Ferulic acid – A promising candidate molecule for the treatment of colitis

Abstract

Ulcerative colitis is an inflammatory bowel disease of multi-factorial etiology and responsible for considerable health and socioeconomic burdens given high global prevalence rates. Since current therapy options are associated with various side effects, alternative or adjunct therapy options are utmost wanted. Ferulic acid (FA) is a phenolic compound found in various plants and has attracted scientific interests due to its anti-oxidant properties and recently been hyped as a longevity compound. This systematic review summarizes current evidence for anti-colitogenic effects of FA. Results of the included studies revealed that FA, its derivatives, and synthesized FA-containing nanoparticles i.) alleviated experimental colitis; ii.) dampened pro-inflammatory immune responses; iii.) tightened the gut epithelial barrier; and iv.) reshaped the gut microbiota composition from a dysbiotic to a well-balanced “healthy” state characterized by high species diversity and dominance of probiotic bacterial taxa. Remarkably, in some studies, the observed anti-colitogenic effects of FA were even more pronounced compared to those exerted by treatment with established medications. In conclusion, FA constitutes a promising alternative or adjunct option in the treatment of ulcerative colitis.

1. Introduction

1.1. Ulcerative colitis and its need of new therapy approaches

Ulcerative colitis belongs to the chronic inflammatory bowel diseases (IBD) characterized by the dysregulation of the innate and adaptive immune system and subsequent mucosal inflammation mainly affecting the rectum and the colon. Patients suffering from ulcerative colitis present with rectal bleeding, diarrhea, weight loss, and abdominal cramps [1]. Since the second half of the 20th century, the incidence of IBD has increased in Europe and North America, reaching a plateau in 1990 which has remained stable or slightly decreased. Nevertheless, IBD remain a global health issue, as incidences rates are still rising in Asia, Africa, and South America. Currently, the global IBD prevalence exceeds 0.3% [2] and the chronic disease course as well as expensive medications contribute to high public health expenses placing a significant socioeconomic burden [3]. It is widely assumed and at least partially proven, that a genetic predisposition and environmental factors are main contributors to disease manifestations [4, 5]. However, the exact etiology of ulcerative colitis remains unclear. Epithelial barrier dysfunction, a dysregulated immune system, and intestinal dysbiosis are key factors in the onset and perpetuation of gut inflammation [6] characterized by endoplasmic reticulum (ER) stress and reactive oxygen species (ROS)-related apoptosis [7]. Resulting tissue defects allow intestinal bacteria to enter the intracellular space, where they aggravate chronic pro-inflammatory immune responses [8]. Current drug therapy options of ulcerative colitis mainly include immune-suppressive compounds such as 5-aminosalicylic acids, corticosteroids, tumor necrosis factor-alpha (TNF-α) inhibitors, anti-integrins, and janus kinase (JAK) inhibitors [9, 10]. These substances are, however, associated with various side effects, such as headache, diarrhea, agranulocytosis, pancreatitis, bone marrow depletion, pericarditis or opportunistic infections due to their immunosuppressive effects [11].

1.2. Ferulic acid – an underestimated phenolic substance?

Ferulic acid (FA), also termed 4-hydroxy-3 methoxy-cinnamic acid, is a polyphenolic plant compound of the Apiaceae, Gramineae, and Ranunculaceae families [12, 13]. As an important precursor of lignin, FA rarely occurs in its free form and is predominantly located within the cell walls. In the human diet, FA is abundant in cereal grains, especially bran products of different grain varieties, rice, bamboo shoots as well as various fruits and vegetables [14]. In recent years, it has attracted mounting scientific interest due to its anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-platelet coagulation properties [15]. These health-beneficial and disease-alleviating effects are implemented in defined cosmetic as well as dermatological applications [16]. According to current scientific findings FA is considered as an optional or supplementary therapy in the treatment of rheumatoid, cardiovascular, and neurological diseases including mood disorders such as depression [15]. Given that free FA is mainly absorbed in the gastrointestinal tract and then rapidly metabolized in the liver rather (too) low free FA concentrations might reach the targeted organs [17]. Consequently, there is a necessity to develop new technologies and drug delivery systems for the purpose of improving bioavailability. Several reviews have been published in recent years on the effects, metabolism, pharmacokinetics, and possible applications of FA [13–15, 18]. Similarly, current publications on phenolic acids in general and their potential to treat IBDs are available [19, 20]. However, data regarding potential disease-alleviating effects of FA in chronic intestinal inflammatory morbidities are scarce.

1.3. Aim of this review

Our actual review aims to summarize current knowledge regarding potential therapeutic effects of FA on colitis including ulcerative colitis due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties to open novel alternative adjunct therapeutic (or preventive) therapeutic approaches with rather minor adverse effects.

2. Methods

2.1. Inclusion and exclusion criteria

For this review, we selected publications examining the effects of FA, its derivatives or FA-containing synthesized nanoparticles in vitro as well as on experimentally induced animal models of intestinal inflammation mimicking key features of ulcerative colitis. Investigations explicitly addressing the impact of FA on the clinical course of the disease, intestinal barrier function, signaling pathways of intestinal inflammation or alterations of the gut microbiome were included. Research on the effect of FA in the pathogenesis of other diseases, e.g. obesity, non-alcoholic fat liver disease or depression, however, was excluded which also held true for reports on FA-containing plants.

