Ellagitannins and Their Derivatives: A Review on the Metabolization, Absorption, and Some Benefits Related to Intestinal Health

Abstract

Ellagitannins are bioactive phenolic acids found in various fruits, plants, and beverages such as wine and spirits. This review aims to discuss the metabolism, absorption, and some health benefits related to the intestinal activity of these molecules, as well as some supplements developed from them. Ellagitannins are first biodegraded to ellagic acid and then to urolithins, which are more easily absorbed. This process is mediated by specific enzymes and intestinal microbiota. Not all individuals can metabolize ellagitannins into urolithins due to differences in the composition of the intestinal microbiota, resulting in three phenotypes: metabotypes A, B, and 0. In recent decades, ellagitannins and their derivatives (ellagic acid and urolithins) have gained significant attention for their potential benefits against various digestive diseases, including irritable bowel syndrome, peptic ulcers, gastritis, colon cancer, esophageal cancer, and pancreatic cancer. As a result, nutraceutical supplements have been developed to treat these conditions, representing significant and promising applications of these compounds in digestive health.

1. Introduction

The digestive system plays a fundamental role in nutrition and the overall well-being of the human body. However, the global burden of mortality from digestive diseases has increased over the past three decades, making them one of the most common reasons for medical consultations [1]. These diseases encompass a wide range of conditions, are very common, and have a high incidence in the population [2]. They can be caused by various factors, ranging from genetics to lifestyle and diet [3]. Therefore, it is essential to diagnose and treat them accurately to improve patients’ quality of life, both in terms of health and economic impact [4,5]. This growing impact has sparked greater interest in their study, particularly in the search for bioactive compounds such as ellagitannins, which represent a promising alternative to conventional treatments due to their low toxicity and minimal side effects [6].

Ellagitannins are bioactive phenolic compounds classified as hydrolyzable tannins [7]. They are currently considered phenolic acids belonging to the hydroxybenzoic acid derivatives [8]. They are characterized by their low molecular weight, approximately between 300 and 3000 g/mol, and the various structural couplings they can present [9,10,11]. Ellagitannins are found in a wide variety of plants, fruits, and some everyday consumer products. These dietary compounds are not essential for metabolism and therefore do not provide nutritional value; however, their intake is of great importance, as those who consume them show a lower incidence of chronic diseases such as cardiovascular conditions and certain types of cancer [12]. Various studies have described their antioxidant, antifungal, antibacterial, antitumor, and anti-inflammatory properties [13,14].

The chemical structure and degradation mechanisms of these compounds have been extensively studied, as their molecular bonds responsible for their stability can be hydrolyzed into subunits when exposed to acids, bases, and certain enzymes [15]. Ellagitannins are ingested through foods that go through the six stages of the digestive system: ingestion, propulsion, mechanical breakdown, chemical digestion, absorption, and excretion [16]. These bioactives undergo initial structural damage upon contact with digestive enzymes that break some of their bonds; nevertheless, research has shown that ellagitannins reach the colon almost intact due to their structural complexity. There, they are metabolized by the gut microbiota to form urolithins, which are better absorbed and can exert greater beneficial effects on health [17].

Therefore, this review aims to contextualize current knowledge about ellagitannins, focusing on their biotransformation into urolithins, the enzymes and microorganisms involved, and their mechanisms of action in the gastrointestinal tract. Special attention will be given to the evidence supporting their beneficial effects on intestinal disorders, highlighting their potential as natural therapeutic agents for gut health and the development of nutraceuticals.

2. Research Methodology

This review article is based on an exhaustive search of a total of 143 articles published between 2005 and 2025, covering topics from the basic and structural aspects of ellagitannins to specific and recent data on their effects on diseases. The literature search was conducted across several reputable scientific databases, including Elsevier, Wiley Online Library, MDPI, ResearchGate, Springer Nature, PubMed, and Taylor & Francis. The following keywords were used: “ellagitannins”, “ellagic acid”, “urolithins”, and “digestive diseases”.

Inclusion criteria encompassed peer-reviewed publications, original research articles, review articles, book chapters, and books published in English or Spanish that explored the relationship between ellagitannins and disorders of the digestive system. Only studies specifically addressing ellagitannins or their derivatives, and no other compounds, were considered.

Exclusion criteria included duplicate publications, non-peer-reviewed works, studies lacking direct relevance to digestive diseases, and studies of low methodological quality. Additionally, retracted or withdrawn studies were excluded (Figure 1).

3. Chemical Structure and Classification of Ellagitannins

There is a great structural diversity of ellagitannins (Table 1). To date, over 1000 different coupling configurations have been identified, contingent on the variation in the position, stereochemistry, and frequency of the hexahydroxydiphenic acid units, the degree of galloylation, and/or the anomeric stereochemistry of the sugar residues [18].

Ellagitannins can be classified as monomeric, dimeric, oligomeric, polymeric, or C-glycosidic, depending on the number of glucose molecules in the structure [19]. Ellagitannin monomers are composed of a glucose molecule linked to the residues of hexahydroxydiphenic acid, with the potential for gallic acid to be present. In contrast, dimers, oligomers, and polymers are formed through the polymerization of monomeric ellagitannins [20].

Table 1. Classification of ellagitannins.

