Pomegranate Metabolites Impact Tryptophan Metabolism in Humans and Mice

Background: We showed that pomegranate juice (PomJ) can help to maintain memory in adults aged >50 y. The mechanism for this effect is unknown, but might involve Trp and its metabolites, which are important in brain function. Objectives: We aimed to test the hypothesis that PomJ and its metabolites ellagic acid (EA) and urolithin A (UA) affect Trp metabolism. Methods: Stool and plasma from a cohort [11 PomJ, 9 placebo drink (PL)] of subjects enrolled in our double-blind, placebo-controlled trial (NCT02093130) were collected at baseline and after 1 y of PomJ or PL consumption. In a mouse study, cecum and serum were collected from DBA/2J mice receiving 8 wk of dietary 0.1% EA or UA supplementation. Trp metabolites and intestinal microbiota were analyzed by LC-MS and 16S rRNA gene sequencing, respectively. Results: In the human study, the change in the plasma Trp metabolite indole propionate (IPA) over 1 y was significantly different between PomJ and PL groups (P = 0.03). In serum of experimental mice, we observed a 230% increase of IPA by EA but not UA, a 54% increase of indole sulfate by UA but not EA, and 43% and 34% decreases of kynurenine (KYN) by EA and UA, respectively. In cecum, there was a 32% decrease of Trp by UA but not EA, and an 86% decrease of KYN by EA but not UA (P < 0.05). The abundance of 2 genera, Shigella and Catenibacterium, was reduced by PomJ in humans as well as by UA in mice, and their abundance was negatively associated with blood IPA in humans and mice (P < 0.05). Conclusions: These results suggest a novel mechanism involving the regulation of host and microbial Trp metabolism that might contribute to the health benefits of ellagitannins and EA-enriched food, such as PomJ.