306
A. Singh et al.
p<0.0001
C
p<0.0001
A
B
p<0.0001
0 100000 200000 300000 400000 500000 600000
0 100000 200000 300000 400000 500000 600000 700000
0 10000 20000 30000 40000 50000
PJ
Mitopure
PJ
Mitopure
PJ
Mitopure
E
F
D
PJ 6h Mitopure 6h
1050 1200
40
10 15 20 40 60 80
PJ 24h
Mitopure 24h
Mitopure 6h
PJ 6h
0 150 300 450 600 750 900
30
20
10
0 5
0
0
300 600 0
300 600
0
550
11000
550
1100
Age 20 30 40 50 60 70 80
UA-Glucuronide ng/mL Mitopure
UA-Glucuronide ng/mL PJ
UA-Glucuronide ng/mL Mitopure
UA-Glucuronide ng/mL PJ
proposed as a marker of gut dysbiosis associated with obesity (and chronic disorders such as metabolic syndrome [22] and in fl ammatory bowel disease [23]). Previous studies have identi fi ed certain gut microbiome groups and species to be associated with urolithin pro- duction [3, 24]. These investigations have highlighted the role of certain Clostridium - and Gordonibacter -linked species in the conversion process of EA and ET into uro- lithin metabolites. Likewise, in our study many differen- tially abundant taxa were also detected between the high UA producer group compared with the non-producer group. In particular, species belonging to the Clos- tridiales and Ruminococcaceae family were found in high abundance in the high UA producer group. Also, of parti- cular interest is the species Akkermansia muciniphilia , a gut residing commensal bacteria often associated with health indicators such as lower BMI, low grade in fl ammation, and improved metabolic health [25 – 27]. A signi fi cantly increased abundance of Akkermansia muciniphilia was observed in high UA producers compared to the no pro- ducers (Supplementary Fig. 3B). These results are pre- liminary and further studies are required in well-de fi ned populations to understand the role of this species and the other taxa in determining UA producer status and the gut- mediated UA conversion process. Fig. 5 Mitopure supplementation delivers >6-fold higher exposure to UA compared to PJ and achieves consistent levels across the adult population. Mean incremental area under the curve (iAUC) within a day following intake of Mitopure compared to the con- sumption of a glass equivalent of 100% PJ, for UA glucuronide ( A ), UA sulfate ( B ), and the parent UA ( C ) showing higher exposure to UA and its metabolites with Mitopure compared to PJ ( N = 100). All data
are expressed as mean ± SEM and analyzed using an unpaired t -test. Correlation of UA glucuronide levels across different age groups at 6 h following either PJ intake or direct UA supplementation ( D ). Fre- quency distribution of UA glucuronide levels observed across the population following both PJ and direct UA supplementation at 6 h ( E ) and 24 h post intake ( F ).
Other examples of how foods can be metabolized dif- ferently based on gut microbiome include the generation of equol and short-chain fatty acids (SCFAs). Equol is a metabolite generated when gut micro fl ora metabolizes dietary iso fl avones such as daidzein [28, 29]. Studies have found that 30 – 40% of the population can naturally generate equol [30, 31]. Similarly, SCFAs are produced upon exposure to dietary fi ber and an inability to produce SCFAs has been intricately linked to microbiome dysfunction that eventually leads to chronic disease development such as in fl ammatory bowel disease and age-related cognitive impairment [32, 33]. Gut metabolites such as UA, equol, and SCFAs are nutrients made available as the end-product of an optimal gut microbial ecosystem. The insight that a majority of people lack the necessary microbiome to make their own UA reveals a gap in our current approaches to achieve a balance in the natural nutrients provided by a healthy diet. This opens the door to dietary supplementation as a strategy to overcome the de fi ciencies both in the natural microbiome and in dietary consumption patterns that lead to UA heterogeneity in the population. In a fi rst-in-human study with direct UA supplementation in healthy elderly it was previously reported that UA glu- curonide is the dominant circulating metabolite, in addition to parent UA and UA sulfate, and that peak concentrations
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