Jacob Schor, ND

If I were prone to magical thinking, the single sole solitary raspberry that caught my eye  perched amid acres of bare raspberry bushes, might be taken as a sign, an attempt by the universe to send me a message, a communication of sorts.  Alan Crabtree who was hiking by my side when I spotted that raspberry, said, “Last one of the season,” And without a further thought I picked it and chewed it down.  It was perfectly tasty and I found myself repeating that line, “last one of the season” as I savored it and ground the seeds between my teeth,  It’s already mid-October as I write, and it’s only after I got home and returned to reading papers on ellagic acid and urolithins that I began to wonder at the anomaly of finding such a perfect raspberry so late in the season.  Perhaps it was a serendipitous reminder to put my thoughts to paper.

I spent two days in Seattle a week before finding that berry and spent much of my time with my old friend Dr. Davis Lamson.  The last time I saw Davis in person was at the OncANP conference in New Mexico just as the pandemic was taking hold. For a guy pushing 90, Dr. Lamson certainly doesn’t look or act like it.  He seems to have stopped aging about a decade back, which is probably why I pay attention when he’s excited about a new supplement.

This time was no different.  He’d recently begun taking urolithin-A and was unabashedly enthusiastic about it.

Urolithin-A is a bacterial metabolite of ellagic acid (EA) and ellagitannins (ETs). Ellagic acid is the chemical found in pomegranates, walnuts, apricots, and, of course, red raspberries that we have been excited about for years.   I’ve written about the health benefits associated with ellagic acid in years past.  It turns out that I was wrong when I wrote those articles. The story altered in about 2015.  That’s when scientists figured out it wasn’t ellagic acid at all that affected health but a series of metabolites that were made from ellagic acid by bacteria in the intestine. Intestinal bacteria can convert ellagic acid into a series of chemicals called urolithins.  Clinically consuming foods containing ellagic acid, never proved as effective as we had hoped.  Doing so seemed to help some, but a minority, of people.  We now understand that it is not ellagic acid that provides the health benefits but the urolithins.  But only some people apparently have the necessary bacteria to perform this conversion from ellagic acid to the urolithins,. Lamson told me that only about 4 people in 10 people can do so.  I’m still looking for that citation.

Back in 2004, when the first evidence from human clinical trials was being published suggesting pomegranate juice might be protective against cardiac atherogenesis, those studies pointed out that little of the ellagic acid or other initial constituent ellagitannins from pomegranate juice could be found in human blood serum but rather, “Three microbial ellagitannin-derived metabolites were detected: 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide, an unidentified aglycone (tentatively, trihydroxy-6H-dibenzo[b,d]pyran-6-one) and hydroxy-6-H-dibenzo[b,d]pyran-6-one glucuronide. ”¹  With names like those I see why I might have skimed  over them.

In recent years it has become apparent that the urolithins are produced by the human gut microbiota from ellagitannins and ellagic acid (EA are much better absorbed than their precursors and are responsible for the health effects we had attributed to ellagitannins and ellagic acid found in food.  While it might be true to say that foods containing these chemicals are healthy, we weren’t being accurate. At the time, our view of things was simpler and we were not considering how important the interplay between food and microbiome is.

While the specifics of ellagic acid and its conversion into active metabolites is good for us to understand, the real importance is that this specific example of how the microbiome interacts with diet in the production of specific metabolites is an excellent model for us to understand the effect of diet on health in a much broader sense.² There are a long list of nutrients that follow a similar pattern; they require bacterial conversion to have an effect.

How does one read about and sing the praises of ellagic acid for so many years as I have, and not realize that there is NO evidence that this chemical can be absorbed from the human digestive tract?³ 

Urolithins are far better absorbed than EA or ETS and are now understood to be responsible for the health benefits of eating foods high in EA or ETS, things like pomegranates, berries, nuts and also many medicinal plants.⁴

The chemical conversion of ETS and EA to urolithin is complex and still not fully understood even with the application of some very high tech modern analytical techniques.  For example, tannases are essential in an early step in the process of hydrolysis of ETS.  A growing list of bacteria have been identified that can produce tannases.  Bacteria that produce tannases are reported to have anti-carcinogenic effects, protecting against colon cancer.⁵

Basically, the various ETS are broken down to hexahydroxy diphenic that is then, via lactonization, converted to ellagic acid and then from there metabolized to one of the forms of urolithins, of which there are 13 that seem to vary depending on where in the body they are isolated from.  Two species of Gordonibacter have been identified that may be responsible for conversion of ellagic acid to urolithins.⁶  A number of significant gaps remain in the understanding of how this process occurs. 

