis primarily through the following mechanisms: direct promotion of GC functions: activation of specific signaling pathways (e.g., BMP4/Smad and BMP2/Wnt3a) directly stimulates GC proliferation, differentiation, and mucin secretion (e.g., MUC2), and indirect modulation of the secretory microenvironment: amelioration of the mucus secretory microenvironment via suppression of oxidative stress (e.g., through Nrf2/HO-1 activation) and inflammation, alongside augmentation of beneficial microbial abundance (e.g., A. muciniphila). The mechanism by which phenolic acids regulate mucus is shown in Fig. 3.

Fig. 3 Mechanisms by which phenolic acids regulate mucus secretion. BMP2, bone morphogenetic protein 2; Smad, small mothers against decapentaplegic; Wnt3a, wingless-type MMTV integration site family, member 3A; β-catenin, beta-catenin; BMP4, bone morphogenetic protein 4; Cdx2, caudal-type homeobox 2; klf4, Krüppel-like factor 4; ER, endoplasmic reticulum; Mucs, mucins.

3.3 Antioxidant effects

3.3.1 Oxidative stress and the intestinal barrier. Oxidative stress is the result of an imbalance between free radical production and the clearance ability of the antioxidant defence system.¹³² Studies have shown that oxidative stress mainly damages intestinal barrier function by promoting the apoptosis of epithelial cells, destroying the integrity of tight junctions, inhibiting mucus secretion by epithelial cells, and inducing the dysregulation of the intestinal flora. First, chronic endoplasmic reticulum oxidative stress initiates apoptosis pathways, induces apoptosis in epithelial cells, and damages the integrity of the intestinal barrier.¹³³ Second, oxidative stress damages the TJ complexes between cells through the MAPK, MLCK, and ERK signalling pathways.^134–137 In addition, oxidative stress inhibits mucus secretion from goblet cells,¹³⁸ causing the thinning of the intestinal mucus layer. Finally, oxidative stress induces an imbalance in the intestinal flora, which also affects microbial metabolic functions and reduces the production of the beneficial metabolites SCFAs. In addition to directly damaging components of the intestinal barrier, oxidative stress also damages the barrier by inducing inflammation through immune activation. Studies have shown that oxidative stress induces immune cell infiltration and activates macrophages and T cells, leading to the release of proinflammatory cytokines such as TNF-α and IL-6. The initiation of intestinal inflammation and oxidative stress form a vicious cycle, which ultimately culminates in the progressive deterioration of intestinal barrier function.¹³⁹ In contrast, multiple studies have shown that consuming foods or supplements with antioxidant properties can repair intestinal barrier damage.^140–142 In summary, oxidative stress causes or accelerates intestinal barrier damage, whereas antioxidants have a protective effect on the intestinal barrier.

3.3.2 Antioxidant effects of phenolic acids. The antioxidant effects of phenolic acids are attributed mainly to the phenolic hydroxyl group in their structure. Shumin Wang et al. found that in the colon tissue of arsenic-exposed mice, malondialdehyde (MDA) levels are significantly increased, whereas the activities of catalase (CAT), glutathione (GSH) and superoxide dismutase (SOD) are significantly decreased. However, these changes are reversed by the administration of ferulic acid (FA), indicating that FA is able to counter arsenic-induced oxidative stress in the colon.⁸⁵ In piglet studies, protocatechuic acid increased the antioxidant capacity by decreasing the activities of thiobarbituric acid reactive substances (TBARS), total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px).¹⁴ Caffeic acid restored the levels of CAT, SOD, and GSH-Px in the serum and HO-1 in the colons of piglets with LPS-induced colitis and increased NQO1 mRNA expression in the colon.⁸³ Supplementation with ferulic acid or vanillic acid increased the total antioxidant capacity (T-AOC) and T-SOD levels in piglets exposed to LPS while reducing TBARS levels.⁹⁷ In a DSS-induced mouse model, chlorogenic acid reversed the significant decreases in T-AOC levels and GSH-Px, SOD, and CAT enzyme activities in the serum and colon tissues of DSS-treated mice and inhibited the increases in MDA and ROS levels in the serum.¹⁰ Caffeic acid increased T-AOC levels and GSH-Px, SOD, and CAT enzyme activities in the serum of DSS-treated mice, decreased MDA levels, and significantly reduced ROS production. It also upregulated the mRNA expression of Nrf2, HO-1 and NQO1.¹² Ferulic acid increased SOD and GSH activities in the serum and colon tissues of TNBS rats and decreased MDA and NO levels.¹³ Gallic acid has been found to reduce lipid peroxidation and maintain the activities of SOD, CAT, glutathione (GSH), glutathione reductase and GPX in Wistar rats.⁷⁷ In in vitro studies in Caco-2 cells, protocatechuic acid, chlorogenic acid, 5-caffeoylquinic acid, caffeic acid, ferulic acid, p-coumaric acid, and vanillic acid significantly reduced the LPS-induced release of reactive oxygen species (ROS),^79,84 whereas chlorogenic acid restored the significant decreases in SOD, CAT and GSH-Px activities and the increase in MDA levels caused by LPS.⁷⁰ Ferulic acid reduced the increase in NO levels in Caco-2 cells following CT stimulation.⁹¹ In summary, phenolic acids exhibit antioxidant effects in intestinal barrier-related models both in vivo and in vitro. These findings suggest that the protective effects of phenolic acids on the intestinal barrier are associated with their antioxidant properties.

