Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome. . .
305
B
A
p<0.0001
p<0.0001
Mitopure
1000 1200 1400 1600
0 100 200 300 400 500 600
Pomegranate Juice (PJ) Mitopure
0 200 400 600 800
PJ
PJ (T24-T0)
Mitopure (T24-T0)
T0
T6 T24
T0
T6
T24h
D
C
p=0.015
80
p<0.0001
100 125 150 175 200
Mitopure
60
PJ
40
0 25 50 75
20
0
T0
T6 T24
T0
T6
T24h
PJ (T24-T0) Mitopure (T24-T0)
F
E
p=0.09
p<0.0001
Mitopure
0 100 200 300 400 500 600 700 800
1000 1200 1400 1600
PJ
0 200 400 600 800
PJ (T24-T0) Mitopure (T24-T0)
T0
T6 T24
T0
T6
T24h
Fig. 4 Mitopure supplementation delivers signi fi cantly higher plasma UA levels compared to PJ. Pharmacokinetic pro fi les at T0, T6 (6 h), and T24 (24 h) and mean absolute change in levels from T0 to T24 (primary outcome of study) between the two interventions of PJ and Mitopure supplementation for UA glucuronide ( A , B ), UA sulfate
( C , D ), and parent UA ( E , F ) showing signi fi cantly higher plasma levels of UA and its metabolites with Mitopure supplementation compared to PJ dietary challenge ( N = 100). All data are analyzed using a repeated measure ANOVA ( A , C , E ) and an unpaired t -test ( B , D , F ).
Discussion
produce these different urolithins, which was observed to range from 30 to 60%. In the studied cohort, only 12% participants had circulating levels of UA at baseline and ~40% signi fi cantly converted the dietary precursors to UA after the PJ dietary challenge (Fig. 2). The current evaluation greatly expands our under- standing of human exposure to UA during the initial 24 h after intake of foods containing UA precursor compounds such as PJ and provides an insight on the dosing of natural foods required in order to achieve biologically active levels of UA in the plasma. We have also characterized the gut microbiome of UA producers vs. non-producers and have been able to identify distinct features that determine the ability to produce UA. Gut microbiome make-up deter- mined UA producer status. Non-producers clearly lacked the richness and diversity needed to transform the poly- phenolic dietary precursors into UA and had a lower F/B ( Firmicutes to Bacteroidetes ) than high producers (Fig. 3). This is particularly relevant as a low F/B ratio has been
This is the fi rst study to compare the levels of exposure to UA obtained via natural dietary exposure to precursors vs. direct dietary supplementation with UA, and to evaluate the prevalence of natural UA producers across a signi fi cant sample size of a hundred healthy adults in a major metro- politan area in USA. This study has led to a further understanding of the complexity of obtaining UA from the diet alone due to dietary differences and the diversity of the microbiome among the general population. Prior to this report, there have been several studies of much smaller scope performed in southern Europe that have explored the identities of the urolithin metabolites produced in indivi- duals following dietary challenges of pomegranate, berries, and nuts rich in ET [1, 3, 13, 21]. These studies have led to the detailed chemical characterization of the family of urolithin metabolites produced following ellagitannin con- sumption as well as an appreciation of the natural ability to
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