Direct supplementation with Urolithin A overcomes limitatio…

European Journal of Clinical Nutrition (2022) 76:297 – 308


Nutrition and Health (including climate and ecological aspects) Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population

1 ● Davide D ’ Amico 1 ● Pénélope A. Andreux 1 ● Gillian Dunngalvin 2 ● Timo Kern 3 ●

Anurag Singh

William Blanco-Bose 1 ● Johan Auwerx 4 ● Patrick Aebischer 5 ● Chris Rinsch 1

Received: 25 January 2021 / Revised: 7 May 2021 / Accepted: 18 May 2021 / Published online: 11 June 2021 © The Author(s) 2021. This article is published with open access

Abstract Background Urolithin A (UA) is produced by gut micro fl ora 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 fi rst 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 signi fi cantly the precursor compounds into UA. UA producers were distinguished by a signi fi cantly higher gut microbiome diversity and ratio of Firmicutes to Bacteroides. Direct supplementation with UA signi fi cantly 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.


Urolithin A (UA) is produced endogenously by human gut bacteria exposed to dietary polyphenolic compounds that include ellagic acid (EA) and ellagitannins (ET), such as punicalagin [1]. These polyphenolic precursors are found widely in fruits (pomegranate and certain berries) and nuts (walnuts and pecans). ET are converted to EA in the upper portion of the human gastrointestinal tract, and further metabolized by gut micro fl ora in the large intestine into compounds known as urolithins, of which UA is among the most common [2, 3]. Individuals show large differences in urolithin production capacity due to variations in the microbiome responsible for ET metabolism [4]. Urolithins, including UA, are absorbed and conjugated in the liver and are subsequently excreted in urine and feces. Several studies have shown that UA and its two main detectable

Supplementary information The online version contains supplementary material available at 021-00950-1.

* Anurag Singh

1 Amazentis SA, EPFL Innovation Park, Lausanne, Switzerland 2 Atlantia Food Clinical Trials, Cork, Ireland 3 Clinical Microbiomics, København, Denmark 4 Laboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland 5 Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

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