3.3.3 Possible mechanisms involved. Keap1 and Nrf-2 are master regulators of the cellular antioxidant defense system. Under basal conditions, Keap1 sequesters Nrf-2 in the cytoplasm, promoting its constitutive ubiquitination and proteasomal degradation. Upon oxidative stress, however, covalent modifications at critical cysteine residues (Cys273/Cys288) within Keap1 disrupt its E3 ligase adaptor function. This inactivation stabilizes Nrf-2, facilitating its nuclear translocation and subsequent heterodimerization with small Maf proteins. The resulting complex activates the transcription of antioxidant response element (ARE)-driven genes, including HO-1, NQO1, and GST.¹⁴³ The encoded antioxidant enzymes scavenge reactive oxygen species (ROS), thereby mitigating oxidative stress-induced damage. In a murine model of DSS-induced ulcerative colitis, dietary supplementation with chlorogenic acid significantly elevated the mRNA expression of the Nrf2, HO-1and NQO1 target genes, concomitantly enhancing Nrf2 and HO-1 protein expression in colonic tissues. Furthermore, chlorogenic acid treatment markedly increased the levels of T-AOC, GSH-Px, SOD and CAT, while significantly reducing MDA and ROS levels. Collectively, these findings demonstrate that chlorogenic acid mediates its antioxidant effects predominantly through the activation of the Nrf2 signaling pathway and its downstream target HO-1.¹⁰ Similarly, in the colonic tissues of DSS-treated rats, caffeic acid administration significantly upregulated the mRNA expression of Nrf2, HO-1, CAT, GPX1, NQO1, and SOD1, indicating that its antioxidant activity is facilitated by the upregulation of the Nrf2/HO-1 pathway.¹² Gallic acid exerts antioxidant effects via activation of the Keap1–Nrf2 pathway.⁷¹ Moreover, rosmarinic acid exerts an antioxidant effect through the Nrf-2/HO-1 pathway, alleviating symptoms of DSS-induced ulcerative colitis in mice.⁷⁵ In summary, phenolic acids confer protection to the intestinal barrier through antioxidant mechanisms centered on the activation of the Keap1–Nrf2 axis and subsequent induction of HO-1, culminating in the modulation of associated antioxidant gene expression. The antioxidant mechanism of phenolic acids is shown in Fig. 5.

3.4 Regulating the balance of the intestinal flora

3.4.1 The intestinal flora and the intestinal barrier. The intestinal microbiota is the largest symbiotic ecosystem in the host and is composed mainly of Firmicutes (accounting for approximately 65%) and Bacteroides (accounting for approximately 25%), as well as small proportions of Actinomycetes, Proteobacteria, Clostridium, and Verrucomicroflora. Studies have shown that the gut microbiota affects the permeability of the gut barrier by regulating the release of inflammatory cytokines and the expression of tight junction proteins.¹⁴⁴ In addition, intestinal bacteria and their metabolites may be involved in the regulation of the intestinal mucus barrier by influencing posttranslational modifications such as MUC2 synthesis and secretion or regulating its glycosylation.^145–147 Finally, the intestinal microbiota can guide the functional maturation of host innate and adaptive immunity through the bacteria themselves or bacterial metabolites.^148–153 In summary, maintaining the balance of the intestinal flora helps protect the intestinal barrier.

3.4.2 Phenolic acids regulate the intestinal flora and protect the intestinal barrier. Many studies have shown that phenolic acids can affect the intestinal barrier by regulating the composition and abundance of the intestinal flora. Chicory root phenolic acids can increase microbial diversity in mice,¹¹¹ and chlorogenic acid can reverse the decrease in microbial abundance and diversity caused by a long-term HFD, restoring microbial abundance and diversity to levels similar to those in the NC group.¹⁵⁴ Oral administration of chlorogenic acid significantly increased the relative abundance of Bifidobacterium while reducing that of Escherichia coli, although it had no significant effects on Lactobacillus or Enterococcus.⁶⁵ The ratio of Firmicutes to Bacteroides in piglets fed a diet supplemented with protocatechuic acid was significantly increased, and the relative abundances of Prevotella9, Prevotella2, Ruminococcus torques and Holdemanella were significantly decreased.¹⁴ Caffeic acid tends to increase the abundances of Alloprevotella, Eubacterium coprostanoligenes and Prevotellaceae_UCG-001 and decrease the relative abundance of Prevotella.⁸³ At the phylum level, both ferulic acid and vanillic acid increase the ratio of Firmicutes/Bacteroidetes, where the effect of vanillic acid was more significant, and both ferulic acid and vanillic acid reduced the relative abundance of Prevotellaceae and increased the relative abundance of Lachnospiraceae. At the genus level, vanillic acid significantly decreased the relative abundances of Prevotella9, Prevotella7, Prevotella2 and Prevotella1 in the genus Prevotella.⁹⁷ Caffeic acid can increase the relative abundances of Alistipes, Dubosiella, and Akkermansia.¹² Compared with the HFD, chlorogenic acid decreased the relative abundances of Blautia and Sutterella,¹⁵⁴ whereas gallic acid increased the relative abundances of the beneficial bacteria Romboutsia, Turicibacter, Allobaculum, Bifidobacterium, Coriobacteriaceae_UCG-002 and Parasutterella, alleviating the intestinal barrier damage caused by the HFD.¹²⁰ Chlorogenic acid may improve the intestinal barrier dysfunction caused by sleep deprivation by promoting the colonization of symbiotic bacteria and inhibiting the colonization of pathogenic bacteria.⁶⁸ Rosmarinic acid improves intestinal barrier damage caused by DSS by reducing the abundances of Bifidobacterium and Faecalibacterium and increasing the abundance of Lactobacillus.¹⁰⁶ Compared with the DSS group, caffeic acid increased the relative abundances of Dubosiella, Ruminococcus, and Alistipes,¹² and gallic acid increased the relative abundances of Bacteroides and Firmicutes and restored the abundance of 27 genera to control levels.⁷³ Collectively, these findings demonstrate that phenolic acids reinforce intestinal barrier function through enrichment of the Bacteroidetes and Firmicutes phyla.