Type of Ellagitannin	Name	Chemical Structure	Molecular Formula	Molecular Weight (g/mol)	Reference
Monomeric	Punicalagin		C48H28O30	1084.71	[21]
	Corilagin		C27H22018	634.5	[22]
	Geraniin		C41H28O27	952.6	[23]
	Casuarictin		C41H28O26	936.6	[24]
Dimeric	Sanguin H-6		C82H54O52	1871.27	[25,26]
	Coriariin A		C82H58O52	1875.3	[27]
	Cornusiin E		C82H58O52	1875.3	[28]
	Oenothein B		C68H48O44	1569.1	[29]
Oligomeric	Nupharin C		C82H58OH52	1875.307	[30]
	Lambertianin C		C123H80O78	2805.81	[31]
	Agrimoniin		C82H54O52	1871.3	[32]
	Hirtellin A		C82H58O52	1875.3	[33]
C-glycosidic	Castalagin		C41H26O26	934.63	[34,35]
	Vescalagin		C41H26O26	934.63	[36]
	Casuarinin		C41H28O26	936.6	[37]
	Grandinin		C46H34O30	1066.7	[38]

Table 1. Classification of ellagitannins.

Type of Ellagitannin	Name	Chemical Structure	Molecular Formula	Molecular Weight (g/mol)	Reference
Monomeric	Punicalagin		C48H28O30	1084.71	[21]
	Corilagin		C27H22018	634.5	[22]
	Geraniin		C41H28O27	952.6	[23]
	Casuarictin		C41H28O26	936.6	[24]
Dimeric	Sanguin H-6		C82H54O52	1871.27	[25,26]
	Coriariin A		C82H58O52	1875.3	[27]
	Cornusiin E		C82H58O52	1875.3	[28]
	Oenothein B		C68H48O44	1569.1	[29]
Oligomeric	Nupharin C		C82H58OH52	1875.307	[30]
	Lambertianin C		C123H80O78	2805.81	[31]
	Agrimoniin		C82H54O52	1871.3	[32]
	Hirtellin A		C82H58O52	1875.3	[33]
C-glycosidic	Castalagin		C41H26O26	934.63	[34,35]
	Vescalagin		C41H26O26	934.63	[36]
	Casuarinin		C41H28O26	936.6	[37]
	Grandinin		C46H34O30	1066.7	[38]

4. Sources of Ellagitannins

Ellagitannins and their derivatives, including glucosides, arabinosides, rhamnoses, acetylated esters, and free ellagic acid, are widely distributed in nature, as is the case in some fruits of the Rosaceae family, including raspberries, blackberries, strawberries, currants, and grapes [39].

In addition to the previously mentioned fruits, pomegranates, rambutans, and other fruits, as well as certain seeds such as pistachios, walnuts, cashews, pecans, and acorns, are also significant sources of ellagitannins [40]. Due to their chemical composition, ellagitannins are found in various plants, many of which are used for medicinal purposes in Asia. Agrimonia pilosa contains the ellagitannin agrimoniin. Similarly, the camellia (Camellia japonica) contains camelliatannin A, the dogwood (Cornus officinalis) contains cornusin A, the geranium (Geranium thunbergii) contains geraniin, the avens (Geum japonicum) contains gemin A, the sweetgum tree (Liquidambar formosana) contains casuarictin, and the mallotus (Mallotus japonicus) contains mallotusinic acid [41].

Other sources of ellagitannins are products, including tea and honey. Alcoholic beverages like red wine, cider, whiskey, and brandy also contain ellagitannins. The presence of ellagitannins is attributed to the processing of these products in wooden barrels, such as oak, which allows for the release of ellagitannins, particularly C-glucosides, including acutissimin A and B, epiacutissimin A and B, as well as mongolicain A. During the aging process, these compounds are released from the wood, enhancing certain organoleptic characteristics of these beverages [42,43].

5. Biosynthesis of Ellagitannins

The biosynthesis of these secondary metabolites in plants occurs in cytoplasmic vacuoles or the cell wall. Their production is closely related to biological functions such as defense against microorganisms (fungi, bacteria, and viruses) and herbivorous animals, as well as protection against ultraviolet rays from the sun, explaining why these molecules have high antioxidant capacity [44]. It has been reported that genetics, species, plant maturity, humidity, luminosity, pruning, foliation by herbivores, and seasonal changes have a profound impact on the qualitative and quantitative content of ellagitannins [45].

The proposed biosynthesis pathway of punicalagin is as follows (Figure 2): phosphoenolpyruvic acid (PEP) and D-erythrose-4-phosphate (E4P) produce 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) through the action of 3-deoxy-D-arabinoheptulosonate-7-phosphate synthase (DAHPS). The conversion of 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) to 3-dehydroquinate is facilitated by the action of 3-dehydroquinate synthase (DHQS). The bifunctional enzyme 3-dehydroquinate dehydratase/shikimate dehydrogenase (DHD/SDH) catalyzes the conversion of 3-dehydroquinate to 3-dehydroshikimic acid, which in turn produces shikimic acid and gallic acid. Under the action of UDP-glucose: gallate glucosyltransferase (UGT), the latter produces β-glucogallin, better known as 1-O-galloyl-β-D-glucopyranose. Β-glucogallin O-galloyltransferase then converts this into digalloylglucose. A series of reactions catalyzed by galloyltransferase (GT) produce pentagalloylglucose, wherein the galloyl groups are oxidatively coupled to form the hexahydroxydiphenoyl (HHDP) group. It is subsequently metabolized into punicalagin (monomeric ellagitannin) by the action of pentagalloylglucose oxygen oxidoreductase (POR) [46,47,48].

