gut health, microbiomes

Urolithin A

Singh A, D’Amico D, Andreux PA, Dunngalvin G, Kern T, Blanco-Bose W, Auwerx J, Aebischer P, Rinsch C. Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population. Eur J Clin Nutr. 2022 Feb;76(2):297-308. PMC free article

The featured image is an attempt to illustrate the experimental cross-over design of this study. Participants were assigned to two groups of 50 each: pomegranate juice or a Mitopure 500 mg tablet of Urolithin A. Blood was drawn followed by a washout period. Then participants crossovered to the other group. Urolithin A, the glucuronidated, and sulfated, metabolites were measured in the blood plasma.

Figure s1 urolithin species: pomegranate juice and Mitopure supplement

Here we are looking at the plant precursors of urolithin A. We are assuming that some of these plant compounds are partially broken down from punicalagins to ellagic acid in the small intestine and to urolithin in the colon.

We’ve got to remember in looking at these data that the units are in milligrams, presumably per serving, rather than molar amounts.

4. Pomegranate juice urolithin is not that bio available

The authors chose to present their pharmokinetics data after the micorbiome data. According to the Mayo Clinic it takes about eight hours for food to pass through the stomach and small intestine and an additional 18 hours to pass through the colon.

Images of the parent compound and the liver metabolite are shown to illustrate that pomegranate juice is not a good source of urolithin or liver metabolites. Even the Mitopure urolithin A is quickly metabolized to sulfated and glucuronidated versions. By 24 hours these also start to disappear presumably in the urine and/or the feces.

Figure 5 Urolithin population comparison

Panels A through C examine the parent compound and liver metabolites. The Mitopure supplement seems to result a greater plasma presence.

Panel D, age does not matter. Panels E and F, the results seem to be scewed by more participants in the pomegranate group having lower plasma levels of the glucuronic acid conjugate at six and 24 hours.

Figure 2 Urolithin A in plasma 24 hr post intake

Figure 2 of the Singh publication examines the urolithin A glururoninide in blood plasma at the baseline, six, and 24 hours post intake of pomegranate juice. Only a small percentage of the participants had detectable levels of the liver metabolite, the glucuronidated form, at baseline. Even after 24 hours, many of the participants had no detectable conjugate in their blood plsama.

Figure 3 It takes a village of microbes to digest pomegranate juice

The feces of the participants were subjected to shotgun sequencing to determine the “village” of microbes. In the wold of big data, this process includes metagenome analysis MGA. The bugs were correlated with no, low, and high producers of glucuronidated urolithin A.

  • A alpha diversity includes number of species and the number of genes.
  • B The Shannon index also takes into account the relative abundance of species, i.e. that one species does not represent 99% of the entire population.
  • C Bray–Curtis dissimilarity. Bray–Curtis dissimilarity can range between 0 and 1, where 0 means that the two samples have identical compositions (they share all species at the same relative abundance), and 1 means that the two samples are completely different (they do not share any species). A principal coordinate analysis of the Bray–Curtis dissimilarities showed a shift in the overall microbiome composition when comparing non-producers with low (p = 0.048) and high producers (p = 0.001), as shown by the clear segregation of the groups.

The Firmicutes (F) /Bacteroidetes (B) ratio is being used as a diagnostic test with unsure meaning. The authors narrowed down the Phyla to species and so on. For instance, a high abundance of species belonging to the Clostridiales and Ruminococcaceae family was found in the high UA producer group. They also found an increased abundance of Akkermansia muciniphilia in the microbial high urolithin group.

Concluding Thoughts

The authors did not address a few things in this exciting study. Perhaps further questions of things that need to be addressed are hallmarks of a good study.

  1. Whether the liver conjugates are biologically active.
  2. The fate of the modifications in the colon, i.e. are there intestinal bacteria with beta glucuronidases and/or sulfidases?
  3. Which form of urothilin A is absorbed and where?
  4. Does having a biological action require having a sustain presence in the blood plasma or are just a few hours sufficient?

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