Therapeutic Implications of Phenolic Acids for Ameliorating Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder, and its complex etiology makes prevention and treatment challenging. Research on new drugs and treatment strategies is currently a focal point. Phenolic acids are widely present in plant-based diets and have demonstrated the potential to alleviate colitis due to their powerful antioxidant and anti-inflammatory properties. In this review, we provide an overview of the structures and main dietary sources of phenolic acids, encompassing benzoic acid and cinnamic acid. Additionally, we explore the potential of phenolic acids as a nutritional therapy for preventing and treating IBD. In animal and cell experiments, phenolic acids effectively alleviate IBD induced by drug exposure or genetic defects. The mechanisms include improving intestinal mucosal barrier function, reducing oxidative stress, inhibiting excessive activation of the immune response, and regulating the balance of the intestinal microbiota. Our observation points towards the need for additional basic and clinical investigations on phenolic acids and their derivatives as potential novel therapeutic agents for IBD.


Introduction
Inflammatory bowel disease (IBD) is a chronic intestinal disease with abdominal pain, diarrhea, bloody stool, and other main symptoms, including ulcerative colitis (UC) and Crohn's disease (CD).CD can occur anywhere in the digestive tract, from the mouth to the anus.It usually involves inflammation of the lining of the digestive tract and can lead to symptoms such as abdominal pain, diarrhea, weight loss, and fatigue.UC mainly affects the colon and rectum.It involves inflammation and ulcers in the lining of the colon, which can cause symptoms such as abdominal pain, diarrhea, and rectal bleeding.IBD is a global condition.Its evolution can be divided into four epidemiological stages: disease emergence, accelerated incidence, disease exacerbation, and disease equilibrium [1].Western countries are in a worsening phase of the disease, with prevalence rising rapidly and reaching as high as 1% in many areas by 2030.Developing countries are currently in the first stage of disease evolution (the disease emergence stage).The number of IBD patients in China is expected to exceed 1.5 million in 2025 [2,3].
The pathogenesis of IBD is associated with the interactions among genetic, environmental, and immune response factors and the intestinal microbiota, which contributes to the challenge of treating IBD.Currently, the clinical therapeutic repertoire for IBD is predominantly constituted by traditional medications (including aminosalicylic acid preparations, glucocorticoids, and immunosuppressants), biological agents (such as anti-tumor necrosis factor (TNF), interleukin (IL)-12/IL-23), and emerging small-molecule drugs (such as Janus-activated kinase (JAK) inhibitors and sphingosine-1-phosphate (S1P) receptor modulators).However, up to 30% of patients still do not respond to initial treatment, and up to Nutrients 2024, 16, 1347 2 of 14 50% of patients respond over time, and long-term use can lead to many complications [4,5].These issues prompt us to explore alternative therapies.
Diet is one of the key factors in the normal intestinal microenvironment, affecting microbial composition, function, the intestinal barrier, and host immunity [6].In recent years, dietary intervention has emerged as a prominent research focus in both the prevention and treatment of colitis, alongside complementary clinical approaches.Phenolic acid is an important secondary metabolite containing phenolic hydroxyl and carboxylic groups widely distributed in higher plants and possessing various physiological functions such as antibacterial, antioxidant, anti-inflammatory, and anticancer properties.In this review, we summarize the main food sources of phenolic acids, as well as their role and possible mechanisms in the prevention and treatment of colitis.This work aims to delve into understanding how dietary adjustments can regulate the intake of phenolic acids, effectively prevent and treat colitis, and provide valuable information and guidance for the management of related diseases.

Chemical Structures and Primary Dietary Sources of Phenolic Acids
Phenolic acid refers to organic acids containing phenolic rings, which can be divided into benzoic acids and cinnamic acids according to their structural characteristics (Table 1).