6. Degradation of Ellagitannins

Ellagitannins are molecules that, due to their structural composition, can be hydrolyzed into progressively simpler compounds. Until recently, the degradation mechanism of these molecules was not well understood. However, recent studies have identified several pathways that elucidate how these molecules degrade [50,51].

Ellagitannins can be hydrolyzed in vitro by promoting the hydrolysis of the ester bonds between the sugar core and the HHDP units, releasing hexahydroxydiphenic acid and glucose units. Because of this separation, spontaneous lactonization occurs, forming ellagic acid molecules (Figure 3) [52].

Figure 3. Diagram of punicalagin degradation by ellagitannase (EAH) action [53].

Figure 3. Diagram of punicalagin degradation by ellagitannase (EAH) action [53].

6.1. Acid Hydrolysis

The recovery and purification of bioactive phytochemicals from plant materials is typically carried out through various extraction methods. The isolation of ellagic acid is achieved by extracting a plant fraction rich in ellagitannins using different solvent mixtures. In addition to the previous step, a hydrolysis process of the ellagitannins is performed using concentrated acids, commonly HCl and H2SO4. The composition and purity of ellagic acid are monitored through high-performance liquid chromatography (HPLC) [54].

The optimization of ellagitannin acid hydrolysis was evaluated by subjecting ellagitannin samples to three HCl concentrations (1.2, 2, and 4 M) for varying durations (1, 2, 4, 6, and 20 h) at a temperature of 85 °C. To prepare the samples, 5, 8.3, or 16.6 mL of 37% HCl was added and diluted with 50 mL of methanol. The degradation of ellagitannins was assessed by detecting the increase in ellagic acid using HPLC [55].

6.2. Microbial Biodegradation

The hydrolysis of ellagitannins through microbial enzymes has been a topic of debate in the scientific community. It has been observed that microbial tannase is active on galloyl residues, as well as on hexahydroxydiphenoyl and other ellagitannin residues [56]. Other enzymes, such as phenol oxidase and decarboxylase, have also been associated with the degradation of gallotannins and ellagitannins. In other reports, crude enzymatic extracts obtained from the fermentation of ellagitannins have been observed to exhibit activities distinct from those of tannase and ellagitannase. These include polyphenol oxidase, glycosyl hydrolases, cellulase, xylanase, and β-glucosidase [57].

Recent studies have demonstrated a new activity, ellagitannin acyl hydrolase (EAH), where an enzyme can biodegrade ellagitannins by promoting the hydrolysis of ester bonds between the sugar core and HHDP units. This enzyme has been tested in solid-state fermentation against other enzymes, including cellulase, xylanase, polyphenol oxidase, tannase, β-glucosidase, and α-L-arabinofuranosidase. The enzyme with the highest activity value (U/L) at the moment of maximum ellagic acid accumulation was found to be ellagitannase, which confirms that this enzyme is directly associated with ellagitannin degradation [58].

6.3. Products of Degradation

6.3.1. Gallic Acid

Gallic acid is the main unit of polyphenols, also known as 3,4,5-trihydroxybenzoic acid. It is a phenolic acid found in various plant sources such as plants, fruits, and beverages like coffee, red wine, and green tea [59]. This compound is attributed to various pharmacological effects such as antioxidant, anti-inflammatory, anticancer, cardiovascular, neurodegenerative, and antidiabetic properties [60,61].

6.3.2. Ellagic Acid

Ellagic acid is a heterotetracyclic organic compound resulting from the dimerization of gallic acid through oxidative aromatic coupling with intramolecular lactonization between both carboxylic acid groups of the resulting barrel, with an approximate molecular weight of 338.2 g/mol [62]. Ellagic acid is a phenolic nutraceutical molecule that can be present in free form in some plant species, including plants, fruits, and vegetables. It can be found in these plant materials as a secondary metabolite or derived from the degradation of its precursors, the ellagitannins [63]. It is considered a thermally stable molecule (melting point of 350 °C) due to the four rings of the molecule representing lipophilic dominance and the four phenolic groups representing the hydrophilic area, which causes high insolubility in water. However, it is soluble in organic acids. Due to its phenolic nature, it tends to react by forming complexes with other molecules, such as proteins, alkaloids, and polysaccharides [64].

Among its biological functions, its antioxidant capacity is particularly noteworthy due to its ability to eliminate free radicals and promote the synthesis of antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT). Additionally, it exhibits antibacterial, antifungal, antiviral, hepatoprotective, and cardioprotective activities [65]. Furthermore, it displays anti-inflammatory properties by regulating the formation of proinflammatory cytokines (IL-6, IL-8, IL-12, TNF-α, etc.). Additionally, it exhibits chemopreventive, neuroprotective, antiviral, antidiabetic, gastroprotective, anti-hyperlipidemic, and antidepressant activities [66].

6.3.3. Urolithins

Urolithins (Uros) are a class of metabolites that originate from ellagitannins and ellagic acid. These metabolites possess a common benzopyran-6-one nucleus, and their number of hydroxyl groups is reduced as they are metabolized in decreasing order [67].

Only 13 urolithins and their conjugated metabolites (glucuronides, sulfates, among others) have been reported (Figure 4). Their presence has been identified in different human fluids and tissues (blood, feces, urine, breast, and colon) [68].