3.4.3 Possible mechanisms involved. Exogenous pathogen invasion displaces commensal microbiota from ecological niches, depleting gut microbial diversity and abundance.¹⁵⁵ Rosmarinic acid effectively mitigates Salmonella-induced dysbiosis in mice, restoring microbial diversity and abundance following infection.¹⁵⁶ Ferulic acid and p-coumaric acid significantly inhibit biofilm formation by Salmonella enterica via reducing biomass, extracellular polymeric substances, and bacterial motility (swimming and chemotaxis). Concomitant downregulation of biofilm-associated genes indicates impaired aggregation and adhesion capabilities.¹⁵⁷ Chlorogenic acid ameliorates sleep deprivation-induced barrier dysfunction, potentially via competitive exclusion of pathogens while enhancing commensal bacteria colonization.⁶⁸ Short-chain fatty acids (SCFAs), key metabolites derived from microbial fermentation of dietary fiber, play pivotal roles in intestinal homeostasis and host metabolism. Bacteroidetes degrade fiber to generate SCFA precursors, while Firmicutes produce butyrate—critical for barrier function. Notably, microbiota-derived SCFAs establish a beneficial feedback loop with commensals through luminal pH modulation, immune regulation, and metabolic cross-feeding.¹⁵⁸ Chlorogenic acid intervention significantly elevated fecal acetate, propionate, and butyrate concentrations versus ethanol-treated controls, indicating enhanced microbial biotransformation capacity.⁶⁶ Pro-inflammatory microenvironments compromise Bifidobacterium viability and metabolism,¹⁵⁹ In a high-fat diet-induced NAFLD model, chlorogenic acid reversed gut barrier damage, suppressed TLR4/NF-κB signaling, and restored inflammation-depleted Bifidobacterium and Lactobacillus populations, indicating microbiota modulation via inflammation resolution.⁶⁵ Microbial biotransformation of phenolic acids yields bioactive derivatives that reshape ecological dynamics: coffee consumption-associated Bifidobacterium enrichment is likely mediated by chlorogenic acid metabolites (dihydroferulic/dihydrocaffeic acids).¹⁶⁰ Dihydroferulic acid attenuated LPS-induced chemokine (MCP-1) and pro-inflammatory cytokine (TNF-α, IL-6) secretion in macrophages, suggesting immunoregulatory roles in microbiota homeostasis.¹⁶¹ 3-Hydroxyphenyl (ferulic acid metabolite) positively correlates with Holdemanella and inversely with Fusobacterium abundance, indicating microbiota-modulating capacity.¹⁶² Collectively, phenolic acids stabilize gut microbiota equilibrium through: (1) pathogen exclusion, preventing exogenous pathogen colonization and biofilm formation; (2) SCFA enhancement, promoting fiber fermentation and establishing metabolic feedback loops; (3) anti-inflammatory activity, mitigating inflammation-driven dysbiosis; and (4) bioactive metabolites, exerting direct/indirect modulation via microbially transformed products. The mechanism by which phenolic acids stabilize gut microbiota balance is shown in Fig. 4.

Fig. 4 Mechanisms by which phenolic acids modulate intestinal microorganisms. SCFA, short-chain fatty acids; TLR4, toll-like receptor 4; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.

3.5 Effects on intestinal immune function

3.5.1 Gut immunity and the intestinal barrier. Intestinal immune function has two effects on the intestinal barrier. On the one hand, a normal immune response helps eliminate bacteria and pathogens, thereby protecting intestinal epithelial cells and maintaining the steady state of the intestinal flora. On the other hand, an excessive immune response can trigger inflammation, which in turn destroys the intestinal barrier. The intestinal immune response involves the synergy of mucus, the intestinal epithelium and the lamina propria. Under healthy conditions, goblet cells and Paneth cells secrete large amounts of mucus. When pathogens invade, antibacterial peptides in the mucus, such as α-defensins and β-defensins, can directly kill or inhibit the growth of pathogens,¹⁶³ However, a long-term persistent immune response can trigger inflammation and have a negative impact on the composition and function of the intestinal barrier. First, long-term immune activation induces the apoptosis of epithelial cells and inhibits intestinal epithelial cell proliferation.^164,165 Apoptotic intestinal epithelial cells shed from the surface of the intestinal mucosa, forming epithelial cell gaps and destroying the integrity of the intestinal mucosa. In addition, the apoptosis of epithelial cells affects the normal secretion and renewal of the mucus layer and impairs its integrity. Second, inflammatory factors (such as TNF-α and IL-1β) can activate the NF-κB signalling pathway, resulting in decreased expression of tight junction proteins (such as claudin and occludin).¹⁶⁶ Third, a long-term immune response may lead to an imbalance in the expression of antibacterial peptides and other immune-related components in the mucus layer, reducing the antibacterial activity of the mucus layer. In addition, inflammatory factors (such as IL-1β and TNF-α) can alter the composition and function of the intestinal microbiota. Finally, long-term inflammatory reactions can lead to the dysregulation of immune tolerance, causing the immune system to overreact to the normal flora, further disrupting intestinal stability. In summary, regulating the immune response to suppress inflammation is an effective measure to protect the intestinal barrier.

3.5.2 Phenolic acids regulate intestinal immunity. Phenolic acids regulate key signalling pathways and cytokine expression, thereby protecting the intestinal mucosal barrier. Protocatechuic acid alleviated LPS-induced inflammatory symptoms in piglets and significantly reduced the levels of IL-2, IL-6, and TNF-α.¹⁴ Both ferulic acid and vanillic acid significantly reduced the LPS-induced increases in the serum levels of IL-1β, IL-2, IL-6 and TNF-α in piglets.⁹⁷ In a DSS-induced colitis mouse model, chicory total phenolic acids significantly reduced serum myeloperoxidase (MPO) and nitric oxide (NO) levels and reduced the levels of the cytokines TNF-α, IL-1β, IL-6 and IL-18.¹¹¹ Rosmarinic acid, chlorogenic acid, and gallic acid significantly reduced the levels of IL-1β, IL-6, IL-33, IL-18 and TNF-α in serum and colon tissue while increasing the expression of the anti-inflammatory cytokine IL-10,^{10,73,74,105,106,167} whereas chlorogenic acid reversed the increase in LPS levels in the serum of colitis mice in a dose-dependent manner. Caffeic acid supplementation reduces the levels of the proinflammatory cytokines IL-6, TNF-α, IL-1β and IL-12 while increasing the levels of IL-10.¹² During acetic acid-induced colitis, coumaric acid regulates the expression of colonic inflammation markers, including NF-κB, TNF-α, iNOS, IL-1β, and IL-6.^107,108 Ferulic acid significantly inhibits the expression of the mRNAs encoding the inflammatory cytokines IL-1β, IL-6, and TNF-α in the colon tissue of rats with acetic acid-induced colitis.¹⁶⁸ In TNBS-treated adult rats, ferulic acid dose-dependently reduced the mRNA expression of the proinflammatory factors TNF-α, IL-1β and IL-6 and upregulated the mRNA expression of the anti-inflammatory factor IL-10.¹³ In addition, at a dose of 1 mg kg⁻¹, chlorogenic acid significantly increased the proportion of CD4+/CD8+ T-cell subsets in Peyer's patches and mesenteric lymph nodes while decreasing the expression levels of iNOS, TNF-α and IL-1β.⁶⁹ In an in vitro model, ferulic acid attenuated the induction of IL-8 in Caco-2 cells treated with both IL-1β and TNF-α and attenuated the proinflammatory response of polarized intestinal epithelial cells through the IRE1a and PERK pathways.⁹¹ Gallic acid inhibits the expression of NF-κB in intestinal epithelial cells stimulated with IL-1β or TNF-α.¹⁶⁹ Chlorogenic acid and gallic acid reduce LPS-induced increases in the levels of the inflammatory factors IL-2, IL-6 and TNF-α in Caco-2 cells,^70,71,79 and protocatechuic acid reduces TNF-α, IL-8 and IL-6 mRNA levels in ETECK88-infected IPEC-1 cells.⁹⁶ In summary, phenolic acids exert intestinal barrier-protective effects in disease models through suppression of inflammatory responses, attenuation of pro-inflammatory cytokine release, and modulation of immune cell subsets.