2.2. Literature research strategy and data extraction

The literature research for this review was conducted from the 24th to 28th of October 2025, by applying the online meta database “PubMed” of the National Library of Medicine (NLM) and U.S. National Institute of Health. First, the terms “ferulic acid” and “sodium ferulate” were connected using the Boolean operator “OR”. These terms were tagged with “Title/Abstract” and filtered to include only English-language publications. The same procedure was then undertaken on the terms “ulcerative colitis”, “colitis”, “inflammatory bowel disease”, “intestinal health” and “intestinal inflammation”. Connecting those two search instructions, the Boolean operator “AND” was applied, which provided a total result of 47 studies. Existing reviews were excluded using the Boolean operator “NOT”. After a careful assessment of the remaining 41 studies, applying the afore-mentioned inclusion and exclusion criteria, 21 studies were selected for this review paper (Fig. 1).

Fig. 1.

PRISMA 2020 flow diagram of the literature selection process [21]

3. Results

3.1. Pure ferulic acid for colitis treatment

Nine of the included studies tested the effects of pure (synthetic) FA in various in vitro and in vivo models. In a very recent in vivo study from 2025, Huang et al. fed FA at different concentrations (i.e., 20, 40, and 80 mg kg⁻¹ body weight) per day to mice prior induction of intestinal inflammation by intraperitoneal application of bacterial lipopolysaccharides (LPS) [22]. Compared to the placebo control group, the animals that received FA exhibited less distinct weight loss, less colonic histopathological damage, and improved organ indices. In jejunal ex vivo biopsies pro-inflammatory cytokines including TNF-α, interleukin (IL) -6 or IL-1β as well as markers of oxidative stress such as malondialdehyde (MDA) were down-regulated, while concentrations of anti-oxidant enzymes such as superoxide dismutase (SOD), glutathione (GSH), and catalase were higher if compared to mock control mice. Furthermore, the expression of intestinal tight junction proteins was upregulated upon FA pretreatment, indicating improved intestinal barrier integrity. The results also demonstrated that FA substitution successfully prevented gut microbial dysbiosis known to contribute to perpetuating intestinal inflammation. Hence, if given in a prophylactic regimen in mice FA application did not only alleviate LPS-induced intestinal inflammation, but also improved gut epithelial barrier integrity and preserved the balanced intestinal microbiome composition [22].

Ekhtiar and colleagues investigated the effect of FA on the anti-oxidant nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO1) pathway in rats with acetic acid-induced colitis [23]. Following intrarectal acetic acid application, the animals were fed 20, 40, or 60 mg FA per kg body weight daily for five consecutive days or received dexamethasone as a treatment control. In both groups, macroscopic and histopathological lesions decreased in a concentration-dependent manner [23] that were accompanied by upregulated colonic mRNA expression of anti-oxidant parameters such as Nrf2, HO1, and NAD(P)H quinone dehydrogenase. The secretion of pro-inflammatory cytokines such as TNF-α and IL-1β, however, were attenuated in FA-fed rats if compared to mock diseased animals. Hence, therapeutic application of FA in experimental ulcerative colitis exerted its anti-inflammatory effects via the Nrf2/HO1 pathway [23].

In a similarly designed study, Ghasemi-Dehnoo et al. also addressed the effectiveness of FA in comparison to dexamethasone [24]. One hour after colitis induction with acetic acid intrarectally, rats received 60 mg FA per kg body weight perorally and displayed a significantly increased total antioxidant capacity (TAC), alongside with less distinct macroscopic signs of inflammation and histopathological damage. The authors further found that high-dose FA administration down-regulated the colonic expression of apoptotic genes and of inflammation-associated nuclear factor κB (NFκB), Toll-like-receptor 4 (TLR-4), and inducible NO synthetase (iNOS) and resulted in attenuated colonic secretion of oxidative stress-inducing MDA and nitric oxide (NO). Surprisingly, the anti-inflammatory effects of oral FA application were even superior compared to dexamethasone used as positive control. In summary, these results demonstrate that FA exerts anti-apoptotic, anti-inflammatory, and anti-oxidant effects in experimental ulcerative colitis by inhibition of the LPS-TLR-4-NFκB and NFκB-iNOS-NO signaling pathways [24].

Han et al. investigated the effects of different polyphenolic compounds including FA on innate immune responses exerted by macrophages and neutrophils [25]. Therefore, neutrophil knock-out mice were perorally treated with FA starting three days prior colitis induction with 3% dextran sulfate sodium (DSS). In the FA challenged mice, markedly attenuated intestinal inflammation was accompanied by reduced formation of neutrophil extracellular traps (NETs). Notably, the anti-inflammatory effect of FA was independent of macrophages, whereas other phenolic acids such as chlorogenic acid were shown to attenuate M1 macrophage polarization [25].