Due to the low bioavailability of these compounds, a significant portion of them reaches the colon, where they are metabolized by the intestinal microbiota [69].

7. Action of the Gut Microbiota in the Degradation of Ellagitannins

The gut microbiota comprises a consortium of microorganisms that live in symbiosis with humans and play a central role in food digestion and host metabolic regulation [70,71]. A significant proportion of ingested food remains undigested by host digestive enzymes, and the unabsorbed residues reach the colon, where many microorganisms with advanced metabolic machinery can facilitate the absorption process [72].

This is the case with ellagic acid, which exhibits extremely low bioavailability and is converted into urolithins by the action of the gut microbiota. Urolithins exert significant bioactivity through cleavage, decarboxylation, and dehydroxylation reactions of the lactone ring, starting with pentahydroxy-Uro (Uro-M5), followed by tetrahydroxy-Uros (Uro-D, Uro-E, and Uro-M6) and trihydroxy-Uros (Uro-C and Uro-M7), culminating in dihydroxy-Uros (Uro-A and isoUro-A) and monohydroxy-Uro (Uro-B), which is regularly detected when isoUro-A is also produced [73].

7.1. Bacteria Capable of Degrading Ellagitannins into Ellagic Acid and Urolithins

Recent studies have focused on identifying specific bacterial strains capable of degrading ellagitannins, such as punicalagin, to enhance the bioavailability of these beneficial compounds (Table 2).

In one study, thirty lactic acid bacteria were isolated from two food products: aged cheese and dry-cured fermented sausage. The bacteria’s ability to biotransform a pomegranate peel extract rich in punicalagin and a food supplement with a high punicalagin content was evaluated. Among the isolated strains, 27 were discarded, and three strains with the highest activity in the degradation of ellagitannins were selected for further analysis. Lactiplantibacillus plantarum 89, Lacticaseibacillus paracasei 116, and Enterococcus faecium 126 were identified. The ellagic acid content in the experimental units was significantly higher, with concentrations up to 25 and 18 times higher than those found in the pomegranate extract. This evidence demonstrates a correlation between lactic acid bacteria and the degradation of ellagitannins [74].

Several bacterial strains of the Eggerthellaceae family have been identified as capable of converting ellagitannins and ellagic acid into urolithins. Among these strains are Gordonibacter urolithinfaciens DSM27213 and Gordonibacter pamelaeae DSM19378, isolated from the feces of healthy individuals. These strains can convert ellagitannins and ellagic acid into urolithin M5, urolithin M6, urolithin C, and isourolithin A under stationary culture and anaerobic conditions (Figure 5) [75,76].

Table 2. Some urolithin-producing bacterial strains.

Family	Bacterial Strain	Urolithin Produced	Source of Insulation	Reference
Streptococcaceae	Streptococcus thermophilus FUA329	Urolithin A	Human breast milk	[77]
Bifidobacteriaceae	Bifidobacterium pseudocatenulatum INIA P815	Urolithin A and B	Human milk and feces and feces of infants	[78]
Streptococcaceae	Lactococcus garvieae FUA009	Urolithin A	Human feces	[79]
Eggerthellaceae	Gordonibacter KGMB12511 T	Urolithin C	Human feces	[80]
Enterococcus	Enterococcus faecium FUA027	Urolithin A	Human feces	[81]
Eggerthellaceae	Ellagibacter isourolithinifaciens DSM 104140 T	Urolithins M5, M6, C and isourolithin A	N/E	[82]
Eggerthellaceae	Gordinobzacter urolithinfaciens DSM 27213 T	Urolithin M5, M6 and C	N/E	[82]
Eggerthellaceae	CEBAS 4A1	Urolithins M6, C and isourolithin A	Human feces	[83]

Source of insulation: (N/E) not specified.

Table 2. Some urolithin-producing bacterial strains.

Family	Bacterial Strain	Urolithin Produced	Source of Insulation	Reference
Streptococcaceae	Streptococcus thermophilus FUA329	Urolithin A	Human breast milk	[77]
Bifidobacteriaceae	Bifidobacterium pseudocatenulatum INIA P815	Urolithin A and B	Human milk and feces and feces of infants	[78]
Streptococcaceae	Lactococcus garvieae FUA009	Urolithin A	Human feces	[79]
Eggerthellaceae	Gordonibacter KGMB12511 T	Urolithin C	Human feces	[80]
Enterococcus	Enterococcus faecium FUA027	Urolithin A	Human feces	[81]
Eggerthellaceae	Ellagibacter isourolithinifaciens DSM 104140 T	Urolithins M5, M6, C and isourolithin A	N/E	[82]
Eggerthellaceae	Gordinobzacter urolithinfaciens DSM 27213 T	Urolithin M5, M6 and C	N/E	[82]
Eggerthellaceae	CEBAS 4A1	Urolithins M6, C and isourolithin A	Human feces	[83]

Source of insulation: (N/E) not specified.

Another study reported the isolation of four intestinal strains (CEBAS 4A1, 4A2, 4A3, 4A4) of the same species, which were found to be capable of transforming ellagic acid into urolithins M6, C, and isourolithin A [84]. Furthermore, Beltrán et al. (2018) identified a bacterium proposed to belong to a new genus named Ellagibacter, within the species Ellagibacter isourolithinifaciens, with the capacity to degrade ellagic acid into urolithins [85].