3.5.3 Possible mechanisms involved. The p38 MAPK/NF-κB, TLR4/NF-κB, and TLR4/PI3K/Akt/mTOR pathways represent core inflammatory signaling axes. Their inhibition significantly diminishes pro-inflammatory cytokine expression (TNF-α, IL-1β, IL-6) and alleviates tissue inflammation.¹⁷⁰ Experimental evidence confirms that chlorogenic acid mitigates chronic stress-induced intestinal barrier damage in rats by suppressing p38 MAPK/NF-κB signaling.⁶⁷ In LPS-challenged piglet models, caffeic acid decreases serum IL-1β, IL-6, and TNF-α while elevating anti-inflammatory IL-10, potentially through TLR4/NF-κB inhibition.⁸³ Total phenolic acid extract from the stems and leaves of Salvia miltiorrhiza preserves intestinal mucosal integrity through blockade of TLR4/PI3K/Akt/mTOR activation and suppression of TNF-α, IL-6, and IL-1β overexpression.¹¹² Sinapic acid downregulates TLR4, MyD88, p-NF-κB p65, p-IKKα, and p-IκB expression in LPS-treated Caco-2 cells, concomitantly reducing IL-1β and IL-18 transcription, validating TLR4/NF-κB-mediated anti-inflammatory activity.¹⁰¹ The NLRP3 inflammasome—a multiprotein complex comprising NLRP3, ASC, and caspase-1—facilitates IL-1β and IL-18 maturation via caspase-1 activation.¹⁷¹ Studies reveal that chlorogenic acid significantly attenuates NLRP3, ASC, p-NF-κB, caspase-1 p45/p20, IL-1β, and IL-18 expression in DSS-induced murine colitis, indicating NF-κB/NLRP3 pathway suppression.⁵⁹ Oral rosmarinic acid downregulates colonic NLRP3, ASC, and caspase-1 expression, implying inflammasome inhibition.⁷⁵ Keap1–Nrf2 pathway activation indirectly modulates inflammation.¹⁷² Gallic acid upregulates Keap1–Nrf2 signaling and downregulates NF-κB, NO, IL-6, and TNF-α in Caco-2 cells, demonstrating Nrf2-mediated NF-κB transcriptional inhibition.⁷¹ Furthermore, chlorogenic acid inhibits M1 macrophage polarization by suppressing PKM2-dependent glycolysis and NLRP3 activation, thereby ameliorating colitis.¹⁷³ Collectively, phenolic acids mediate anti-inflammatory activity through three primary mechanisms: direct pathway inhibition: targeting p38 MAPK/NF-κB, TLR4/NF-κB, and TLR4/PI3K/Akt/mTOR cascades to reduce pro-inflammatory cytokine release; inflammasome suppression: impeding NLRP3/ASC/caspase-1 complex assembly to limit IL-1β/IL-18 maturation; and indirect transcriptional regulation: attenuating NF-κB activity via Keap1–Nrf2 activation while modulating macrophage polarization. The mechanism by which phenolic acids regulate immunity is shown in Fig. 5.

Fig. 5 Effect of phenolic acids on oxidative stress and immune response. Drawn using Figdraw. PI3K, phosphatidylinositol-3-kinase; AKT, AKR mouse strain thymoma oncogene; mTOR, mechanistic target of rapamycin; TLR4, toll-like receptor 4; MyD88, myeloid differentiation primary response 88; IRAK1, interleukin-1 receptor-associated kinase 1; IKKα, inhibitor of nuclear factor κB kinase α; IKBα, inhibitor of κB alpha; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLPR3, NOD-like receptor family pyrin domain containing 3; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin-6; IL-1β, interleukin-1 beta; P38 MAPK, P38 mitogen-activated protein kinase; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response element; HO-1, heme oxygenase-1; NOQ1, NAD(P)H:quinone oxidoreductase 1.

4. Application prospects of phenolic acids in treating intestinal diseases

Emerging evidence highlights the importance of intestinal permeability as a key indicator in the pathogenesis of multiple diseases, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), gastrointestinal infections, and metabolic disorders such as obesity, diabetes and nonalcoholic fatty liver disease. The protective effects of phenolic acids on the intestinal barrier highlight their potential therapeutic applications in gastrointestinal diseases.

