Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome. . .
one was a natural UA producer or not with minimally invasive methods. Advanced nutrition approaches that allow the delivery of a nutritional bioactive such as UA in a calibrated manner will likely play a key role in fi lling the gap created by the natural heterogeneity of the gut micro- biome to deliver health bene fi ts. Acknowledgements We would like to thank the volunteers for their cooperation in the study and Atlantia Food Trials study staff for subject recruitment, data collection and processing, and Drs Aedin Cassidy and Navindra Seeram for their insightful discussion during the study conceptualization. Author contributions AS, PA, and CR contributed to the design of the study. AS, DD, PAA, and CR wrote the manuscript, with the help of the other co-authors. AS, DD, WB-B, and PAA collected all the ex vivo data. TK analyzed the metagenomics data. GD analyzed the study and bioavailability data. All authors reviewed the manuscript.
are achieved at 6 h after intake with the half-life in circu- lation being approximately a day. In this study, 500 mg of direct UA supplementation was reported to be safe, bioa- vailable, and have an impact on cellular and mitochondrial health , as such this dose was chosen for the current study. PJ containing ET and EA was chosen as the com- parator with the most balanced and highest precursor pro fi le and having good batch-to batch consistency in the levels of these precursors (Supplementary Fig. 1). Also, regular consumption of a glass of PJ is the easiest approach to integrate foods into our daily diets for potential exposure to UA. In the present study, we measured UA glucuronide levels at baseline, at the reported peak of 6 h following direct UA supplementation and fi nally at 24 h after intake. Absolute change in mean concentrations of UA glucur- onide, UA sulfate, and parent UA were signi fi cantly higher with the direct supplementation (>30-fold at 6 h and >2-fold higher at 24 h; Fig. 4 and Supplementary Table 4). When considering total exposure to UA during the initial 24 h following intake, 500 mg of UA supplementation led to a greater than six-fold ( p ≤ 0.0001) higher iAUC to UA glu- curonide when compared with PJ (Fig. 5A – C and Supple- mentary Table 4). Age had no impact on UA generation or absorption as well as UA producer status as levels were consistent across the different age groups of young, middle- aged, and elderly (Fig. 5D) both with direct UA supple- mentation and following PJ intake. Following PJ intake by UA producers, very few subjects exhibited plasma levels in the range observed with direct UA supplementation within the fi rst 6 h and the levels obtained at 24 h (Fig. 5E, F). The UA and its conjugate levels were also much more variable following PJ intake compared to direct UA supplementation that ensured a consistent and a more uniform distribution in the levels within the population. We also validated a minimally invasive method to determine UA producer status via few drops of dried blood collected via capillary blood (Supplementary Fig. 6) to plasma levels and found an excellent correlation. Such methods would allow for delivery of precise and calibrated dietary supplementation based on existing nutrient levels achieved via dietary exposure. Based on the fi ndings of the current study, to achieve the equivalent dosing of 500 mg supplementation of UA from dietary exposure via PJ, on average, an individual would need to drink six glasses (approx.1.5 L) of PJ that contained the necessary dietary precursors. The results observed pose an important question in terms of nutritional practices: is an optimal diet suf fi cient by itself? And how can someone know whether they are likely to harness the appropriate nutrients from the diet via their gut microbiome? Equally important would be to understand better how to harness the various gut microbiome species that would confer the UA producer capacity to an individual, and measure precisely if
Funding This study was funded by Amazentis SA.
Compliance with ethical standards
Con fl ict of interest The authors declare the following competing interests: AS, DD, PAA, WB-B, and CR are employees; PA and CR are board members; and JA and PA are members of the Scienti fi c Advisory Board of Amazentis SA, who is the sponsor of this clinical study.
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