It is crucial to emphasize that the number of bacteria comprising the gut microbiota is 10 times greater than that of human cells [86]. It indicates that additional microorganisms or enzymes are likely involved in this biotransformation process, which has not yet been identified [87].

7.2. Urolithin Metabotypes

It has been demonstrated that the bacterial strains responsible for converting ellagitannins/ellagic acid into urolithins are not present in the gut microbiota of all individuals. This results in significant discrepancies among individuals in the positive effects that these compounds can have on health. Consequently, a classification of individuals capable of producing specific types of urolithins has been established [88].

Individuals capable of metabolizing ellagitannins and ellagic acid into urolithins are classified into three phenotypes, designated metabotypes (Figure 6). Individuals who produce urolithin A are classified as metabotype A, while those who produce urolithin B and/or isourolithin A and urolithin A are classified as metabotype B. Metabotype B in adult populations ranges from 20% to 30%. Individuals unable to produce detectable levels of urolithins are grouped into metabotype 0 [89]. The distribution of metabotypes is influenced by several factors, including age, diet, physical activity, health status, sex, and body mass index [90].

The digestive system is responsible for the physical and chemical breakdown of food through a complex series of processes to release its nutrients in a manner that allows for optimal metabolism, transport to related organs, and the expulsion of remaining waste [91]. It comprises the digestive tract, which can be described as a tube with a total length of 8 to 9 m, starting at the mouth and ending at the anus. This tract includes the pharynx, esophagus, stomach, and small and large intestines [92]. Additionally, it consists of accessory organs, namely the tongue, teeth, salivary glands, liver, gallbladder, and pancreas [93].

In terms of human anatomy, the digestive system operates in a sequential manner, with strict control over the transition from one process to the next. These processes correspond to the mouth (oral processing), the stomach (gastric processing), the small intestine (intestinal processing), and the large intestine or colon (fermentation) [94]. Following the ingestion of food, oral processing is the first step, considered a mechanical process as it breaks down food into small particles, which are hydrated by saliva to form the food bolus. This process includes mastication and salivation [95]. After oral processing, ingested food mixes with gastric juices containing acid, pepsin, lipase, and salts, with a pH value of approximately 2. Through this process, food is degraded both physically and chemically due to the peristalsis of the stomach walls and acid/enzymatic reactions [96].

The small intestine is where starch digestion and absorption occur. It is divided into the duodenum, jejunum, and ileum. A large portion of starch is digested in the duodenum, where it receives digestive secretions from the pancreas and liver, and is subsequently absorbed in the jejunum and ileum [97]. The large intestine is characterized by slow flow and a neutral or slightly acidic pH. It has three main functions: the absorption of water and electrolytes, the absorption of vitamins, and the solidification and storage of feces prior to expulsion [98].

8. Digestive System Diseases

Digestive diseases encompass a broad range of chronic disorders that primarily cause issues in the stomach and intestines (Figure 7), significantly and negatively impacting the quality of life of affected individuals [99]. These types of diseases pose a substantial health threat, and their detection and treatment result in a considerable economic burden on the healthcare sector, with little to no reduction in prevalence and incidence [100]. In 2019, digestive diseases accounted for more than one-third of prevalent diseases and approximately one-fifth of incident disease cases [101].

In the United States alone in 2015, the annual healthcare expenditure on gastrointestinal diseases reached $135.9 billion. There were 54.4 million outpatient visits with a primary diagnosis of gastrointestinal disease, 266,600 new cases of gastrointestinal cancer were diagnosed, and there were 144,300 cancer-related deaths [102].

The following section describes some of the most common digestive diseases and some alternative treatments with ellagitannins.

9. Impact of Ellagitannins, Ellagic Acid, and Urolithins on Intestinal Health

Several studies have shown that ellagitannins and their derivatives, such as ellagic acid and urolithins, have beneficial effects on digestive system health. (

Table 3. Ellagitannins and their derivatives: positive effects on digestive diseases.

Ellagitannin or Derivatives	Health Effects	Concentration	Type of Study	Reference
Urolithin A	Improvement in liver and kidney dysfunction.	150 mg kg −1	In vivo	[103]
Punicalagin	Gastroprotective effects against gastric ulcers.	4 mg/kg	In vivo	[104]
Enothein B	Anti-inflammatory activity in gastric epithelial cells (potential support in anti-gastritis therapy).	20 μM	In vitro	[105]
Ellagic acid	Inhibits the proliferation of pancreatic cancer cells.	100–1000 µM	In vitro	[106]
Geraniin	Significantly reduces the nuclear division index, increases chromosomal instability homeostasis, and promotes apoptosis in colorectal cancer cells (Colo205 and Colo320).	25, 50 o 100 μg/ml	In vitro	[107]
Urolithin B	Reduced intestinal inflammation.	100 o 200 mg kg −1	In vivo	[108]

) presents the reported effects of these compounds on various intestinal diseases.

9.1. Effect of Ellagitannins on Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is one of the most common intestinal conditions. It significantly impacts the daily lives of affected individuals and places a substantial economic burden on society [109]. The main symptoms of IBS include abdominal pain and alterations in bowel movements, primarily diarrhea or constipation, which cannot be explained by any structural or biochemical anomaly [110].