4.1 Inflammatory bowel disease

Inflammatory bowel disease (IBD) is a complex, multifactorial, chronic, recurring immune-mediated inflammatory disease of the gastrointestinal tract. The two most common forms are Crohn's disease (CD) and ulcerative colitis (UC). CD can affect the entire gastrointestinal tract and manifests as discontinuous transmural inflammation that occurs below the mucosa layer; UC is limited to mucosal inflammation, usually starting from the rectum and extending continuously to the proximal colon. Current treatment strategies for IBD include biologics, immunomodulators, aminosalicylates, and corticosteroids. However, due to the heterogeneity of the disease, the treatment effects vary.¹⁷⁴ In addition, existing therapeutic drugs are often accompanied by multiple side effects, such as hyperglycaemia, hypertension, liver necrosis and pancreatitis, limiting their long-term use in patients with IBD. The pathogenesis of IBD is thought to involve multiple mechanisms, including inflammation, oxidative stress, intestinal barrier dysfunction, and intestinal flora dysfunction,^175–178 among which impaired intestinal barrier function is an important feature of the disease. As natural plant metabolites, phenolic acids have almost no toxic side effects and have been shown to have a protective effect on the intestinal barrier, highlighting their potential in the treatment of IBD. Therefore, phenolic acids can be used as adjuvant or alternative therapeutic agents to develop safer treatments for IBD. DSS-induced colitis is a classic model of UC in animal experiments. Various phenolic acids and pharmaceutical foods rich in phenolic acids have been shown to have therapeutic effects on DSS-induced colitis in animals. Chlorogenic acid improves the pathological state of colitis in mice by reducing intestinal inflammation, activating the Nrf-2/HO-1 signalling pathway to reduce oxidative stress, and improving intestinal barrier function, as demonstrated by improvements in weight loss, shortening of the colon length and intestinal barrier damage caused by DSS.¹⁰ Caffeic acid regulates intestinal flora disorders related to colitis and restores the intestinal barrier to further reduce inflammatory cell infiltration in the colon and alleviate the course of colitis.¹² Studies have shown that the consumption of natural products rich in phenolic acids, such as fruits, vegetables, tea, and traditional Chinese medicines, can effectively prevent and relieve typical symptoms of UC. Zheng Li et al. showed that purslane, which is rich in phenolic acids, repairs intestinal barrier damage by inhibiting the NF-κB signalling pathway, increasing the expression of the tight junction proteins claudin-1, occludin, and ZO-1, and increasing the diversity of the intestinal flora, alleviating DSS-induced ulcerative colitis.¹⁷ In patients with intestinal inflammation, eating fruits rich in phenolic acids can protect the intestinal barrier and reduce intestinal inflammation by regulating apoptosis and inflammatory factors.¹⁸ Given the limited clinical research data on phenolic acid monomers for treating inflammatory bowel disease (IBD), we attempted to extrapolate preclinical findings to humans to offer preliminary insights. However, it is important to note that phenolic acids undergo extensive microbial metabolism in the gut following oral administration. Substantial differences exist between the intestinal microbiota of animal models and humans, complicating the extrapolation of preclinical data. Elucidating species-specific microbial differences or addressing the impact of gut microbiota on drug metabolism may help mitigate these challenges.

4.2 Irritable bowel syndrome

Irritable bowel syndrome is a very common functional digestive disease characterized by repeated abdominal pain, abdominal distension, cramps, flatulence, and altered bowel habits according to the Rome IV diagnostic criteria.¹⁷⁹ The aetiology and mechanism of IBS are not fully understood but are believed to be caused by interactions among multiple factors, including visceral hypersensitivity, abnormal gastrointestinal motility, nervous system dysfunction, gastrointestinal infections, intestinal flora disorders, and psychological disorders. At present, a radical cure is not available for IBS. The purpose of treatment is to relieve symptoms and improve quality of life. Treatments include reducing food intolerance through diet modifications; medical intervention with anticonvulsants, antidiarrhoeal drugs, laxatives and antidepressants; and maintaining a healthy lifestyle. Studies have shown that some patients with IBS, especially those with the diarrhoea type (IBS-D) and postinfectious type (PI-IBS) subtypes, have impaired intestinal mucosal barrier function.¹⁸⁰ A recent animal and human study has shown that inhibiting or restoring barrier dysfunction can correct visceral hypersensitivity reactions¹⁸¹ and pain, respectively, in individuals with irritable bowel syndrome.¹⁸² Most studies have shown that a loss of barrier function is positively correlated with symptom severity (such as abdominal pain and changes in bowel habits), suggesting that impaired intestinal mucosal barrier function may exacerbate the severity of IBS symptoms.^183,184 When treating IBS, in addition to symptomatic drug treatment, treatment strategies for intestinal barrier dysfunction are sometimes considered. For example, probiotics and prebiotics are used to improve the composition of the intestinal microbiota, and certain drugs are used to enhance intestinal mucosal barrier function. In general, impaired intestinal mucosal barrier function appears to be part of the pathophysiological mechanism of IBS, and targeting this process may represent a new strategy to ameliorate IBS symptoms.

Phenolic acids can improve symptoms related to irritable bowel syndrome. Studies have shown that irritable bowel syndrome is strongly associated with visceral pain and depression.¹⁸⁵ The occurrence of visceral pain and depression complicated by IBS is related to increased expression of the P2X7 receptor. In a rat model of concurrent visceral pain and depression created by Lequan Wen et al., gallic acid reversed the increases in IL-1β and TNF-α levels and the decreases in IL-10 and BDNF levels caused by the increased expression of the P2X7 receptor in a comorbid model, alleviating the pain threshold and degree of depression in model rats.¹⁸⁶ In patients with diarrhoea (IBS-D), the 5-HT3 receptor mediates the release of 5-HT from enterochromaffin (EC) cells, increasing the number of productive colonic contractions.¹⁸⁷ 5-HT3 receptor antagonists have been shown to be effective at inhibiting IBS-D emergencies, prolonging small and large intestine transit, and alleviating symptoms.¹⁸⁸ Talley et al.¹⁸⁹ and Steadman et al.¹⁹⁰ showed that in patients with irritable bowel syndrome dominated by diarrhoea, the 5-HT3 antagonist ondansetron improved the faecal consistency by reducing rectal movement and sensitivity to balloon inflation in patients with irritable bowel syndrome. Chlorogenic acid is believed to be an antagonist of 5-HT3 and D2 receptors. In a 5-HT-induced IBS-D mouse model, a chlorogenic acid-rich methanol extract of lotus flowers was shown to ameliorate IBS-D by functioning as a 5-HT3 receptor antagonist.¹⁹¹ Depression is a common complication of IBS. The intake of phenolic acids can prevent the development of depressive symptoms, which is related mainly to the anti-inflammatory and antioxidant activities of phenolic acids. Ferulic acid¹⁹² and chlorogenic acid¹⁹³ reduce the protein and mRNA expression of proinflammatory cytokines (IL-6, IL-1, and TNF-α) in depressed rats. In addition, ferulic acid increases the expression of the glucocorticoid receptor (GR) by reducing the serum levels of adrenocorticotropin (ACTH) and corticosterone and regulating the function of the hypothalamic–pituitary–adrenal (HPA) axis.¹⁹² In addition, phenolic acids can relieve symptoms of IBS disease by improving the intestinal barrier. CGA alleviates symptoms in mice with postinfectious irritable bowel syndrome (PI-IBS) by reducing inflammation and regulating the intestinal flora to maintain mucosal barrier function.¹⁹⁴ In summary, phenolic acids can improve the symptoms of IBS complications and achieve the current treatment goals for IBS.