Phenolic Compounds Substituent Group
Benzoic acid receptor modulators).However, up to 30% of patients still do not respond to initial treatment, and up to 50% of patients respond over time, and long-term use can lead to many complications [4,5].These issues prompt us to explore alternative therapies.Diet is one of the key factors in the normal intestinal microenvironment, affecting microbial composition, function, the intestinal barrier, and host immunity [6].In recent years, dietary intervention has emerged as a prominent research focus in both the prevention and treatment of colitis, alongside complementary clinical approaches.Phenolic acid is an important secondary metabolite containing phenolic hydroxyl and carboxylic groups widely distributed in higher plants and possessing various physiological functions such as antibacterial, antioxidant, anti-inflammatory, and anticancer properties.In this review, we summarize the main food sources of phenolic acids, as well as their role and possible mechanisms in the prevention and treatment of colitis.This work aims to delve into understanding how dietary adjustments can regulate the intake of phenolic acids, effectively prevent and treat colitis, and provide valuable information and guidance for the management of related diseases.

Chemical Structures and Primary Dietary Sources of Phenolic Acids
Phenolic acid refers to organic acids containing phenolic rings, which can be divided into benzoic acids and cinnamic acids according to their structural characteristics (Table 1).

Phenolic Compounds Substituent Group
Benzoic acid Phenolic acids are omnipresent in edible vegetables, fruits, and nuts, with an estimated average daily consumption of 1-2 g of these components in a human diet [7].Salicylic acid, a secondary metabolite associated with plant disease resistance and abiotic stress response, exhibits higher levels in nectarines (3.29 mg/kg), asparagus (1.29 mg/kg), and spices like cumin (29.76 mg/kg), black cumin (25.05 mg/kg), and paprika (28.25 mg/kg) [8].Protocatechuic acid is more abundant in traditional Chinese medicine and berries such as Eucommia ulmoides (1720 mg/100 g), black olives (21 mg/100 g), and black raspberries (8.35 mg/100 g) [9].Gallic acid is plentiful in plants like rhubarb, eucalyptus, ornus officinalis, and Chinese pistache [10].Vanillic acid is prominent in the roots of Angelica sinensis and is also found in wine, vinegar, and argan oil.Syringic acid, as one of the abundant phenolic compounds, is present in olives, dates, spices, pumpkins, grapes, Brazilian palm trees, honey, red wine, and other plants.Cinnamic acid is found in high

Cinnamic acid
Nutrients 2024, 16, 1347 2 of 14 receptor modulators).However, up to 30% of patients still do not respond to initial treatment, and up to 50% of patients respond over time, and long-term use can lead to many complications [4,5].These issues prompt us to explore alternative therapies.Diet is one of the key factors in the normal intestinal microenvironment, affecting microbial composition, function, the intestinal barrier, and host immunity [6].In recent years, dietary intervention has emerged as a prominent research focus in both the prevention and treatment of colitis, alongside complementary clinical approaches.Phenolic acid is an important secondary metabolite containing phenolic hydroxyl and carboxylic groups widely distributed in higher plants and possessing various physiological functions such as antibacterial, antioxidant, anti-inflammatory, and anticancer properties.In this review, we summarize the main food sources of phenolic acids, as well as their role and possible mechanisms in the prevention and treatment of colitis.This work aims to delve into understanding how dietary adjustments can regulate the intake of phenolic acids, effectively prevent and treat colitis, and provide valuable information and guidance for the management of related diseases.

Chemical Structures and Primary Dietary Sources of Phenolic Acids
Phenolic acid refers to organic acids containing phenolic rings, which can be divided into benzoic acids and cinnamic acids according to their structural characteristics (Table 1).

