Data published in the European Journal of Clinical Nutrition indicated that direct supplementation with Urolithin A (500mg) led to urolithin A (UA) levels six times higher than consumption of 8oz (240ml) of 100% pomegranate juice.
“This is the first 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 significant sample size of a hundred healthy adults in a major metropolitan area in USA,” wrote researchers from Amazentis, Atlantia Food Clinical Trials, Clinical Microbiomics (Denmark), and the Ecole Polytechnique Fédérale de Lausanne (Switzerland).
“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.”
Producers vs low producers vs non-producers
Urolithin A is a compound generated by gut microflora from ellagitannins found in food such as pomegranate. The compounds are hydrolyzed in the stomach into ellagic acid, which is subsequently converted by the gut microflora into urolithin A. However, not everyone has the right microflora to be able to make the compound.
“Several studies have shown that UA and its two main detectable metabolites, UA glucuronide and UA sulfate, are the predominant urolithin forms in circulation,” explained the researchers.
As reported previously by NutraIngredients-USA, Amazentis has developed a method to deliver finely calibrated doses of urolithin A. Preliminary data published in Nature Medicine indicated that urolithin A may improve mitochondrial function by stimulating mitophagy, a process by which damaged mitochondria are recycled to permit a renewal with healthy mitochondria. These potent beneficial effects were observed in C. elegans, mammalian cells and rodents.
This was followed up by human data from a Phase 1 double-blind, randomized, placebo-controlled clinical trial in healthy elderly individuals that were presented at the 2017 International Conference on Frailty and Sarcopenia Research (ICFSR) in Barcelona, Spain.
The data supported the safety of the Mitopure-branded Urolithin A and indicated that the compound upregulated mitochondrial gene expression in elderly skeletal muscle tissue and decreased plasma acylcarnitine metabolites, which has been linked to skeletal muscle insulin resistance and lipid-induced mitochondrial stress.
The function of mitochondria declines with age, while aging is a known risk factor for a number of common age-related and neurodegenerative disorders. This led to the proposition that secondary mitochondrial dysfunction may lead to degenerative diseases.
The new study found that only 12% of the 100 subjects recruited for the study actually had detectable levels of UA at the start of the study. After consuming pomegranate juice, approximately 40% of the participants were found to exhibited significant conversion of the ellagitannin precursor compounds to UA.
Gut microbiota analysis revealed that the producers of UA had a significantly higher diversity of their gut microbiota and a higher ratio of Firmicutes to Bacteroides. The Firmicutes/Bacteroidetes ratio is reportedly a good biomarker for obesity and inflammatory bowel disease. Indeed, a 2005 study by Jeffrey Gordon and his group at Washington University in St. Louis indicated that obese mice had lower levels of Bacteroidetes and higher levels of Firmicutes, compared with lean mice.
Supplementation
The study also included a direct supplementation phase where the subjects were given a single 500 mg dose of Amazentis’ Mitopure urolithin A, and the researchers found that this led to significantly increased levels of urolithin A in plasma, with levels six times higher than occurred after drinking the pomegranate juice.
“The results observed pose an important question in terms of nutritional practices: is an optimal diet sufficient by itself? And how can someone know whether they are likely to harness the appropriate nutrients from the diet via their gut microbiome?” wrote the researchers.
“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 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 filling the gap created by the natural heterogeneity of the gut microbiome to deliver health benefits.”
Source: European Journal of Clinical Nutrition
Published online ahead of print, doi: https://doi.org/10.1038/s41430-021-00950-1
“Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population”
Authors: A. Singh, et al.