Another in vivo study examined the effect of dietary FA (100 mg kg⁻¹ body weight) on the intestinal homeostasis, function, and microbiota composition of Tianfu broiler chickens suffering from LPS-induced gut inflammation [26]. The authors found that FA application could attenuate the LPS-induced impairment of gut epithelial barrier function and hence, counteract the “leaky gut” as indicated by elevated expression of tight junction proteins such as claudin and zona occludens-1 (ZO-1) if compared to mock control animals, whereas serum concentrations of diamine oxidase (DAO) and D-lactate acid were lower in the former versus the latter indicative for less distinct intestinal permeability. FA-treated animals also exhibited elevated serum immunoglobulin A levels and enhanced anti-oxidant properties as indicated by higher total anti-oxidant capacity, GSH, and SOD levels if compared to mock counterparts. The authors further found that FA rectified the composition of the gut microbiota towards a rather healthier state given increased abundances of Firmicutes and Euryarcheota, whereas Bacteroidota, Desulfobacterota, and Actinobacteriota were decreased in fecal samples [26]. Hence, FA application improved gut epithelial barrier function, exerted anti-inflammatory including anti-oxidant effects, and reversed an inflammation-induced gut dysbiosis.

In 2022, Yu et al. addressed the impact of FA on the Nod-like-receptor protein 3 (NLRP3) inflammasome playing a crucial role in the immunopathogenesis of ulcerative colitis [27]. After colitis induction by intrarectal application of 2,4,6-trinitrobenzene sulfonic acid (TNBS), rats were challenged with FA at different concentrations (i.e., 10, 20, and 250 mg kg⁻¹ body weight per day). FA treatment could alleviate macroscopic and microscopic signs of ulcerative colitis, decrease colonic levels of pro-inflammatory cytokines such as IL-1β, IL-6, and IL-12 in a concentration-dependent manner, and furthermore, down-regulate colonic expression of NLRP3 and its upstream signaling protein thioredoxin-interacting protein (TXNIP). The authors also observed a reduction in the apoptotic markers caspase 1/3 in the FA treatment groups and in support, potent anti-inflammatory and anti-apoptotic effects in vitro when applying the phenolic compound to human intestinal microvascular endothelial cells that had been stimulated with TNF-α. These results underscore that FA treatment attenuates experimental ulcerative colitis by inhibition of the TXNIP/NLRP3 signaling pathway [27].

Cheng et al. tested whether distinct food-derived electrophilic compounds including FA could alleviate DSS-induced colitis [28]. Compared to the placebo control group, colitis mice that were fed FA (20 mg kg⁻¹ body weight) gained body weight, displayed longer colonic lengths, and improved disease activity index (DAI) scores indicative for less distinct macroscopic intestinal inflammation, and reduced signs of histopathological gut mucosal damage. Furthermore, the authors reported elevated total anti-oxidant capacity and Nrf2 expression levels in colonic ex vivo biopsies derived from the verum group suggestive of enhanced anti-oxidative effects of FA, while IL-6 concentration were lower if compared to placebo counterparts [28].

Hwang et al. investigated the anti-oxidant effects of FA in more detail applying both in vitro and in vivo models [29]. Therefore, mice were fed a high-fat diet with or without FA supplementation for 8 weeks. The colonic tissues of the mice that received the FA supplement displayed markedly less lymphocyte infiltration and epithelial disruption. In polarized Caco-2 and T84 cells that had been stimulated with a pro-inflammatory cytokine cocktail, FA concentrations exceeding 50 pM could reduce NO secretion, whereas cell permeability was diminished at all applied concentrations. In addition, IL-6, IL-8, binding-immunoglobulin protein (BiP) and X-box binding protein 1 (XBP1) levels decreased in a concentration-independent manner following FA application. Collectively, the data provide evidence that FA can attenuate pro-inflammatory processes by alleviating endoplasmatic reticulum (ER) stress via the IRE1α/XBP1/PERK pathway [29].

In their study, Sadar and coworkers investigated the anti-inflammatory, anti-oxidative, and anti-apoptotic effects of oral FA in experimental ulcerative colitis [30]. Following colitis induction with TNBS, rats were perorally challenged with 10, 20, or 40 mg of FA per kg body weight daily for two weeks. The authors were able to show that particularly the two highest FA concentrations could ameliorate clinical signs including macroscopic as well as microscopic histopathological features of colitis [30]. Furthermore, colonic expression of pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, NO, and cyclooxygenase-2 (COX-2) were down-regulated, while expression of the anti-inflammatory cytokine IL-10 was enhanced upon FA treatment. Furthermore, anti-oxidative enzymes such as SOD and GHS were also elevated, while the oxidative stress response marker MDA was decreased. Flow cytometry analysis further revealed reduced apoptotic cell responses in the verum group. Hence, these results indicate that FA treatment ameliorates experimental colitis by combinations of anti-inflammatory including anti-oxidant and anti-apoptotic modes of action [30].