Phenolic Compounds Substituent Group
Benzoic acid Phenolic acids are omnipresent in edible vegetables, fruits, and nuts, with an estimated average daily consumption of 1-2 g of these components in a human diet [7].Salicylic acid, a secondary metabolite associated with plant disease resistance and abiotic stress response, exhibits higher levels in nectarines (3.29 mg/kg), asparagus (1.29 mg/kg), and spices like cumin (29.76 mg/kg), black cumin (25.05 mg/kg), and paprika (28.25 mg/kg) [8].Protocatechuic acid is more abundant in traditional Chinese medicine and berries such as Eucommia ulmoides (1720 mg/100 g), black olives (21 mg/100 g), and black raspberries (8.35 mg/100 g) [9].Gallic acid is plentiful in plants like rhubarb, eucalyptus, ornus officinalis, and Chinese pistache [10].Vanillic acid is prominent in the roots of Angelica sinensis and is also found in wine, vinegar, and argan oil.Syringic acid, as one of the abundant phenolic compounds, is present in olives, dates, spices, pumpkins, grapes, Brazilian palm trees, honey, red wine, and other plants.Cinnamic acid is found in high Phenolic acids are omnipresent in edible vegetables, fruits, and nuts, with an estimated average daily consumption of 1-2 g of these components in a human diet [7].Salicylic acid, a secondary metabolite associated with plant disease resistance and abiotic stress response, exhibits higher levels in nectarines (3.29 mg/kg), asparagus (1.29 mg/kg), and spices like cumin (29.76 mg/kg), black cumin (25.05 mg/kg), and paprika (28.25 mg/kg) [8].Protocatechuic acid is more abundant in traditional Chinese medicine and berries such as Eucommia ulmoides (1720 mg/100 g), black olives (21 mg/100 g), and black raspberries (8.35 mg/100 g) [9].Gallic acid is plentiful in plants like rhubarb, eucalyptus, ornus officinalis, and Chinese pistache [10].Vanillic acid is prominent in the roots of Angelica sinensis and is also found in wine, vinegar, and argan oil.Syringic acid, as one of the abundant phenolic compounds, is present in olives, dates, spices, pumpkins, grapes, Brazilian palm trees, honey, red wine, and other plants.Cinnamic acid is found in high concentrations in cinnamon and is also present in citrus fruits, tea, spinach, and celery.p-Coumaric acid is extensively found in fruits (such as apples, pears, grapes, oranges, tomatoes, and berries), vegetables (including legumes, potatoes, and onions), and grains (such as corn, oats, and wheat).It is also present in Ganoderma lucidum (1386.4mg/kg), Cantharellus cibarius (2420 mg/kg), lingonberry (85 mg/kg), northern crowberry (122 mg/kg), and sea buckthorn (37 mg/kg) [11].Sinapic acid is found in fruits, vegetables, grains, oil crops, and certain medicinal plants.In citrus fruits, lemons and Meyer oranges exhibit the highest sinapic acid content, reaching 72.1 µg/g and 50.1 µg/g (dry weight), respectively.Among berries, strawberries and American cranberries demonstrate sinapic acid content reaching 450 µg/g and 210 µg/g, respectively.Caffeic acid is widely present in fruits, vegetables, and beverages, with coffee being a major source.Ferulic acid has a higher content in traditional Chinese medicine, such as Angelic Sinensis Diels (0.05%) and Cimicifuga foetida L. (2%), and is also found in daily dietary items, including Zea mays (1.65%) and onions (0.32%) [12,13].Chlorogenic acid, a derivative of hydroxycinnamic acid, is widely found in foods such as coffee, cherries, and apples.It is also a major component in many traditional Chinese herbs, especially honeysuckle and Eucommia ulmoides [14].