4.3 Intestinal infection

Intestinal infections are infectious diseases caused by a variety of bacteria, viruses, parasites or fungi and mainly present as digestive tract symptoms. Common intestinal infections include cholera, bacterial diarrhoea, viral hepatitis A, typhoid fever, infectious diarrhoea, and hand, foot and mouth disease. These diseases require urgent attention as they spread quickly, are highly contagious, and highly harmful. If effective prevention and control measures are not implemented in a timely manner, these diseases can easily lead to epidemics. Phenolic acids have shown anti-infective potential in vitro against microorganisms that cause various diseases. Therefore, we believe that phenolic acids have the potential to improve or treat infectious diseases caused by intestinal infections. Nontyphoid Salmonella enteritis (ST) is a prominent pathogen. During infection, ST can adhere to and subsequently invade multiple cell types in the gastrointestinal tract of human hosts, especially intestinal epithelial cells, which are important virulence factors of ST. Studies have shown that gallic acid and vanillic acid display antibacterial activity against ST through their effectiveness in preventing ST adhesion and invasion during the infection of epithelial cell lines.¹⁹⁵Candida albicans affects the gastrointestinal tract, and systemic infections mainly originate from the host. Host-related factors can cause harmless Candida to easily transform into opportunistic pathogens, causing infection on the superficial mucosal surface.¹⁹⁶ Natural extracts containing phenolic acids have been shown to have antifungal activity against Candida. The main virulence factors of Candida are the production of proteases, biomembrane formation, adhesion and dimorphism. Sung et al. found that caffeic acid derivatives have antibiofilm effects on Candida and can affect the dimorphism of Candida.¹⁹⁷ In addition, protocatechuic acid shows broad-spectrum antibacterial activity against species such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus cereus, Streptococcus pneumoniae, Acinetobacter pasteurii, and Helicobacter pylori.^198,199 In summary, the antipathogenic microbial activity of phenolic acids makes them valuable for research and use in treating intestinal infectious diseases.

4.4 Intestinal barrier-related metabolic diseases

The integrity of the intestinal barrier is crucial for maintaining systemic metabolic homeostasis and damage to this barrier is closely related to the occurrence and progression of multiple metabolic diseases, including diabetes, obesity, and fatty liver disease. Gut barrier dysfunction may trigger or exacerbate these metabolic disorders. Diabetes is one of the major chronic diseases worldwide. It is divided into two types: type 1 diabetes (T1DM) and type 2 diabetes (T2DM). T1DM is an autoimmune disease characterized by damage to pancreatic beta cells and reduced insulin secretion. Studies have shown that a loss of intestinal barrier integrity can cause the symbiotic intestinal microbiota to activate islet-responsive T cells, thereby promoting the development of autoimmune diabetes.²⁰⁰ T2DM is the most common form of diabetes and is characterized by insulin resistance and insufficient insulin secretion, with elevated blood sugar levels. Impaired intestinal barrier function affects the secretion of glucose-dependent insulin-releasing peptide (GIP) and glucagon-like peptide-1 (GLP-1), thereby promoting the occurrence or worsening of T2DM.^201,202 Various treatment strategies have been reported to improve disease outcomes by restoring intestinal barrier integrity.^203–205p-Coumaric acid ameliorated high-fat diet (HFD)-induced glucose intolerance and hyperglycemia through restoration of small intestinal barrier integrity and improved hepatic glucose handling.¹⁰³ Phenolic acid-enriched Salvia miltiorrhiza aerial parts repaired ileocolonic mucosal architecture and attenuated hyperglycemia in diabetic murine models.²⁰⁶ Obesity is a complex chronic metabolic disease characterized by the excessive accumulation of adipose tissue in the body, leading to significant weight gain beyond the healthy range. The development of obesity is closely related to an imbalance in the intestinal flora and intestinal barrier damage. Multiple studies demonstrate that enhanced tight junction protein expression improves intestinal barrier dysfunction, thereby reducing lipid accumulation in hepatic and adipose tissues and ameliorating obesity.^207,208 Norigool extract (NFE), which is rich in phenolic acids, significantly alleviates obesity induced by a high-fat diet by regulating the intestinal flora, improving intestinal barrier function, and inhibiting inflammatory reactions.²⁰⁹ Dietary ferulic acid supplementation mitigated high-fat diet (HFD)-induced weight gain and significantly reduced plasma lipid profiles, hepatic triglyceride accumulation, and systemic cholesterol levels in murine models.²¹⁰ Fatty liver disease, characterized by excessive accumulation of fat in the liver, is one of the most common liver diseases worldwide. It is divided into two main categories: alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD). Damage to the intestinal barrier can allow endotoxins such as LPS to enter the blood, triggering systemic inflammatory responses and oxidative stress, thereby disrupting liver metabolism, increasing fat synthesis, reducing fatty acid oxidation, and leading to fat accumulation in the liver. Studies have shown that intestinal farnesol X receptor (FXR) signalling protects intestinal integrity and barrier function and that FXR deficiency in mice exacerbates AFLD.²¹¹ These findings highlight the importance of intestinal barrier integrity in the pathogenesis of fatty liver disease. Studies have shown that protection against NAFLD and AFLD is achieved by attenuating intestinal mucosal dysfunction, reducing intestinal mucosal permeability, and regulating intestinal innate immunity.^212,213 Phenolic acids and foods rich in phenolic acids have been reported to repair the intestinal barrier and prevent or treat related metabolic diseases. For example, the phenolic acid-rich extract of Citrus trifoliata leaves maintains intestinal barrier integrity and regulates the intestinal flora, thereby alleviating oxidative stress, lipid accumulation, and inflammation in mice with NAFLD.²¹⁴ Chlorogenic acid increases the relative abundance of beneficial bacteria and reduces alcoholic liver injury in ALD mice by promoting the production of N-butyric acid, which helps maintain the integrity of the intestinal barrier.²¹⁵ Chlorogenic acid also ameliorates NAFLD by increasing the expression of ZO-1 and occludin and regulating the integrity of the intestinal barrier.⁶⁵ In summary, maintaining intestinal barrier integrity is critical for overall metabolic health. Restoring intestinal barrier function is a promising treatment strategy for metabolic diseases. Phenolic acids and phenolic-rich foods provide potential benefits in this context by repairing the intestinal barrier and regulating the intestinal flora, thereby alleviating the symptoms of multiple metabolic disorders.