3.2. Ferulic acid derivatives

Five included papers addressed the influence of FA derivatives on intestinal inflammation, particularly ulcerative colitis. Very recently, the group of Hu and coworkers published a study investigating the mechanisms by which FA and its derivative N-feruloylserotonin (NFS) alter the gut microbiome, serum metabolome, and transcriptional network in murine models of LPS-induced gut inflammation [31]. The authors demonstrated that FA and NFS dampened histopathological damage to the inflamed colon, reduced pro-inflammatory mediators such as IL-1β and iNOS, and increased the abundance of CD206 and arginase-1 constituting markers of anti-inflammatory M2 macrophages. Furthermore, application of FA and NFS could inhibit the necroptosis-related Rip1/Rip3/MLKL pathway [31]. In addition, both phenolic compounds had beneficial effects on the gut microbiome composition as indicated by increased diversity indices, elevated abundances of potentially health-beneficial bacteria such as Bacteroidaceae, Prevotellaceae, and Bifidobacteriaceae, whereas rather pro-inflammatory commensal bacterial taxa such as Gammaproteobacteria, Enterobacterales or Escherichia shigella belonging to the Proteobacteria were decreased. Overall, NFS was found to result in even more pronounced (i.e., inflammation-dampening) effects compared to FA [31].

Kim and coworkers synthesized new FA derivatives by conjugating the polyphenol with (±)-octopamine to produce N-(E)-feruloyloctopamine (C1) and 4-O-(E)-feruloyl-N-(E)-feruloyloctopamine (C1a) [32]. Both molecules were applied to colitis models in vivo and in vitro by using sulfasalazine treatment as controls. The results revealed that C1a was considerably more effective than sulfasalazine and C1 given less pronounced histopathological damage and improved spleen indices as well as DAI scores in murine DSS-induced colitis models following application of the former versus the latter. C1a was found to exert most pronounced anti-inflammatory activities given down-regulation of colonic mRNA expression of myeloperoxidase (MPO), C-reactive protein (CRP), IgA, TNF-α, IL-1β, IL-6, monocyte-chemoattractant protein 1 (MCP-1) and COX-2 [32]. Conversely, expression of the tight junction proteins occludin and ZO-1 was found to be significantly higher in the large intestines of C1a versus mock treated mice which is consistent with the finding, that the epithelial barrier was less distinctly infiltrated by pro-inflammatory immune cells. In in vitro experiments, Caco-2 cells were stimulated with a pro-inflammatory cytokine cocktail and challenged with respective derivatives. The obtained cell culture results were consistent with those derived from the in vivo experiments, demonstrating the down-regulation of pro-inflammatory markers and attenuated epithelial permeability. Again, C1a exhibited the most pronounced “beneficial” (i.e., disease-alleviating) changes across all examined parameters as opposed to C1 [32].

Katayama et al. tested whether FA rutinoside (FAR) could attenuate experimental colitis [33]. After screening 17 phytochemicals for their ability to induce immune tolerance by enhancing transforming growth factor β1 (TGF-β1) secretion using a dendritic cell-based assay, the authors found that FA and its glycosides, especially FAR, induced the highest levels of TGF-β1 [33]. In order to test FA and FAR for their anti-colitogenic effects in vivo, mice where perorally challenged with respective compounds prior colitis induction by DSS. Results revealed that both compounds attenuated body weight loss, colonic shortening, clinical scores, and histopathological changes in the colonic mucosa. Interestingly, FAR was proven to result in better outcomes than FA and furthermore, to increase the number of regulatory T cells and down-regulate the expression of pro-inflammatory cytokines such as TNF-α and IL-17 in the inflamed colon [33].

In earlier work from 2008, Islam et al. tested γ-oryzanol (γ-ORZ), constituting a phytosteryl-ferulate that is discussed as potential precursor of FA in vivo, for its anti-inflammatory efficacies in experimental colitis [34]. Following colitis induction by DSS, mice receiving γ-ORZ exhibited a gain of body weight and lengthening of the colon as well as improved DAI indices and histopathological scores, whereas MPO activity and the mRNA expression levels of pro-inflammatory cytokines and COX-2 in the colon decreased. The authors also investigated cycloartenyl-ferulate (CAF), a phytosteryl-ferulate contained in γ-ORZ, and pure FA. Even though neither CAF nor FA were as potent as γ-ORZ, CAF and FA could alleviate colitis signs such as body weight, colon shortening, and clinical scores, reduce MPO activity, and increase the anti-oxidant capacity in diseased mice as opposed to mock treatment [34].

In an older work, Dong et al. investigated the colitis-ameliorating effects of sodium ferulate [35]. Colitis was induced in rats by intrarectal administration of 8% acetic acid. Diseased rats received sodium ferulate at doses of 200, 400, or 800 mg kg⁻¹, 5-aminosalicylic acid or placebo as positive or negative controls, respectively. Results revealed that histopathological damages were alleviated, particularly in the high-dose sodium ferulate group, whereas anti-oxidant SOD concentrations increased in the colon. Furthermore, intestinal expression of inflammatory molecules such as MPO, MDA, iNOS, NO, NFκB, prostaglandin E₂, COX-2, and thromboxane B₂ were significantly reduced, surpassing the efficiency of 5-aminosalicylic acid as conventional treatment option [35].

3.3. Ferulic acid as a major component of synthesized drug delivery nanoparticles

This review includes seven studies investigating the synthesis of FA-containing nanoparticles for precise drug delivery and biodegradability and their colitis-alleviating properties. The summary of the results focusses on the colitis-related aspects of these studies, rather than the synthesis and characterization of the nanoparticles themselves.

