Pomegranate Ellagitannins Improve Gut Microbial Metabolism and IAPP Regulation: Findings from a Randomized Controlled Trial

Pomegranate Ellagitannins Improve Gut Microbial Metabolism and IAPP Regulation: Findings from a Randomized Controlled Trial Diets rich in (poly)phenols such as ellagitannins have been associated with improvements in metabolic health. Dietary ellagitannins, metabolized by the gut microbiota into bioactive urolithins, have demonstrated protective effects on pancreatic β-cells in vitro by attenuating islet amyloid polypeptide (IAPP)–induced cytotoxicity. This study aimed to evaluate the effects of pomegranate-derived ellagitannin supplementation on colonic microbiota metabolism and IAPP regulation in participants without a diagnosed condition, thereby exploring its potential contribution to β-cell function and metabolic homeostasis. A 12-week, double-blind, randomized, placebo-controlled study (Clinical trial register NCT06659523) was conducted with 69 adults (52.2% women, 47.8% men; mean age 54.4 ± 7.93 years) recruited from a primary healthcare center. Participants were randomly assigned to receive either a commercially available ellagitannin-rich pomegranate extract supplement (n = 37) or a placebo (n = 32). Sociodemographic characteristics, blood, and urine samples were collected to assess biochemical changes and profiles of urolithin metabolites and short-chain fatty acids (SCFAs). Inter- and intra-group statistical comparisons were performed. The study received ethical approval (CE.ECTS/P05-24) and followed standard practices for studies with humans. At baseline, more than 70% of participants were classified as high risk for developing type 2 diabetes mellitus (T2DM), with no significant differences between groups (p ≥ 0.05). After the intervention, the supplement group showed a tendency toward improvement in glycemic markers and reductions in IAPP and proIAPP levels, effects not observed in the placebo group. Within the supplement group, comparisons between baseline and week 12 demonstrated a significant reduction in both IAPP and proIAPP concentrations. Additionally, urolithin production also changed significantly over the intervention period, reflecting substantial interindividual variability, with an increase in the proportion of urolithin B producers. In addition, supplementation resulted in significant increases in the SCFA propionate, butyrate, and valerate relative to baseline (p < 0.05 for all), with these effects being particularly pronounced among urolithin B producers. These findings suggest a modulatory influence of ellagitannin supplementation on gut microbial activity and associated metabolic outputs. Overall, this study indicates that microbial colonic metabolites of pomegranate ellagitannins, in particular urolithin B, contribute to IAPP regulation and metabolic health. Ellagitannin-rich dietary strategies may therefore offer a promising early nutritional approach for supporting β-cell function and reducing the risk of T2D progression. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.