Effect of Phenolic Acids on Intestinal Mucosal Barrier
The mucosal barrier plays a crucial role in maintaining the stability of the intestinal environment, serving as a protective shield that prevents harmful substances, pathogens, and inflammatory responses from compromising the intestinal tract.In this context, we have summarized the effects of phenolic acid interventions on improving experimental colitis phenotypes, particularly emphasizing improvements in colonic histology and tight junction proteins.The summary of phenolic acids in IBD is shown in Table 2.
The oral administration of 4-hydroxybenzoic acid (at doses of 10-40 and 100 mg/kg) demonstrated a dose-dependent elevation in tight junction proteins (e-cadherin and occludin) and goblet cell numbers [15,16].Similarly, treatment with 4-hydroxybenzoic acid (at concentrations of 3, 10, and 30 µM) resulted in an increased expression of tight junction proteins in mice and Caco-2 cells exposed to TNF-α (10 ng/mL) [15].Protocatechuic acid, administered at doses of 5, 10, and 20 mg/kg, effectively alleviated the dextran sulfate sodium salt (DSS)-induced reduction in occludin protein expression in mice treated with 3.5% DSS [17].Furthermore, intraperitoneal administration of protocatechuic acid at doses of 10, 30, or 60 mg/kg per day prevented both the macroscopic and microscopic damage to the colonic mucosa, as well as the decline in body weight gain in mice treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS) and rats treated with DSS [18,19].
Gallic acid, administered at doses ranging from 10 to 200 mg/kg, demonstrated a significant attenuation of the disease activity index, colon shortening, and reduction in histopathological evidence of injury [20][21][22][23][24]. Additionally, gallic acid upregulated the expression of nuclear factor erythroid 2-related factor 2 (NRF2) and mitigated the activation and nuclear accumulation of p-STAT3.As a result, this prevented the degradation of the inhibitory protein IκB and hindered the nuclear translocation of p65-nuclear factor kappa-B (NF-κB) in the colonic mucosa [22,23].
Vanillic acid, provided at a dose of 4000 mg/kg in the diet, elevated the expression of the tight junction protein occludin in a weaned piglet model challenged with 10 mg/kg lipopolysaccharides (LPS) [25].Additionally, at a dose of 200 mg/kg, vanillic acid mitigated DSS-induced body weight loss and colon shortening [26].
Syringic acid, administered at concentrations of 0.1, 1.0, and 10.0 µM, effectively mitigated the disruption of the intestinal barrier in Caco-2 cells in response to oxygen-glucose deprivation/reoxygenation (OGD/R).This protective effect was assessed through the preservation of intestinal epithelial integrity and the modulation of protein expression levels, including claudin-3, claudin-2, and ZO-1 [27].Additionally, in mice with DSS-induced colitis, syringic acid at doses of 25 and 50 mg/kg prevented colon damage, alleviated proptosis, and increased the mRNA expression of intestinal barrier proteins (claudin-1, ZO-1, and occludin) [28,29].Furthermore, treatment with 25 and 50 mg/kg of syringic acid decreased the mean macroscopic ulcer score in rats with acetic acid-induced colitis [30].
Coumaric acid, at doses of 100 and 150 mg/kg, exhibited a positive impact on the macroscopic changes in the colons of rats with acetic acid-induced colitis [30].
Caffeic acid, administered at doses of 50 and 250 mg/kg, mitigated the disease severity in mice with DSS-induced colitis [33,34].
Ferulic acid, provided at doses of 20 and 40 mg/kg, not only alleviated TNBS-induced ulcerative colitis but also inhibited cell apoptosis, as evidenced by the modulation of caspase-1 and caspase-3 expression in rats [35,36].
Sinapic acid, administered at doses of 10, 30, and 100 mg/kg, demonstrated improvement in the macroscopic changes associated with TNBS-induced colitis in mice.This improvement was evidenced by morphological observations of the mouse colon, measurements of colon length, weight, and the colon weight/length ratio, as well as macroscopic scoring [37].Additionally, sinapic acid exhibited a positive effect on colonic claudin-1, occludin, and ZO-1 in Kunming mice with DSS-induced colitis [38].Furthermore, sinapic acid impeded the impairment of intestinal permeability and the redistribution of tight junction proteins in differentiated Caco-2 cells provoked by 20 µg/mL LPS and 20 ng/mL TNF-α.Moreover, it suppressed the myosin light chain kinase (MLCK)/myosin light chain (MLC)/NF-κB signaling pathways and the phosphorylation of activating transcription factor 2 (ATF-2) in response to stimulus-induced conditions in differentiated Caco-2 cells [39,40].
Chlorogenic acid, at a concentration of 1 mM, mitigated various effects of DSS-induced colitis, including weight loss and increased disease activity [41].Additionally, treatment with chlorogenic acid at a dose of 20 mg/kg alleviated mucosal damage induced by both DSS and TNBS, operating through the MAPK/ERK/JNK signaling pathway [42,43].Furthermore, the administration of chlorogenic acid at a dose of 50 mg/kg protected against body weight loss, preserved intestinal morphology, and maintained integrity in mice treated with indomethacin [44].