The first report on synthetically produced FA-derived nanoparticles as new strategy for colitis treatment was published in 2023 by Zhao and colleagues [36]. The FA-derived lignin nanoparticles (FALNPs) were able to bypass the gastric acid environment and could hence directly target the intestinal tissues. Following colitis induction by oral DSS application, mice were challenged with 30 or 50 mg FALNPs per kg body weight perorally for 5 days. The treatment alleviated colitis symptoms and reversed both macroscopic and microscopic inflammatory changes to a nearly healthy state in a dose-dependent manner. Significant reduction of colonic ROS, TNF-α, IL-1β, IL-6, and interferon-gamma (IFN-γ) concentrations were observed, whereas anti-inflammatory signaling molecules such as TGF-β and IL-10 increased, as did the tight junction proteins ZO-1 and occludin in colonic biopsies. Treatment with the FALNPs was also accompanied by a shifting of the dysbiotic gut microbiota composition towards a more diverse (i.e., “healthier”) state characterized by increased fecal abundances of beneficial Lactobacillaceae, whereas the pro-inflammatory Enterobacteriaceae overgrowing the inflamed intestines were decreased. These results viewed in summary indicate that lignin-derived nanoparticles containing FA were not only potent carriers for direct drug delivery in the intestinal tract but could also alleviate acute colitis due to potent anti-inflammatory including anti-oxidant, epithelial barrier-tightening, and gut microbiota-modifying modes of actions [36].

The following six studies were all published very recently in 2025. Xue and coauthors tested a folate-functionalized ROS-scavenging covalent organic framework for the targeted oral FA delivery in animal models of ulcerative colitis [37]. In their in vivo experiments, mice suffering from DSS colitis received either pure FA or a ROS-sensitive covalent organic framework from γ-cyclodextrin functionalized with folic acid (COF-FOL) that had been loaded with FA (FA@COF-FOL) perorally (400 mg kg⁻¹ body weight each) from days 3 to 7 post colitis induction. The authors could show that FA@COF-FOL exhibited slow and precise FA delivery, high drug-loading capacity, and extensive biocompatibility. Treatment with FA@COF-FOL alleviated clinical colitis symptoms, which also held true for macroscopic changes such as colon shortening and histopathological damage of the colonic mucosa. The concentrations of pro-inflammatory cytokines, namely TNF-α and IL-6, were lower in the colon in the treatment cohort if compared to diseased placebo controls, whereas conversely, the concentrations of the anti-inflammatory cytokine IL-10 were higher. In vitro data further revealed potent reactive oxygen species (ROS) scavenging properties of the FA delivery system. Of note, FA@COF-FOL outperformed pure FA and hence, opened novel avenues for even more effective targeted treatment of murine ulcerative colitis [37].

Badihi et al. presented their findings on the synthesis and colitis-ameliorating properties of quinic acid (QA) and FA containing Chitosan-tripolyphosphate/Eudragit® S100 nanoparticles (CS-TPP/EU100 NPs) [38]. Following colitis induction by rectal instillation of acetic acid, rats were perorally treated with the following regimens for 7 days: either pure FA or pure QA alone; FA plus QA, CS-TPP/EU100 NPs alone; FA or QA plus CS-TPP/EU100 NPs; and the triple combination (FA plus QA plus CS-TPP/EU100 NPs). As negative and positive controls, rats received placebo or mesalazine, respectively. The authors showed that in all verum groups, CS-TPP/EU100 NPs, QA, and FA (either alone or in combination) reduced clinical scores including colitis-associated weight loss and colon shortening, and histopathological damage of the colonic mucosa. The large intestinal expression levels of pro-inflammatory cytokines like TNF-α, IL-1β, IL-6, IL-8, and IL-36α were downregulated, while the anti-inflammatory cytokines such as TGF-β, IL-17A, and IL-23 were upregulated. The authors suggested that the decrease in pro-inflammatory cytokines was mainly due to the reduction in colonic Th17 cells. Of note, FA- and QA-loaded CS-TPP/EU100 NPs exhibited the best outcomes in most parameters and alike pure FA, even exceeded the colitis-alleviating effects of mesalazine [38].

In their research on alternative therapeutic approaches for ulcerative colitis, Xiao et al. synthesized pectin-loaded FA particles (PC-FA) and tested the compound in murine DSS-induced colitis [39]. The effects of 50 mg kg⁻¹ and 100 mg kg⁻¹ of PC-FA were compared with those of FA alone at different concentrations, pure pectin, or the potent ROS scavenger N-acetylcystein. The results showed that PC-FA was superior in its ability to diminish macroscopic and microscopic disease parameters and alleviated clinical symptoms in diseased mice if compared to FA. The authors further demonstrated that PC-FA could effectively inhibit the pro-inflammatory cGAS–STING pathway by directly suppressing STING phosphorylation and by scavenging ROS, in turn reducing DNA damage and the associated expression of γH2AX, which would otherwise activate the cGAS–STING pathway. Consistent with these results, the levels of downstream inflammatory and oxidative signals, including TNF-α, IL-1β, NO, and GSH were considerably reduced in both models. Notably, PC-FA even outperformed the other treatment regimens, while pure FA alone already demonstrated considerable anti-colitogenic effects [39].

