Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population

Abstract

Background Urolithin A (UA) is produced by gut microflora from foods rich in ellagitannins. UA has been shown to improve mitochondrial health preclinically and in humans. Not everyone has a microbiome capable of producing UA, making supplementation with UA an appealing strategy. Objective This is the first detailed investigation of the prevalence of UA producers in a healthy population and the ability of direct UA supplementation to overcome both microbiome and dietary variability. Dietary intake of a glass of pomegranate juice (PJ) was used to assess UA producer status (n = 100 participants) and to characterize differences in gut microbiome between UA producers from non-producers. Methods Subjects were randomized (1:1) to either PJ or a food product containing UA (500 mg). Prevalence of UA producers and non-producers were determined in the PJ group. Diet questionnaires and fecal samples were collected to compare differences between UA producers and non-producers along with plasma samples at different time points to assess levels of UA and its conjugates between the interventions. Results Only 12% of subjects had detectable levels of UA at baseline. Following PJ intake ~40% of the subjects converted significantly the precursor compounds into UA. UA producers were distinguished by a significantly higher gut microbiome diversity and ratio of Firmicutes to Bacteroides. Direct supplementation with UA significantly increased plasma levels and provided a >6-fold exposure to UA vs. PJ (p < 0.0001). Conclusions Differences in gut microbiome and diet that dictate natural exposure to UA can be overcome via direct dietary UA supplementation.

Combinatory Exposure to Urolithin A, Alternariol, and Deoxynivalenol Affects Colon Cancer Metabolism and Epithelial Barrier Integrity in vitro

“…Generally, the binary mixture exposure scenarios led to higher recovery rates (apical and basolateral compartment together) for all three substances. In relevance for the metabolism of Uro A, a recent Uro A intervention study described the bioavailability of DAP in vivo, with Uro A and its Phase II-metabolites reaching significant plasma levels within 24 h after oral supplementation (105). We found both, Uro A-S and Uro A-GlcA in all three compartments (Supplementary Figure 3).…”

Main drivers of (poly)phenol effects on human health: metabolite production and/or gut microbiota-associated metabotypes?

“…One of them described cellular health improvement by regulating gene expression associated with cellular and mitochondrial function. 165 The second one claimed the consumption of 500 mg of synthetic Uro-A as the solution to achieve more plasma Uro-A-derived conjugates than the single intake of a specific pomegranate juice and after only 6h, 166 not enough time to achieve a substantial conversion of ellagic acid into Uro-A, which can take around 48h. 48,167 Besides, walnuts intake would have yielded much more Uro-A production.…”

“…Therefore, the definition of "low and high producers" has been commonly used to stratify those individuals capable of producing a high or low amount of metabolites, respectively. 43,55,62,104,105,166,195,199,[216][217][218] However, as previously mentioned, this cut-off concentration is arbitrary and conditioned by external factors, including the lag period between the last intake of (poly)phenolic precursor and the sample analysis, the sensitivity of the analytical procedure and the food matrix. Regarding food matrix effects, flavanones metabolism is a paradigmatic example.…”

Urolithins: The Colon Microbiota Metabolites as Endocrine Modulators: Prospects and Perspectives

“…Urolithins are detected in high concentrations in the colon and can also reach the systemic tissues such as the prostate and mammary gland ( 13 ). Direct supplementation with UA significantly increases plasma levels and provides more than six-fold exposure to UA vs. pomegranate juice ( 17 ).…”