I should probably leave it to Davis Lamson to come up with a concise description of the process.  After all he’s the retired one-time college chemistry professor.

Researchers categorize people into three basic metabotypes depending on qualitative and quantitative proportions of urolithins they produce.  Metabotype A people produce urolithin A, metabotype B produce Urolithin B in addition to urolithin A and metabotype 0 produce no significant amount of urolithin.  There seems to be great variability and dependence on intake of ETS from various foods, making human research on dietary effect exceedingly complex.

The percentage of people categorized as each metabotype shifts with age, In general the young are more likely to convert ETs and EA to urolithin-A, decreasing from 85% of to 45% as individuals go from childhood to adulthood.

A number of bacterial species have been identified that play a role in the production of urolithin-A and urolithin-B in particular Gordonibacter urolithinfaciens, and Ellagibacter isourolithinifaciens.

The urolithins are now given credit for the anticancer, anti-inflammatory, cardio-metabolic, antioxidant, neuroprotective, and antimicrobial effects once attributed to consumption of those foods high in EA or ETs. 

Several newer biological actions are now linked to urolithins.  The most striking effect, that has been revealed using urolithin in human trials is data that suggest people taking oral urolithin see improvements in exercise endurance.  This is believed to result from improvements in mitochondrial health.⁷

A 2016 paper introduced the term mitophagy to our vocabularies and suggested urolithin A was “…. a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption.”   (While the term mitophagy is new, apparently the process itself was first described by the microbiologist Margaret Lewis in 1915.⁸)

Mitophagy combines the term ‘mitochondria’ with ‘-phagy’ (which means to eat a specific food) so mitophagy roughly means the eating (or chewing up) of mitochondria.  Think of this as a quality control mechanism that allows the degradation and removal of damaged or excess mitochondria and ‘reinstates cellular homeostasis in response to stress’. Current evidence suggests that impaired mitophagy plays an important causative role in human disease particularly those associated with aging, including neurodegeneration, heart disease and cancer.  Inducing mitophagy may ameliorate these conditions.⁹

A 2016 paper from Ryu et al., published in Nature Medicine, reported that urolithin A triggered mitophagy and prolonged lifespan first in C. elegans and then in mice.¹⁰ Since then, at least two human clinical trials using urolithin A have reported effects on mitochondrial function.

What may be the first report of a human trial using urolithin A appeared in Nature Metabolism in 2019. Penelope Andreaux et al described giving urolithin A at doses from 250 of up to 1000 mg/day to small cohorts of older adults for four weeks. Several molecular markers of mitochondrial health were followed and showed significant impacts on mitochondrial health after four weeks with doses of 500 or 1000 mg/day.¹¹

In 2021 Jayatunga et al reviewed the research supporting urolithin-A as a possible treatment for Alzheimer’s disease. Their review concludes that when it comes to the, prevention and treatment of AD: “Urolithins are particularly promising, as they represent microbial metabolites of ingested polyphenols and initial studies suggest that they may have a multifaceted therapeutic value for AD by their actions to reduce BACE1 activity, Aβ fibrillation, ROS damage, inflammation, and atherogenesis and most importantly, their ability to restore/induce mitophagy, which is impaired in AD.”¹²

In January 2022, Liu et al. reported on their double-blind, placebo-controlled randomized clinical trial in older adults aged (n=66:  65 to 90 years-old) that they had conducted in Seattle, Washington.  Half of participants received urolithin-A (1000 mg/day) and the rest placebo for four months.  While acylcarnitines, ceramides and C-reactive protein decreased in the urolithin A group, the increase in minute-walk distance, a measure of physical performance, although greater, did not reach statistical difference.¹³

 In May 2022, Singh et al.  reported on a clinical trial in which study participants (n=88) were divided into three groups to receive either placebo, urolithin A 500 mg/day, or 1000 mg/day for four months.  Both doses were associated with significant improvements in a series of key markers, including muscle strength (about 12%), and exercise performance. Proteins associated with mitophagy were found in muscle tissues.¹⁴

So maybe this stuff works.  Based on Davis Lamson’s enthusiastic recommendation, I’m inclined to try it and see if I feel anything.

Whatever we eventually conclude to be true about urolithin-A and its effect as a dietary supplement, there is something larger going on that we should take notice of.  There is a shift occurring in how the relationship between diet and health is explained that needs to be acknowledged.

At one time, the focus was overwhelmingly on the chemicals in foods called vitamins that were essential for life.  In more recent years, interest shifted toward the nutrients, those other chemicals found in foods that were seen to improve health.  The idea that all good things were antioxidants took firm hold and persists in the common imagination.  The names of various families of chemicals, things like polyphenols, isoflavones, bioflavonoids, or in this case ellagic acid and ellagitannins in pomegranates, crept into our vocabularies. 