5. Clinical applications and safety profiles of phenolic acids

5.1 Clinical applications

In a clinical trial enrolling 85 type-2 diabetic patients, oral administration of phenolic acid complexes (12 or 20 mg kg⁻¹ every 48 hours for 6 months) significantly improved glycemic control in both dosage groups. However, serious adverse events – exclusively diarrhea – were reported in 13% and 16% of participants in the 12 mg kg⁻¹ and 20 mg kg⁻¹ groups, respectively.²¹⁶ A randomized double-blind trial revealed that acute single-dose administration of 400 mg chlorogenic acid (4.8–6.8 mg kg⁻¹ based on mean body weight 69.9 ± 12.7 kg) significantly reduced systolic and diastolic pressures.²¹⁷ Similarly, six-week supplementation with grape seed extract (chlorogenic acid: 300 mg day⁻¹ in divided doses) significantly lowered blood pressure in hypertensive patients while elevating plasma concentrations of phenolic acid metabolites, primarily hippuric acid and 3-hydroxyphenylacetic acid.²¹⁸ Current evidence suggests lower phenolic acid doses confer physiological benefits, whereas higher doses may lead to adverse effects (e.g., diarrhea) in susceptible populations. Notably absent are clinical investigations evaluating phenolic acids’ effects on intestinal barrier function, leaving their therapeutic index undefined for gastrointestinal disorders. Most clinical studies assess phenolic acids through dietary matrices rather than standardized preparations. Despite attempts to extrapolate doses from food phenolic content, significant bioavailability disparities persist between whole-food matrices and purified phenolic acids due to three primary factors: food matrix interactions, digestive liberation kinetics, and variable microbial biotransformation dynamics. Consequently, food-derived dose approximations exhibit compromised translational validity for therapeutic applications, resulting in critical gaps in human dose–response data. To address these limitations, future clinical trials must prioritize four key objectives: establishing intestinal barrier enhancement dose–response relationships; determining maximum tolerated doses; characterizing pharmacokinetic and pharmacodynamic profiles; and validating clinical efficacy in gastrointestinal pathologies.

5.2 Safety profiles

High-dose protocatechuic acid administration (500 mg kg⁻¹, intraperitoneal) induced subclinical hepatorenal impairment in ICR mice, significantly elevating plasma ALT and urea levels, consistent with oxidative stress-mediated toxicity.²¹⁹ Cumulative subcutaneous salicylic acid dosing (428 mg kg⁻¹) produced embryotoxic effects in pregnant rats, manifested as minor skeletal malformations.²²⁰ Conversely, oral vanillic acid (1000 mg kg⁻¹ day⁻¹ × 14 days) in Wistar rats elicited no significant alterations in hematological or biochemical parameters, demonstrating favorable toxicological profiles at this dosage.²²¹ Similarly, 2,4-dihydroxybenzoic acid (6000 mg day⁻¹ × 16 days, oral gavage) was well tolerated in rats.²²² Collectively, phenolic acid toxicity exhibits significant route dependency, with oral administration conferring substantially enhanced safety margins compared to parenteral routes (intraperitoneal/subcutaneous). Human trials consistently demonstrate excellent tolerability of high oral doses. Ferulic acid (1000 mg day⁻¹ × 6 weeks) improved lipid parameters without adverse events or clinically significant hepatorenal biomarker deviations.²²³ Critical clinical considerations reveal that while orally administered phenolic acids exhibit minimal intrinsic toxicity, parenteral administration may present safety hazards in clinical settings. Importantly, comorbid populations demonstrate differential susceptibility to phenolic acids, as evidenced by dose-dependent adverse effects in diabetic patients.²¹⁶ Furthermore, safety profiles in gastrointestinal pathologies remain unestablished, necessitating targeted clinical evaluation. Based on cumulative evidence, oral delivery represents the therapeutically optimal administration route. To address existing knowledge gaps, future investigations must: (1) establish safety thresholds in disease-specific populations; (2) characterize gastrointestinal disorder-associated risk profiles; and (3) quantify comparative bioavailability across administration routes.

6. Discussion and outlook

Phenolic acids have been shown to exert protective effects on the intestinal barrier through multiple mechanisms, and these effects can be systematically divided into direct and indirect modes of action. The direct mechanism of action involves the targeted regulation of intestinal barrier components, such as regulating the intestinal microbial composition by promoting the proliferation of beneficial bacteria and inhibiting the growth of conditioned pathogens; enhancing tight junction integrity through dual-pathway regulation/inhibition of the ROCK/MLC and MLCK/MLC signalling cascades; activating the CaMKKβ/AMPK/SIRT-1/ERK axis; upregulating tight junction proteins (claudin-1, claudin-2, occludin and ZO-1); preventing dissociation caused by occludin phosphorylation; and activating the BMP4/Smad1 pathway to stimulate goblet cell differentiation and subsequent MUC2 secretion, ensuring adequate mucus layer formation. Indirect protection appears to reduce barrier damage caused by inflammation and oxidative damage. Mechanistic studies have shown that phenolic acids inhibit the nuclear transport and transcriptional activity of NF-κB by inhibiting upstream regulatory factors such as the TLR4, PI3K and p38MAPK pathways, thereby reducing the production of proinflammatory cytokines. Phenolic acids activate the Nrf2/Keap1/HO-1 signalling axis to combat barrier dysfunction mediated by oxidative stress.

