A Review of the Dietary Intake, Bioavailability and Health Benefits of Ellagic Acid (EA) with a Primary Focus on Its Anti-Cancer Properties

Polyphenols are a large group of phytochemicals forming part of a plant immune system and are abundant in foods such as pomegranate, raspberries, strawberries, walnuts and almonds. Ellagitannins (ETs) and ellagic acid (EA) are commonly occurring polyphenols of growing interest due to potential health benefits across cancer, cardiovascular disease, inflammation, diabetes and neurodegeneration. This review aims to explore the dietary intake, bioavailability, metabolism and health effects of ETs and EA, with a primary focus on their anti-cancer properties, given their antioxidant, anti-inflammatory, antimicrobial and anti-proliferative actions.

The review synthesizes evidence across multiple domains: (1) Dietary intake: population estimates of total polyphenols and ETs vary widely by country; strawberries, pomegranate and nuts are notable sources. (2) Bioavailability and metabolism: ETs hydrolyze to EA, which is poorly bioavailable; gut microbiota convert EA to urolithins that are more readily absorbed and considered the bioactive forms. (3) Toxicology: high-dose animal studies suggest a wide safety margin relative to dietary intake; potential nutritional and pharmacological interactions include iron chelation and digestive enzyme binding. (4) Antioxidant effects: EA and urolithins counter oxidative stress via ROS scavenging, metal chelation and inhibition of oxidase enzymes, with urolithins C and D showing potent activity in cell-based assays. (5) Anti-inflammatory effects: ET-rich extracts attenuate inflammatory mediators, adhesion molecules and cytokines in vitro and in animal models; small clinical data suggest symptom improvement in IBS with EA. (6) Antimicrobial and probiotic effects: ETs/EA can enhance beneficial gut bacteria (bifidobacteria, lactobacilli) and inhibit pathogens including H. pylori, MRSA and M. abscessus, though some polyphenols also suppress commensals. (7) Anti-cancer evidence: across prostate, colon and breast cancer models, EA/ETs/urolithins modulate signaling (NF-kB, STAT3/AKT/ERK, Wnt), inhibit proliferation and angiogenesis, induce apoptosis and may synergize with chemotherapies (e.g., 5-FU). Limited early clinical studies (pomegranate juice, black raspberries) indicate biomarker modulation. (8) Synergy: complex mixtures (e.g., whole pomegranate juice) often outperform isolated compounds, indicating synergistic polyphenol effects.

Narrative review of the literature. Data sources: PubMed, Web of Science, Scopus, and reference lists of selected articles. Search terms included 'polyphenol', 'ellagitannins', 'antiinflammatory', 'anti-oxidant', and 'cancer'. Inclusion limited to English-language articles; full texts were reviewed prior to inclusion. Recently published articles were prioritized. Reference management was performed using Endnote.