Effect of Phenolic Acids on Oxidative Stress
Oxidative stress is characterized by an imbalance in cellular oxidative status due to an excess of free radicals and oxidizing agents, potentially leading to cellular damage and inflammation.Phenolic acids are considered to play a positive role in modulating oxidative stress in the intestines due to their antioxidant properties.
When administered intraperitoneally at doses of 10, 30, or 60 mg/kg/day, protocatechuic acid successfully averted both visible and microscopic harm to the colonic mucosa.Furthermore, it alleviated the decline in body weight gain and the rise in myeloperoxidase activity triggered by TNBS-treated mice and DSS-treated rats [18,19].Moreover, mice subjected to protocatechuic acid treatment exhibited a decreased ratio of oxidized to reduced glutathione, coupled with elevated levels of antioxidant enzymes and Nrf2 expression amidst TNBS-induced colitis [18].
Coumaric acid demonstrated an improvement in oxidative stress, including SOD and total antioxidant capacity (TAC), induced by acetic acid-induced colitis in the colon [45].Furthermore, at doses of 100 and 150 mg/kg, coumaric acid increased the mRNA expression of HO-1, NRF2, and NQO1 in acetic acid-induced rats [30].
Caffeic acid treatment resulted in a significant decrease in MDA levels and an increase in TAC, SOD, glutathione peroxidase (GSH-PX), and catalase (CAT) in serum [34].
Ferulic acid, administered at doses of 20, 40, and 60 mg/kg, significantly increased the activity of antioxidant factors, including TAC content and SOD and CAT activity, in the colon tissue of rats with acetic acid-induced colitis [46].Animals treated with sinapic acid at a dose of 40 mg/kg exhibited a noteworthy replenishment in mean CAT and GSH levels compared to those with acetic acid-induced colitis, indicating a restoration of free radical scavenging activity [47].
Chlorogenic acid, at a dose of 20 mg/kg, ameliorated DSS-induced oxidative stress in the colon [43].

Effect of Phenolic Acids on Immune System
The immune system plays a pivotal role in the intestines by safeguarding the body against external pathogens and harmful substances.Phenolic acids are recognized for their anti-inflammatory properties, effectively mitigating inflammatory responses and thereby preserving the equilibrium of the intestinal immune system [48].Furthermore, phenolic acids have the potential to modulate the activity and differentiation of immune cells, thereby influencing the regulation of immune responses.This regulatory impact serves to prevent undue immune activation and uphold the normal functionality of the immune system.
Vanillic acid, provided at a dose of 4000 mg/kg in the diet, decreased serum levels of IL-1β, IL-2, IL-6, and TNF-α in a weaned piglet model challenged with 10 mg/kg LPS [25].Additionally, vanillic acid at a dose of 200 mg/kg reduced the level of IL-6 in the plasma of DSS-treated mice [26].
Cinnamic acid administration at doses of 25 and 50 mg/kg resulted in reduced levels of TNF-α and IL-6 in mice with DSS-induced colitis [31].
Caffeic acid suppressed the production of inflammatory cytokines (TNF-α, IL-6, IL-12, and IL-1β) in the colon and interfered with the infiltration and function of mononu-clear macrophages in the mucosa, mediastinal lymph nodal, and spleens of DSS-induced mice [33,34,49].