In their very recent work, Guo et al. tested the effects of distinct FA-containing nanoparticles in murine colitis [40]. Therefore, the authors constructed a Zein/FA-pectin/chitosan (Zein/FA-PC/CS) nanocomplex and administered them perorally to mice (100 and 200 mg kg⁻¹ body weight daily) following DSS colitis induction. Nanoparticle treatment alleviated acute colitis as indicated by improved DAI scores, reduced weight loss and colonic shortening, and dampened histopathological damages of the colonic mucosa. Furthermore, pro-inflammatory and oxidative stress mediators such as TNF-α, IL-1β, NO, and MDA decreased in the large intestines of treated colitis mice, while the expression of anti-oxidative enzymes like SOD and GSH was upregulated. The improved outcome was accompanied by increased diversity of the commensal gut microbiome as determined by the Operational Taxonomic Units (OTUs), the Simpson-Index, the Goods-coverage index, PCoA analysis, and the relative abundance of distinct commensal species at the phylum and family levels [40]. The group receiving the highest dose of the synthesized nanocomplexes exhibited the best colitis outcome although it was not superior to the sulfasalazine treatment control [40].

Zou et al. tested a newly developed nanoparticle complex, consisting of shikonin and zinc (S-Z), chitosan (CS), hyaluronic acid (HA) and FA (S-Z@ChF) for their anti-colitogenic properties upon oral application [41]. Therefore, mice were challenged with DSS to induce colitis and subjected to the following treatment regimens: either shikonin or zinc in their pure forms, S-Z@CS, S-Z@CS/HA or S-Z@ChF. S-Z@ChF was found to improve colitis-related symptoms and histopathological changes. Furthermore, S-Z@ChF attenuated oxidative stress given decreased ROS concentrations, whilst regulating the NFκB-, JAK-STAT-, TNF-, and TGF-β-pathways and macrophage activation to basal levels as indicated by concentrations of pro-inflammatory cytokines, MPO, and pyruvate kinase-2 (known to be associated with the polarization of pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages) that did not differ from those detected in naive mice. Application of S-Z@ChF could restore the intestinal epithelial barrier given scavenged H₂S, which affects the integrity of the mucous layer, and additionally upregulate the colonic expression levels of the tight junction proteins ZO-1 and occludin. The nanoparticle treatment was additionally accompanied by changes in the bacterial gut microbiota composition given that the abundance of health-beneficial bacteria such as Lactobacillaceae and Bacillaceae increased, while the abundance of potentially pro-inflammatory bacteria including Desulfovibrionaceae and Rikenellaceae decreased. Overall, the nanocomplex was superior to encapsulated FA regarding the anti-colitogenic outcome upon oral application. The authors concluded that the nanoparticle complex S-Z@ChF proved effective in alleviating acute ulcerative colitis due to its potent anti-inflammatory, anti-oxidant, and microbiota-modulating properties [41].

Zhang et al. incorporated trans-FA known for its potent anti-oxidant capacities into newly developed nanoparticles that also contained silk sericin exerting proliferative and intestinal barrier-reinforcing characteristics, and inulin, which can be converted into short-chain fatty acids (SCFA). These nanoparticles were then loaded on poly-L-lysine and poly-glutamic acid-coated Bifidobacterium longum [42]. In murine DSS colitis, oral application of the synthesized nanoparticles led to a reduction in colitis symptoms and macroscopic as well as microscopic pathological sequelae. Large intestinal inflammation was markedly dampened by the nanoparticle complex as indicated by downregulated colonic expression of TNF-α, IL-6, and MPO, whereas the large intestinal epithelial barrier became less permeable resulting in lowered serum levels of LPS, diamine oxidase, and D-lactate acid [42]. Improved clinical outcome upon nanoparticle application was accompanied by changes in gut microbiota composition characterized by increased diversity and abundance of probiotic SCFA-producing bacteria such as Lactobacillaceae and B. longum, whereas overgrowth with potentially pro-inflammatory taxa such as Enterobacteriaceae and Desulfovibrionaceae were dampened in the treatment groups [42].

3.4. Cell toxicity assessment

Nine of the included studies tested for cytotoxic effects of FA, its derivatives or synthesized nanoparticles [27, 29, 32, 33, 36, 37, 39–41]. Hwang et al. found that cell viability was reduced by pure FA in concentrations above 250 µg in vivo and above 500 µg in vitro [29]. Biotoxicity examinations of the remaining studies revealed no signs of reduced cell viability or organ injury caused by any of the compounds.