Despite the fact that phenolic acid demonstrates better intestinal barrier protection, there are still some challenges in its application. The first is the issue of bioavailability. The bioavailability of phenolic acid compounds is generally poor, which limits their potential to exert biological activities in the body. Numerous in vivo studies have confirmed that phenolic acids are rapidly absorbed and metabolized in the gastrointestinal tract, resulting in low and inconsistent oral bioavailability.^41,224–229 Structural modifications during metabolism also have important effects on the biological activity of phenolic acids. Studies have shown that both the methylation and demethylation of phenolic acids lead to a decrease in their antioxidant activity,^230–232 which may be related to changes in the number and position of phenolic acid hydroxyl groups during metabolism. In addition to their structures, the form in which phenolic acids exist also affects their bioavailability. When these compounds are present in complex substrates (grains), their absorption and metabolism are inhibited.^34,230,231 This may weaken the rapid protective effect of phenolic acids on the intestinal barrier, but has a greater advantage in improving chronic low-grade inflammation related barrier damage.²³³ Advanced delivery systems offer promising solutions: polycarboxylate-loaded gels increase local drug concentrations,²³⁴ calcium-loaded nanoparticles extend drug retention times in the colon,²³⁵ and glycerolipid complexes extend serum half-lives in rats.²³⁶ Despite these advances, challenges remain in optimizing colloidal delivery systems for clinical translation, requiring a comprehensive assessment of the bioavailability enhancement and safety. The complex dose–response relationship of phenolic acids is the second major challenge for their clinical application. The phenolic acid dose–response relationship shows great individual variability. In preclinical models, the administration of chlorogenic acid at 1 mg kg⁻¹ and 500 mg kg⁻¹ had anti-inflammatory effects but was not effective in all experimental animals.^61,69 In diabetic patients, a certain amount of phenolic acids can improve blood sugar control, but individual responses vary.^237,238 In addition, in vitro studies have confirmed a concentration-dependent vasodilatory effect of phenolic acids,²³⁹ but the vascular effect in vivo is not dose dependent.²⁴⁰ The wide range of therapeutic doses and unpredictable efficacy may stem from changes in microbial metabolism. Since most phenolic acids undergo biotransformation by colonic microorganisms before systemic absorption,²³⁷ differences in the microbiota composition between individuals have important impacts on metabolite profiles and pharmacological activity. These metabolic differences pose fundamental challenges in establishing clear dose–response relationships. Although the health benefits of phenolic acids have been observed, conclusive evidence for treatment remains difficult to obtain, and mechanistic research is needed to resolve dose–response uncertainties.

The intestinal barrier-protective effects of phenolic acids are closely associated with their bioavailability and antioxidant activity. However, within food matrices, phenolic acids frequently interact with various nutrients and non-nutrient components, which can either enhance or inhibit their bioavailability and antioxidant potential. Regarding nutrient interactions, β-casein in milk has been shown to reduce the antioxidant capacity of phenolic acids such as gallic acid, kaempferol, caffeic acid, ferulic acid, and chlorogenic acid by binding to hydroxyl groups on their phenolic rings, thereby masking active sites.²⁴¹ Milk fat is considered a key factor in improving the bioaccessibility of chlorogenic acid from coffee. In contrast, caffeine and high-molecular-weight food components may reduce its bioaccessibility through complex formation with chlorogenic acid or pro-oxidant mechanisms, while calcium content exhibits no significant correlation with chlorogenic acid bioaccessibility.²⁴² Clinical studies further indicate that milk proteins and fats significantly suppress the absorption efficiency and in vivo antioxidant activity of phenolic acids via binding interactions.²⁴³ Moreover, both flaxseed and soybean proteins have been found to impair the antioxidant capacity of phenolic acids, with soybean protein demonstrating a more pronounced inhibitory effect.²⁴⁴ Polysaccharides and dietary fiber, on the other hand, hinder the release of phenolic acids and attenuate their antioxidant effects by delaying gastrointestinal transit and engaging in molecular interactions.^245,246 Vitamin E exhibits antagonistic effects toward chlorogenic acid activity,²⁴⁷ and vitamin B3 has been shown to inhibit the antioxidant activity of caffeic acid in both CUPRAC and Folin–Ciocalteu assays.²⁴⁸ As for non-nutrient components, carotenoids exert a bidirectional influence on the antioxidant capacity of phenolic acids: when carotenoids are predominant, the activity of phenolic acids is suppressed, whereas a higher proportion of phenolic acids leads to a synergistic enhancement effect with carotenoids.²⁴⁹ This phenomenon may be attributed to the ability of phenolic acids to facilitate the absorption of carotenoids at low concentrations, thereby indirectly amplifying their own antioxidant-related signaling capacity.²⁵⁰ The chemical structure of phenolic acids influences their synergistic effect with carotenoids. Compared with p-coumaric acid, caffeic acid, which possesses a catechol hydroxyl group, exhibits a stronger synergistic interaction with carotenoids, while p-coumaric acid tends to produce additive or mildly antagonistic effects.²⁴⁹ Additionally, non-phenolic constituents in willow bark (e.g., salicin and flavonoids) and phenolic acids in coffee display a complex bidirectional behavior in antioxidant activities: although the former may inhibit phenolic acid activity in certain contexts such as free radical scavenging and reduction reactions, they significantly enhance phenolic acid efficacy in processes such as enzyme inhibition, metal chelation, and hydroxyl radical scavenging.²⁵¹ In summary, the development of functional foods rich in phenolic acids should strategically leverage synergistic interactions with other food components, while minimizing inhibitory factors through rational formulation design.

Collectively, phenolic acids exhibit substantial therapeutic promise and broad clinical applicability, yet they cannot supplant conventional synthetic pharmaceuticals. To establish clinical safety, comprehensive human trials must characterize in vivo metabolic fate and define safety profiles. A critical limitation remains their inherently poor systemic bioavailability, necessitating advanced delivery system development to enhance bioavailability and targeted food-processing technologies to improve bioaccessibility of matrix-bound compounds. Particularly limited are clinical validations of preclinical findings regarding intestinal barrier protection. Therefore, definitive clinical trials are imperative.

Author contributions

Li Xia: conceptualization, data curation, and writing – original draft. Xiulian Lin: writing – review and editing and conceptualization. Yuanjiao Zhou: writing – review and editing and data curation. Yamei Li: writing – review and editing and supervision. Yingyan Liao: writing – review and editing. Yan Lin: writing – review and editing. Limei Lin: writing – review and editing and supervision. Ping Wu: writing – review and editing and funding acquisition. Jingchen Xie: writing – review and editing and supervision. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

The authors declare no conflict of interests.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

This work was supported by the Provincial Natural Science Foundation Project (2023JJ604787) and the Joint Cultivation Base for Postgraduates’ Top Innovative Talents in Hunan Province (Xiangtong [2023] No. 372).

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Footnote

† These authors contributed equally to this work.

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