Polyphenols, plant-based phytochemicals, act as a plant's defense mechanism against pathogens. Ellagitannins (ETs) and ellagic acid (EA) are common polyphenols present in fruits, nuts, and seeds like pomegranates, raspberries, and walnuts. Extensive research focuses on their potential health benefits, primarily their antioxidant capabilities demonstrated in studies related to cancer, cardiovascular disease, inflammation, diabetes, and Alzheimer's disease. This review specifically explores the bioavailability, metabolism, and health effects of ETs and EA, with a primary emphasis on their anti-cancer properties. A comprehensive literature review was conducted using databases such as PubMed, Web of Science, and Scopus, focusing on recent English-language publications. Keywords like 'polyphenol,' 'ellagitannins,' 'anti-inflammatory,' 'anti-oxidant,' and 'cancer' were used to refine the search. The full text of each selected article was reviewed and references managed using EndNote software.

Several studies have estimated the daily intake of polyphenols and ETs, showing significant variations across different countries. While total polyphenol intake ranged from 744 mg/day (Greece) to 3016 mg/day (Spain), ET intake varied from 5 mg/day (Germany) to 13 mg/day (America). The bioavailability of ETs and EA is low due to factors such as their large size, high polarity, and low water solubility, leading to extensive degradation before absorption and irreversible DNA binding, impacting transcellular absorption. Studies on mice and humans showed minimal EA detection in blood, while its metabolites, urolithins, displayed higher bioavailability and systemic circulation after consumption of foods rich in EA.

This review utilized a narrative approach. The researchers searched PubMed, Web of Science, Scopus, and reference lists of relevant articles, using keywords such as 'polyphenol,' 'ellagitannins,' 'anti-inflammatory,' 'anti-oxidant,' and 'cancer'. Only English-language papers were included, with a preference given to recently published research. The full text of each selected paper was reviewed, and references were managed using EndNote software.

EA's toxicity studies showed a high no-observed-adverse-effect level in rats, significantly higher than typical dietary amounts. However, potential negative effects include iron binding (potentially leading to anemia), enzyme inhibition (affecting digestion), and microbiome disruption. EA demonstrates antioxidant effects through both type 1 and type 2 mechanisms, scavenging ROS and inhibiting hydroxyl radical production. Urolithins, particularly Urolithin C and D, showed superior antioxidant activity compared to EA. Anti-inflammatory effects are demonstrated through downregulation of pro-inflammatory enzymes (COX-2, iNOS), decreased adhesion molecule expression, and reduction of inflammatory markers in various studies. EA and pomegranate extracts exhibit antimicrobial activity against various bacterial strains, including MRSA and H. pylori, by mechanisms that may include cell membrane disruption. In various in vitro and in vivo studies, EA and urolithins demonstrated anti-cancer effects against prostate, colon, and breast cancer cell lines, influencing cell proliferation, apoptosis, and signaling pathways. These effects include the inhibition of NF-kB pathways, angiogenesis, and Wnt signaling pathways, often showing synergistic effects when combined with other pomegranate polyphenols. Clinical trials have shown promising results, such as prolonged PSA doubling time in prostate cancer patients after consuming pomegranate juice.

The findings demonstrate that EA and its metabolites, urolithins, have promising anti-cancer properties through antioxidant, anti-inflammatory, and antimicrobial mechanisms. The low bioavailability of EA emphasizes the significance of urolithins as the active compounds. The research highlights the potential of using EA-rich foods as chemopreventive agents and potentially enhancing the effectiveness of existing cancer therapies. However, the variation in polyphenol concentrations in natural foods is a limiting factor. Further research is needed to determine optimal dosing, synergistic effects, and the potential for using EA or urolithins in combination with conventional cancer treatments.

This review highlights the substantial evidence supporting the potential health benefits of EA and its metabolites, particularly their anti-cancer effects. While preclinical data is promising, a critical need exists for large-scale human clinical trials to confirm the efficacy and safety of EA and urolithins in cancer prevention and treatment. Future studies should focus on optimizing dosage, exploring synergistic effects with other compounds, and addressing limitations associated with the variability in polyphenol content of natural sources. Furthermore, research should investigate the mechanism underlying the organ-specific accumulation of EA and urolithins.

The primary limitation of this review is the reliance on existing literature, which includes a significant number of in vitro and in vivo studies, but limited human clinical trials. The bioavailability of EA and the varying concentrations of polyphenols in different food sources present challenges in extrapolating findings to real-world dietary applications. Moreover, the lack of standardization across studies regarding EA/ET extraction methods and assay procedures makes direct comparisons difficult.