A randomized, double-blind, placebo-controlled trial involving 44 individuals with irritable bowel syndrome evaluated the effect of ellagic acid on gastrointestinal symptoms. The participants were randomly assigned to two groups: one group received 180 mg of ellagic acid per day (n = 22), and the other group received a placebo (n = 22) for two months. After the experiment, it was observed that ellagic acid consumption had a beneficial effect, as it reduced the symptoms of irritable bowel syndrome. It was attributed to the anti-inflammatory and antioxidant properties of ellagic acid [111].

Ellagitannins and their derivatives are emerging as promising preventive alternatives or adjuvant therapies for various health conditions. However, in the case of irritable bowel syndrome, more scientific evidence is still needed to support their beneficial effects. Additional clinical studies are required, as well as the establishment of effective and safe dosages.

9.2. Ellagitannins and Their Activity Against Gastric Ulcers

Gastric ulcers are defects in the gastric wall that occur when there is a disruption in the mucosal barrier lining the stomach [112]. Gastric ulcers occur when mucosal protection is compromised by harmful factors such as hypersecretion of gastric acid, nonsteroidal anti-inflammatory drugs (13% of cases), and H. pylori infection, which is associated with damage such as hemorrhagic erosion, neutrophil infiltration, lymphoid follicles, and epithelial damage [113].

The gastroprotective activity of casuarinin, an ellagitannin extracted from Melaleuca leucadendra, was evaluated in a previous study. They conducted a study with mice in which ethanol-induced ulceration was induced, and casuarinin was administered in three concentrations (25, 50, and 100 mg/kg), resulting in a reduction in ulcer area by 45%, 78%, and 99%, respectively, compared to the group not receiving the ellagitannin. Casuarinin (100 mg/kg) increased mucin content by up to 1.8 times and decreased acidity by 48%. Histological data demonstrated that ellagitannin exhibited a protective effect against tissue modifications caused by the induced ulcer [114].

In the case of the positive effects of ellagitannins on gastric ulcers, this is one of the conditions discussed in this review for which a greater number of studies have been conducted, mainly in vitro in cells and in vivo in rodents. However, evidence from human studies is still limited.

9.3. Ellagitannins Against Gastritis

Gastritis is defined as inflammation of the mucosa and submucosa of the stomach and is one of the most prevalent diseases globally, with an estimated 1.8 to 2.1 million cases annually [115]. It can be classified into two types: non-atrophic, which causes mucosal damage that may be extensive and/or severe and can be restored with some sequelae or progress to atrophic phenotypes; and atrophic, characterized by long-lasting periods, non-self-limiting, and resulting from harmful agents that drastically modify the resident population of gastric glands [116].

Several studies have reported that ellagitannins possess antibacterial and anti-inflammatory activities [117]. The anti-inflammatory effect of ellagitannins from strawberries was demonstrated, although not exclusively related to their ability to inhibit the NF-κB pathway, a key factor in inflammatory diseases such as gastritis. They used the two pure ellagitannins most prevalent in strawberries (agrimoniin and casuarictin), showing that agrimoniin moderates IL-8 secretion by inhibiting the NF-kB pathway. Additionally, they demonstrated for the first time that casuarictin, in its pure state, possesses anti-inflammatory properties, specifically targeting the NF-kB pathway in human gastric epithelial cells [118].

In a study by Piazza et al. (2023), ellagitannins extracted from leaves of Castanea sativa L., commonly known as a chestnut tree (castalagin and vescalagin), were used against gastritis [119]. Approximately 1% w/w of the dry extract was employed. In this assay, GES-1 cells infected with pathogenic strains of H. pylori, highly associated with this condition [120], were used since they activate NF-kB and IL-8 expression at the epithelial level. Ellagitannins inhibited IL-8 release (IC50 ≈ 28 µg/mL and 11 µM, respectively), and their anti-inflammatory activity was partly due to decreased NF-kB signaling. Moreover, ellagitannins reduced bacterial growth and cell adhesion.

Although ellagitannins have shown positive effects in the prevention and treatment of gastritis in preclinical studies, due to their antioxidant, anti-inflammatory, and cytoprotective properties, most of the evidence comes from in vitro or animal models. The lack of clinical trials in humans represents a significant limitation for translating these findings into clinical practice.

9.4. Ellagitannins Against Colon Cancer

Ellagitannins exhibit a wide range of biologically and clinically significant activities, with the potential to promote health and applications in medicine, including cancer prevention and treatment [121]. Colon cancer is the third most prevalent disease worldwide, with the highest mortality rate. Its prognosis is dependent on the clinical status of the patient. According to the World Health Organization, 1.93 million cases were reported in 2020 [122].

Ellagitannins extracted from raspberry seeds were evaluated against HT-29 colon cancer cells in a previous study. Ellagic acid was observed to induce a slight cell cycle arrest in the G1 phase, while urolithins were found to arrest the cell cycle in the G2/M phase and increase p21 expression. The apoptotic cells were identified using the Annexin V-FITC/PI assay. The observed variations in mitochondrial membrane potential and the activation of caspases 8 and 9 indicated that both extrinsic and intrinsic apoptotic pathways might be involved. The anticancer activity of ellagitannins, ellagic acid, and urolithins A and B was demonstrated by their ability to halt the cell cycle and induce apoptosis in human colon cancer cells (HT-29) [123].