4. Discussion

4.1. Main findings of the research

To date a multitude of in vitro as well as in vivo studies including very recently published ones have underscored the health-beneficial and disease-alleviating effects of FA in a variety of morbidities including inflammatory diseases of the gastrointestinal tract. The reviewed scientific evidences demonstrate that FA, its derivatives, and FA-containing nanoparticles were able to i.) alleviate ulcerative colitis as indicated by less pronounced macroscopic and microscopic including clinical signs and histomorphological changes, respectively; ii.) dampen pro-inflammatory and enhance anti-inflammatory including anti-oxidant immune responses; iii.) tighten the gut epithelial barrier thereby preventing bacterial translocation and endotoxin spread from the intestinal tract to extra-intestinal including systemic compartments; and iv.) reshape the gut microbiota composition from a dysbiotic state (with overgrowing pro-inflammatory bacteria) to a well-balanced “beneficial” state characterized by high species diversity and dominance of probiotic bacterial taxa. Remarkably in some instances, the observed anti-colitogenic effects were reported to be even more pronounced if compared to those exerted by positive treatment control compounds.

4.2. Potential mechanisms underlying FA's anti-colitogenic effects

Regarding molecular mechanisms underlying the anti-inflammatory effects of FA, it could be demonstrated that FA interfered with inflammatory signaling such as NFκB, TXNIP/NLRP3, and cGAS/STING pathways, for instance [24, 27, 39]. The anti-oxidant properties of FA were studied and confirmed in 13 out of the 21 experimental papers, primarily through demonstrating its ROS-scavenging and anti-oxidant enzymes-increasing effects [22–24, 26, 28, 30, 34–36, 39–42]. Two studies reported that FA enhanced the anti-oxidant Nrf2 pathway [23, 28], whereas also inhibitory effects on ER stress responses were shown [29]. When assessing the effects of FA on innate immune cell responses in colitis, one report supported the hypothesis that FA blocks the NETs of neutrophilic granulocytes [25]. Whereas one study showed that the anti-colitogenic effect of FA was independent of macrophages [25], others reported that FA and derivatives promoted polarization of anti-inflammatory M2 macrophages, and decreased pro-inflammatory M1 macrophages [31, 41]. Studies unraveling the interaction of FA with adaptive immune cells showed that FA promoted intestinal Treg proliferation [33, 38], whereas pro-inflammatory T helper 17 (Th17) cell numbers were shown to be dampened [33, 38], modifying the adaptive immune cell balance towards a dominance of anti-inflammatory over pro-inflammatory responses. Hence, FA interfered with innate as well as adaptive immune cells involved in the immunopathogenesis of colitis development which further explained the broad anti-inflammatory and disease-alleviating potency of the phenolic compound.

4.3. Microscopic and macroscopic including clinical sequelae of FA application

In all included studies addressing histopathological damage in ulcerative colitis models FA and FA-containing derivatives and nanoparticles were shown to improve the microscopic outcome of disease following administration. In support, FA and its containing compounds alleviated clinical signs of colitis in vivo in ten studies [25, 28, 32, 33, 37–42]. Five reports observed increased expression of tight junction proteins such as occludin or ZO-1 following FA administration [22, 26, 32, 36, 41] indicative for a tightened epithelial barrier and hence, improvement of the “leaky gut” syndrome seen in ulcerative colitis. In consequence, translocation of viable pro-inflammatory gut bacteria and cell wall constituents from the intestinal tract to extra-intestinal and even systemic compartments further perpetuating the inflammatory scenario could be prevented.

Several studies compared the impact of FA or FA-derivatives or nanoparticles with that of the current standard colitis medications such as dexamethasone, sulfasalazine, 5-aminosalicylic acid or mesalazine [23, 24, 30, 32, 35, 36, 38–40] many of which providing evidence for superior anti-colitogenic effects of the former versus the latter [24, 32, 35, 38]. Seven of the reviewed studies addressed gut microbiota changes during FA treatment of experimental colitis and found that the application of the compound was accompanied by reshaped gut microbial signatures from a dysbiotic state with pro-inflammatory bacteria overgrowing the inflamed intestinal lumen to a well-balanced “beneficial” state characterized by high species diversity and predominance of probiotic including SCFA-producing bacteria [22, 26, 31, 36, 40–42].

4.4. Novel FA formulations for targeted drug delivery

Very recently, several papers have been published on the synthesis of new FA-containing nanoparticles for precise and effective drug delivery in ulcerative colitis models [36–42]. This growing body of research in recent years demonstrates that the FA-based therapeutic approach is gaining recognition and support. The beneficial properties of FA are being combined with various highly biocompatible and biodegradable compounds, such as pectin and chitosan, to enable targeted drug delivery and prevent FA from dissociation before the colon is reached and hence resulting in more pronounced anti-colitogenic efficacy.

4.5. Results of not included but related studies

Additional studies were found that did not match the predefined selection criteria but reported results that are worth to discuss. In a recent work published in 2025, for instance, Cai et al. addressed the correlation between FA and ghrelin (constituting a peptide involved in regulatory processes within the microbiota-gut-brain axis) in traumatic brain injuries and subsequent gastrointestinal morbidity characterized by hypomotility, intestinal barrier impairment, and inflammatory cell responses such as pyroptosis [43]. Induction of traumatic brain injury in mice by controlled cortical impact resulted in decreased ghrelin levels, gastrointestinal morbidity and a dysbiotic gut microbiota characterized by a predominance of pro-inflammatory bacteria. Application of FA, however, could reverse the traumatic brain injury-induced sequelae and particularly restore the ghrelin concentrations thereby inhibiting the TLR4/NFκB/NLRP3 signaling pathway and pyroptosis and in consequence, protecting the gastrointestinal tissue from inflammation and intestinal dysbiosis [43].