Effect of Phenolic Acids on Gut Microbes
The gut microbiota plays a crucial role in maintaining intestinal health and immune balance [54].Phenolic acids may impact the composition of the gut microbiota through their antioxidant and anti-inflammatory properties.This influence may result in an increase in beneficial bacteria and a decrease in harmful bacteria, thereby promoting a balance in the gut microbial ecosystem.Phenolic acids may create a favorable environment for probiotics, enhancing their survival and functionality in the gut.This promoting effect contributes to maintaining the diversity and stability of the gut microbiota, exerting a positive impact on overall intestinal health.
Oral administration of 4-hydroxybenzoic acid (100 mg/kg) effectively relieved the DSSinduced colitis in mice, which were largely dependent on the gut microbiota, as antibiotic treatment substantially attenuated the improvement of colitis by 4-hydroxybenzoic acid, and transplantation of gut microbiota from colitis mice treated with 4-hydroxybenzoic acid significantly reduced the colitis.The transplantation of colitis mice treated with HA increased the abundance of Akkermansia muciniphila [16].
Protocatechuic acid, at a dose of 20 mg/kg, regulated the composition of the gut microbiota.In the DSS group, the relative abundances of Bacteroidetes and Verrucomicrobiota decreased compared to the control group.The treatment with protocatechuic acid partially restored their relative abundances [17].
Gallic acid, administered at a dose of 200 mg/kg, improved gut microbiota dysbiosis induced by DSS.Further fecal microbiota transplantation demonstrated that gallic acid's anti-colitis effects were mediated by the gut microbiota.At the taxonomic level, gallic acid replenished the presence of all primary phyla except Actinobacteria.Regarding order-level taxonomy, treatment with gallic acid replenished the presence of Clostridiales, Enterobacterales, and Bacteroidales.Moreover, among the genera identified as differentially abundant by the linear discriminant analysis effect size algorithm, the gallic acid group exhibited enrichment in Erysipelatoclostridium and Eubacterium [24].
Vanillic acid elevated the Firmicutes/Bacteroidetes ratio while diminishing the proportional presence of Prevotellaceae.It additionally bolstered the Lachnospiraceae family, particularly the Lachnospiraceae FCS020 group.Furthermore, vanillic acid decreased the relative occurrence of Prevotella 7 and Prevotella 1 but enhanced Lachnospira, the Eubacterium eligens group, and the Eubacterium xylanophilum group in a weaned piglet model exposed to a 10 mg/kg LPS challenge [25].
Research on syringic acid has indicated its potential similarity to the impact of transplanted healthy mouse feces in addressing DSS-induced colitis [29].
Supplementation with caffeic acid (250 mg/kg) altered the composition of the gut microbiome by decreasing the relative abundance of Bacteroides and Turicibacter while enhancing the relative abundance of Alistipes and Dubosiella in DSS-induced colitis [34].
Oral administration of sinapic acid (2 and 10 mg/kg) alleviated DSS-induced IBD and modified the gut microbiota.At the genus level, sinapic acid was found to inhibit DSS-induced declines in the relative abundance of Ligilactobacillus and Limosilactobacillus in the feces of C57BL/6J mice, and it suppressed the DSS-induced decrease in the Firmicutes/Bacteroidetes (F/B) ratio [39].
Chlorogenic acid (1 mM) decreased the proportion of Firmicutes and Bacteroidetes and increased the proportion of the mucin-degrading bacterium Akkermansia in DSS-induced colitis mice [41].Moreover, chlorogenic acid (2% in the diet) reversed the decrease in diversity caused by DSS and improved the relative abundance of organisms in the genus Lactobacillus [55].Additionally, at a dose of 50 mg/kg, chlorogenic acid inhibited the growth of Bacteroides and the accumulation of Bacteroides-derived LPS in indomethacininduced colitis [44].

Conclusions and Future Perspectives
Numerous studies have focused on the potential therapeutic effects of phenolic acid compounds on colitis and their potential roles in the prevention and treatment of this inflammatory gastrointestinal disease.Some studies suggest that phenolic acids possess anti-inflammatory and antioxidant properties, which may play a beneficial role in alleviating inflammation and oxidative stress associated with colitis.These compounds are believed to influence the development and progression of colitis by mitigating inflammatory responses, regulating the immune system, and protecting the mucosal barrier.
However, despite some promising research findings, there is currently a lack of comprehensive studies and a thorough understanding of the mechanisms of action regarding the role of phenolic acids in colitis treatment.Researchers are actively working to delve deeper into questions related to the molecular mechanisms of phenolic acids, their applicability across different disease stages, and the optimal intake levels.These efforts aim to provide a more comprehensive assessment of the potential role of phenolic acids in the management of colitis.

Table 1 .
Chemical structure of phenolic acids.

Table 1 .
Chemical structure of phenolic acids.

Table 1 .
Chemical structure of phenolic acids.

Table 2 .
Summary of phenolic acids on IBD.