The impact of urolithin A on SW620 colorectal cancer cells was investigated in a separate study. They demonstrated urolithin A-induced autophagy in damaged cells at submicromolar concentrations. Moreover, the dose-dependent reduction in cell proliferation and matrix metalloproteinase-9 activity observed in this study suggests that urolithin A may have a role in treating colorectal cancer. The inhibition of autophagy by Atg5-siRNA and caspases by Z-VAD-FMK suppressed cell death induced by urolithin A [124].

9.5. Ellagitannins Against Esophageal Cancer

Esophageal cancer is one of the most frequently occurring neoplasms, ranking eighth worldwide and third among gastrointestinal cancers [125]. It is regarded as one of the most aggressive digestive tract diseases, with tumors developing in the surrounding tissues of the esophagus, the muscular tube through which food is transported from the throat to the stomach. This results in a high morbidity and mortality rate of [126]. Esophageal cancer is classified into two main types: adenocarcinoma and squamous cell carcinoma. Squamous cell carcinoma is the most prevalent type, accounting for approximately 90% of cases. The two types of cancer do not share epidemiological, histopathological, or etiological characteristics [127].

High antitumor activity of ellagic acid against esophageal squamous cell carcinoma has been demonstrated. The inhibitory effect of ellagic acid on carcinoma cell survival was concentration- and time-dependent. The compound significantly reduced luciferase activity (reporter gene) induced by STAT3, a transcription factor involved in the tumorigenesis of various tumors. Ellagic acid inhibited both endogenous and cytokine-induced activation of STAT3 in esophageal squamous carcinoma cells. Furthermore, it was indicated that ellagic acid could suppress the expression of RNF6, an E3 ligase of SHP-1. It was also observed that the overexpression of RNF6 could significantly diminish the inhibitory effects of ellagic acid on cancer cell survival. It suggests that STAT3 signaling can be inhibited by modulating RNF6/SHP-1. The findings of this study indicate that ellagic acid may be a promising therapeutic option for the treatment of esophageal squamous cell carcinoma [128].

9.6. Ellagitannins Against Pancreatic Cancer

Pancreatic cancer is one of the most aggressive diseases and is considered nearly incurable since symptoms occur in very advanced stages, making diagnosis and treatment very challenging [129]. It is estimated that 50% of patients die within the first six months. The American Cancer Society reports a five-year relative survival rate of 9% for all combined stages. For patients diagnosed at an advanced stage (approximately 53%), the five-year survival rate is estimated at 3% [130].

The efficacy of pomegranate extract (Punica granatum) was evaluated on pancreatic cancer cells at concentrations of 5, 10, and 20 mg/mL. The extract demonstrated the ability to attenuate angiogenesis through tumor morphology, weight, and hemoglobin concentration changes [131].

The impact of urolithin A was investigated in mice xenografted with subcutaneous injections of pancreatic ductal adenocarcinoma cell lines. The mice were orally administered a dose of 20 mg/kg/day of urolithin A orally via a probe once the subcutaneous tumors had already formed. The treatment resulted in a reduction and cessation of tumor growth. Additionally, they collaborated with genetically modified mice (Ptf1acre/+; LSL KrasG12D/+; Tgfbr2flox/flox—PKT mice), which spontaneously develop pancreatic cancer at an early age (4–5 weeks). The mice were orally administered 20 mg/kg/day of urolithin A through a probe, increasing overall survival from approximately 59 to 71 days [132].

9.7. Ellagitannins Against Liver Cancer

Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, accounting for 90% of all cases. It is a highly malignant neoplasm that typically arises in individuals with a history of chronic liver disease and/or cirrhosis. It is the fifth most common cancer in men and the seventh most common cancer in women [133]. Globally, HCC represents the most common malignant neoplasm. Liver cancer is frequently diagnosed in advanced stages, which often results in a poor prognosis. For the treatment of liver cancer, chemotherapy and immunotherapy are the most common options. However, natural compounds may help patients achieve better outcomes with lower systemic toxicity and fewer side effects [134].

The chemopreventive efficacy of ellagic acid against N-nitroso diethylamine-induced hepatocarcinogenesis a potent hepatocarcinogenic dialkyl N-nitrosamine found in tobacco smoke, cured meats, and some beverages was evaluated in rats. Rats were classified into four groups: a normal control group, a group injected with a single dose (200 mg/kg body weight) of N-nitrosodiethylamine, a group administered ellagic acid orally daily at a dose of 50 mg/kg body weight for 7 days before and 14 days after N-nitrosodiethylamine administration, and a fourth group that received the same dose of ellagic acid for 21 days after N-nitrosodiethylamine administration. It was observed that in hepatocellular carcinoma rats, ellagic acid significantly decreased the activities of liver antioxidant enzymes. Additionally, oral administration of ellagic acid as a protective agent promoted a significant increase in tested antioxidant enzyme activities and total serum protein levels, concomitant with a reduction in tumor markers such as arginase and α-fucosidase, as well as liver enzymes and total and direct bilirubin levels. Similarly, oral application of ellagic acid as a therapeutic agent inhibited partial DNA fragmentation produced by hepatocellular carcinoma in the rat model [135].

Although various preclinical studies have demonstrated promising antitumor effects of ellagitannins and their derivatives in different types of cancer affecting the digestive system, such as colon, esophageal, pancreatic, and liver cancer, most of this evidence comes from in vitro or animal models. There is a clear need for clinical studies in humans to confirm these findings and to assess their safety, efficacy, and bioavailability. Additionally, it is important to elucidate the underlying mechanisms of action and explore potential synergistic effects with conventional cancer therapies.