- Dietary intake: Estimated daily total polyphenols ranged from ~744 mg/day (Greece) to ~3,016 mg/day (Spain). ET intake estimates: ~12 mg/day (Finland), 13 mg/day (USA), 5 mg/day (Germany). In France, ~1.7 kg/year strawberry consumption corresponds to ~0.4 mg/day total EA. - Bioavailability: After ingestion, ETs hydrolyze to EA, which shows low plasma levels and rapid elimination (peak ~1 h post-ingestion, near-baseline by 4 h). Urolithins appear in circulation within hours and peak at 24–48 h, existing in free and conjugated forms; considered the main bioactive metabolites. - Toxicity: In F344 rats, no-observed-adverse-effect level for EA estimated at 3,254 mg/kg/day in females; minor, non-treatment-related biochemical/histological changes reported. Potential adverse effects include iron chelation (risk of iron deficiency), inhibition of digestive enzymes, microbiome disturbance, and drug-metabolism interactions. - Antioxidant: Urolithin A showed weak direct radical scavenging (DPPH IC50 ~152.66 mM) vs EA (~6.6 mM) but inhibited oxidase enzymes (MAO-A IC50 ~71.44 mM; tyrosinase IC50 ~29.4 mM). Urolithin C and D exhibited strong cell-based antioxidant activity (IC50 0.16 and 0.33 μM), surpassing EA (IC50 ~1.1 μM in the cited assay), with C more lipophilic/bioavailable than D. - Anti-inflammatory: In collagen-induced arthritis mice, pomegranate extract (POMx) delayed onset and reduced incidence at 13.6–34 mg/kg; inhibited NO production in LPS-stimulated macrophages at 20 μg/ml; reduced joint inflammatory cell infiltration and IL-6 levels. EA from walnuts reduced TNF-α-induced VCAM-1 and ICAM-1 expression in human aortic endothelial cells at 0.1–10 μM. In a randomized controlled trial, 180 mg/day EA for 2 months reduced IBS severity scores. - Antimicrobial/probiotic: POMx enhanced total bacteria, bifidobacteria and lactobacilli in human fecal samples, without promoting proteolytic Clostridium groups linked to colorectal risk. EA and related compounds showed dose-dependent inhibition of H. pylori (via arylamine N-acetyltransferase inhibition) and S. aureus (IC50 ~0.47 mM); EA inhibited Mycobacterium abscessus with MIC ~1.56 mg/mL and MBC ~3.12 mg/mL. Some polyphenols also inhibit commensal microbes. - Prostate cancer: EA reduced proliferation and phosphorylation of STAT3/ERK/AKT in PC3 cells (0–100 μM); pomegranate fractions inhibited proliferation and growth of xenografts in mice; urolithins inhibited both androgen-dependent and -independent lines (IC50 values lower than EA but above physiological levels). EA/ETs inhibited NF-kB-driven inflammatory signaling. POMx reduced angiogenesis markers (VEGF, HIF-1α) and tumor vascular density in mice. In men with rising PSA post-therapy, daily pomegranate juice prolonged PSA doubling time (Phase II study). - Colon cancer: Raspberry EA content correlated with antiproliferative effects on colon carcinoma cells. Urolithin A inhibited Wnt signaling (IC50 ~39 μM) at physiologically relevant levels; ET/EA required higher, non-physiological doses for Wnt effects. ETs/urolithins inhibited CYP1 enzymes and induced cell-cycle arrest and apoptosis in HT-29 cells; EA, urolithins A/B modulated phase I/II detoxifying enzymes in Caco-2 cells. Urolithin A potentiated 5-FU by lowering its IC50, causing G2/M arrest and modest caspase-8/9 activation. In a pilot clinical study, black raspberry powder modulated β-catenin, Ki-67, TUNEL and CD105; increased epithelial Smad4 expression. - Breast cancer: Pomegranate polyphenols inhibited breast cancer cell growth in vitro, more strongly in ER-positive MCF-7 than ER-negative MDA-MB-231; fermented juice had roughly twice the antiproliferative effect of fresh juice; aromatase activity reduced by ~60–80%. EA inhibited VEGFR-2 kinase and downstream MAPK and PI3K/Akt signaling; suppressed endothelial proliferation/migration/tube formation at 2.5–20 μM; reduced xenograft growth and p-VEGFR2; low observed toxicity with reversible vascular effects in chick models. - Synergy: Whole pomegranate juice induced greater reductions in viable cancer cell numbers and stronger pro-apoptotic effects than isolated EA or punicalagin, supporting polyphenol synergy.

The compiled evidence supports the hypothesis that ellagitannins, ellagic acid and their gut-derived urolithins contribute to cancer prevention and adjunctive therapy via antioxidant, anti-inflammatory, antimicrobial, anti-proliferative and anti-angiogenic mechanisms. Bioavailability considerations are central: EA exhibits low systemic exposure, whereas urolithins achieve higher, sustained levels and likely mediate many systemic effects. Localization of urolithins and/or EA to the prostate and intestines may underlie stronger signals in prostate and colorectal models. Modulation of key oncogenic pathways (e.g., NF-kB, STAT3/AKT/ERK, Wnt, VEGF/VEGFR-2) provides plausible mechanistic bases for observed antiproliferative and anti-angiogenic outcomes. Early clinical findings (PSA kinetics with pomegranate juice; biomarker changes with black raspberries) are consistent with preclinical data, and the potentiation of 5-FU by urolithin A suggests translational value in combination regimens. However, variability in dietary sources, inter-individual microbiome-dependent urolithin production, and discrepancies between in vitro effective concentrations and physiological levels temper generalizability. Overall, ET-rich foods and EA/urolithins show promise as chemopreventive agents and as adjuncts to conventional therapies, warranting rigorous clinical evaluation.

Abundant preclinical research indicates that ETs, EA and urolithins may protect against cancer and other chronic diseases. Given the side effects of conventional chemotherapy, natural chemopreventive strategies are appealing, cost-effective and potentially synergistic with standard care. Yet, human clinical evidence is limited, and EA’s poor bioavailability complicates translation; urolithins, with better absorption, may be more clinically relevant. Reported tissue accumulation in the prostate and intestines suggests organ-specific opportunities. Future research should: (1) conduct randomized controlled trials assessing ET/EA/urolithins as neo/adjuvant adjuncts to chemo-, radio- or hormone therapy; (2) evaluate impacts on recurrence and survival; (3) define therapeutic dosing and timing; (4) investigate synergy with agents such as 5-FU; (5) account for microbiome-dependent metabolite production; and (6) balance benefits against potential nutritional and pharmacological interactions.

- Evidence base is dominated by in vitro and animal studies; few human clinical trials with small sample sizes. - EA has low bioavailability; many effective in vitro concentrations exceed physiological levels. Urolithin production varies by individual microbiome (metabotypes), affecting exposure and response. - Dietary sources (e.g., berries) have variable phenolic content, hindering dose standardization and reproducibility. - Potential adverse effects and interactions: iron chelation (risk of deficiency), inhibition of digestive enzymes, microbiome perturbation, and modulation of drug metabolism. - Mechanistic uncertainties remain (e.g., reasons for tissue localization to prostate/intestines; precise anticancer mechanisms of specific urolithins).