The group of Tian et al. investigated on the anti-obesity effects of FA in mice on a high-fat diet and confirmed that FA improved the integrity of the intestinal barrier by upregulating tight junction proteins. FA was also capable of increasing the occurrence of SCFA-producing bacteria in the colon, leading to an improved microbiological balance [44]. These results could be confirmed by Fu and coworkers who showed that FA could prevent mice from non-alcoholic fatty liver disease induced by high-fat diet due to preserved epithelial barrier function and balanced gut microbiota composition [45].

In their in vitro experiments on FA metabolites, Serreli et al. provided evidence that different FA derivatives such as dihydro-FA and iso-FA conjugated with sulfate or glucuronide can exert even more pronounced inhibitory effects on LPS-induced pro-inflammatory including oxidative response mechanisms [46]. Collectively, these results further underscore the potential of FA and derivatives as target molecules for the treatment or even prevention of inflammatory morbidities also beyond the gastrointestinal tract.

4.6. Limitations

This review is subject to certain limitations. The literature research was based on the “PubMed” database only, which may affect the completeness of the included literature. Since described search terms were not extended by further varying search terms or other search strategies, studies might have been overlooked. Furthermore, the inclusion and exclusion criteria submitted were rather restrictive. Studies that investigated certain pathomolecular aspects influencing the pathogenesis of ulcerative colitis, but did not specifically induce colitis, were not included, for instance, and may result in an incomplete overview of detailed data. As the etiology and pathogenesis of ulcerative colitis are not yet fully understood, it is also possible that blind spots have been overlooked in current research. Finally, the included studies exhibit a broad variety of study designs. The experimental setups including methods of colitis induction and even the concentrations of the same chemical compound used to induce colitis differed between studies. This also held true for different concentrations of a variety of FA formulations making direct comparisons of the results obtained from the included publications rather difficult. Despite such methodological limitations, however, the overall evidence for potent anti-colitogenic effects of FA and derivatives appears convincing.

4.7. Conclusion and outlook

Given the increasing incidence of IBD including ulcerative colitis and the multiple side effects of commonly used therapies, the necessity of novel alternative and/or adjunct therapeutic (and prophylactic) approaches is inevitable. FA represents a promising candidate with potent anti-colitogenic effects. However, data from humans in clinical studies are virtually missing to date. Hence, further research into FA treatment - particularly involving randomized controlled clinical trials - is essential to establish FA as an alternative or adjunct treatment option for ulcerative colitis patients.

List of abbreviations:

BiP

binding-immunoglobulin protein

CAF

cycloartenyl-ferulate

COF-FOL

Covalent organic framework functionalized with folic acid

COX-2

cyclooxygenase-2

CRP

C-reactive protein

CS

Chitosan

CS-TPP/EU100 NP

Chitosan-tripolyphosphate/Eudragit® S100 nanoparticle

DAI

disease activity index

DAO

diamine oxidase

DSS

dextran sulfate sodium

ER

endoplasmic reticulum

FA

ferulic acid

FA@COF-FOL

Ferulic acid-loaded COF-FOL

FALNPs

Ferulic acid-derived lignin nanoparticles

FAR

ferulic acid rutinoside

GSH

glutathione

HA

Hyaluronic acid

HO1

heme oxygenase 1

IBD

inflammatory bowel diseases

IFN-γ

Interferon gamma

IL

interleukin

iNOS

inducible nitric oxide synthetase

JAK

janus kinase

LPS

lipopolysaccharides

MCP-1

monocyte-chemoattractant protein 1

MDA

malondialdehyde

MLKL

Mixed lineage kinase domain-like protein

MPO

myeloperoxidase

NETs

neutrophil extracellular traps

NFκB

nuclear factor κB

NFS

N-feruloylserotonin

NLRP3

Nod-like-receptor protein 3

NO

nitric oxide

Nrf2

nuclear factor erythroid 2-related factor 2

ORZ

oryzanol

OTU

Operational Taxonomic Unit

PC-FA

pectin-loaded ferulic acid

PERK

Protein kinase RNA-like endoplasmic reticulum kinase

QA

quinic acid

Rip1/Rip3

Receptor-interacting protein kinases 1 and 3

ROS

reactive oxygen species

S-Z

Shikonin and zinc complex

S-Z@ChF

Shikonin-zinc complex with chitosan, hyaluronic acid and ferulic acid

SCFA

short-chain fatty acid

SOD

superoxide dismutase

STING

Stimulator of interferon genes

TAC

total antioxidant capacity

TGFβ1

transforming growth factor β1

Th17

T helper 17 cells

TLR

Toll-like-receptor

TNBS

trinitrobenzene sulfonic acid

TNF-α

tumor necrosis factor alpha

TXNIP

thioredoxin-interacting protein

XBP1

X-box binding protein 1

Zein/FA-PC/CS

Zein/ferulic acid-pectin/chitosan

ZO-1

zona occludens 1