10. Food Products with Ellagitannins and Their Derivatives as Bioactive Ingredients

A patent was developed for an antioxidant product based on camu-camu fruits, showing high potential for use in the food or pharmaceutical industry. The patent delineates the optimal conditions for the extraction of bioactive compounds, commencing with the selection of fruit (soluble solids/acidity, seed removal, and fruit dehydration), grinding, sieving (0.2 to 0.8 mm), and the mixing of the obtained flour with an acidic solution, followed by agitation and subsequent decantation to separate the liquid phase from the solid phase, which underwent a freeze-drying process. The product described is notable for its high concentration of vitamins and polyphenols, including ellagic acid (100 to 200 mg/100 g) and ellagitannins such as castalagin, vescalagin, ellagitannin, pedunculagin, HHDP-galloyl-glucose, Di-HHDP-galloyl-glucose, and tri-galloyl-HHDP-glucose (350 to 450 mg/100 g), among other compounds. The total polyphenol concentration of the product is estimated to be between 3500 and 5000 milligrams per 100 g [136].

A patent outlines the formulation of nutritional and medical products involving a medium-chain triglyceride, lecithin, and a compound from the urolithin family (urolithin A). This combination gives urolithin A a superior bioavailability and pharmacokinetic profile compared to urolithin A alone in a simple saline solution suspension. Specifically, this composition is applicable in treating and managing healthy individuals who would benefit from improved muscle function, including those with a deteriorated physique, low endurance capacity, and muscle atrophy. Furthermore, this composition offers an alternative treatment for conditions such as diabetes, obesity, reduced metabolic rate, metabolic syndrome, cardiovascular diseases, stress, anxiety disorders, and others [137].

A patent presents a method for obtaining ellagic acid from a polyphenolic extract of pomegranate, particularly from its seeds. This method has high potential as a nutritional or food supplement due to the multiple beneficial effects of ellagic acid. Initially, pomegranate seeds are immersed in an ethanol solution on multiple occasions, after which the resulting fractions are stored and combined. The solid fraction is discarded, and the liquid fraction is concentrated at a 20:1 ratio. Subsequently, further extractions with acetic ether are combined and concentrated to produce a solid material, which is then reduced to a dry powder. The final product for oral use can be presented in the form of hard gelatin capsules, where the active ingredient is integrated with an inert solid diluent (calcium carbonate, calcium phosphate, etc.), or as soft gelatin capsules, where the active ingredient is integrated with water or an oily medium. Each capsule contains approximately 200 mg of ellagic acid in a bioavailable form [138].

A patent describes the development of functional nutritional products containing pomegranate extract for the prevention and/or treatment of cardiovascular diseases, arterial plaque buildup, hypertension, and metabolic syndrome. The mentioned products include orange juice supplemented with pomegranate extract, functional dairy products with pomegranate extract, functional cooked ham with pomegranate extract, and functional canned tuna with pomegranate extract. In all products, the pomegranate extract content ranged from approximately 400 to 4000 mg/kg, with punicalagin content at 50% w/w. These products were evaluated using the ABTS technique to determine their antioxidant activity [139].

It is important to highlight that the use of this type of molecule may cause mild side effects, although there is very little literature addressing this issue [140]. However, most available studies in the scientific literature mainly emphasize their positive effects, which outweigh the reported adverse events in both frequency and clinical relevance [141,142]. This trend suggests a favorable safety profile when these compounds are used in food matrices or nutraceutical products under controlled conditions and at appropriate doses [143].

11. Future Perspectives and Conclusions

Ellagitannins and their derivatives, such as ellagic acid and, particularly, urolithins, have emerged as promising alternatives for the prevention and adjunctive treatment of various digestive system disorders. This is attributable to their potent antioxidant, anti-inflammatory, and anticancer properties, which have been extensively documented in numerous preclinical and clinical studies. Moreover, these compounds can be sourced from agro-industrial residues, promoting sustainable resource utilization and offering the possibility of developing economically accessible products for the general population, thereby providing relief from the high costs associated with conventional pharmacological treatments.

However, significant challenges limit their immediate clinical application. Among these, the low oral bioavailability of ellagitannins and the marked interindividual variability in the gut microbiome’s capacity to convert these compounds into urolithins—metabolites with enhanced biological activity and more potent therapeutic effects—stand out. This variability complicates dose standardization and the prediction of therapeutic responses. Therefore, it is imperative to deepen the molecular understanding of this microbial biotransformation and explore strategies to modulate it, such as supplementation with specific probiotics, to maximize the therapeutic potential of these compounds. Additionally, more controlled, long-term clinical trials are needed to validate their efficacy and safety, establishing clear protocols for their use in various digestive pathologies.

Finally, although the demand for and commercialization of nutraceuticals and dietary supplements containing ellagitannins have increased significantly, a lack of specific regulation remains that ensures the quality, efficacy, safety, and traceability of these products. Consequently, the development and implementation of robust regulatory standards and guidelines are a priority to protect consumers and foster confidence in these products. This should be accompanied by educational campaigns targeted at healthcare professionals and the public, promoting responsible use grounded in scientific evidence. In this way, ellagitannins and their derivatives could become valuable and accessible tools within the therapeutic arsenal against digestive diseases, contributing to sustainable improvements in public health.