Even more recently, the focus has shifted from food to our internal populations of micro-organisms and the realization that good health was greatly influenced by the presence or absence of the microbiota in the digestive tract.  Great effort has been put toward identifying the specific organisms or species of bacteria associated with certain health outcomes in the hope that those having beneficial effects might be cultivated, that is encouraged to grow, in the intestinal environment, and those associated with negative effects might be dissuaded from habitation.  These efforts have met with limited success.  Although certain families of bacteria have been identified and sometimes associated with specific outcomes, results of comparative studies hoping to identify specific types of bacteria have been inconsistent.  

It is now understood that one specific bacteria or conglomerate of several species are not necessarily responsible for any given effect.  As an example, consider specifically the efforts to improve response rates to checkpoint inhibitor drugs now used in treating cancer.  In this and in other examples, apparently, it is neither the food nutrient itself, nor the specific bacteria that are linked to an outcome, but the metabolites produced by bacteria from the food nutrients that are the responsible agents that affect health.

Often there are a range of different bacteria that can perform a specific chemical process that metabolizes a specific ingredient and yields a specific metabolite: the responsibility of who, that is which bacterial species, performs the task may shift with diet, genetics, exposure and even geography.¹⁵

Dr. Heather Zwickey summed this up rather simply for me recently, “…. The reason that bacteria data is inconsistent is it’s not the bacteria that matters so much as it’s what those bacteria are doing. This paper by Visconti came out in 2019.¹⁶ It shows that microbes are not highly conserved between people (40% at best), but metabolites are (84% and more). That means that in some people, Akkermansia may be producing a particular metabolite. And in someone else, Bifidobacterium may be producing that same metabolite. So, it’s the metabolite that matters and not the microbe that is making it.”

In that same note she pointed out the new online atlas by Dekkers et al, which attempts to catalog nearly a thousand different metabolites found in the blood serum with the far greater number of possible bacterial species that can produce them.¹⁷ 

A considerable number of bacteria have been identified that play a role in the production of urolithin-A and urolithin-B in particular Gordonibacter urolithinfaciens, and Ellagibacter isourolithinifaciens.  The results are inconsistent.

Ellagic acid and the ellagitannins are not the only food nutrients converted by the gut microbiome into active metabolites.  For example, it is now understood that the soy isoflavone daidzein is converted by the gut microbiome into to S-equol, the ‘most biologically potent among all soy-isoflavones….” This helps explain much of the discrepancies seen in epidemiological data from East Asia where soy foods are consumed regularly and are inversely associated with cognitive decline and dementia.  Randomized controlled trials of soy isoflavones in Western countries show little if any impact on cognitive health.  These inconsistent findings are explained by differences in the production of S-equol from soy food.  Greater numbers of East Asians, 40-70%, produce isoflavones while less than 30% of Westerners do.  Recent Japanese studies tell us that it is this bacterial metabolite S-equol rather than soy isoflavones that is associated with cognitive health.¹⁸

[A brief tangent while writing about equol, the dietary supplement berberine appears to enhance the production of S-equol by altering the gut microbiome and this may explain its wide range of apparent health benefits.  Thus, we may want to employ both at the same time, soy plus berberine.¹⁹ ]

The list of gut metabolites that affect health is growing rapidly.  To urolithin-A and S-equol, we should add short chain fatty acids, trimethylamine-N-oxide (TMAO), imidazole proprionate , Gamma-Aminobutyric Acid (GABA), serotonin, kynurenine, and other chemicals I’ve never heard of before.²⁰

Indeed, it seems that many of the phyto-nutrients we have often employed over the years as dietary supplements require “gut microbiota-mediated biotransformation” in order to enhance effectiveness.  These include “the major dietary polyphenols (resveratrol, curcumin, quercetin, rutin, genistein, daidzein, ellagitannins, proanthocyanidins).”²¹

We are at a point in time that the relationships between diet and health have grown more complex.  It’s not just the nutrients in food that are crucial to health but the conversion by the gut microbiome of these chemicals into metabolites that may be either beneficial or deleterious that now needs inclusion in our calculations.

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References

1. Cerdá B, Espín JC, Parra S, Martínez P, Tomás-Barberán FA. The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans. Eur J Nutr. 2004 Aug;43(4):205-20.

2. Tomás-Barberán FA, González-Sarrías A, García-Villalba R, et al. Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol Nutr Food Res. 2017 Jan;61(1).

3. Cerdá B, Espín JC, Parra S, Martínez P, Tomás-Barberán FA. The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans. Eur J Nutr. 2004 Aug;43(4):205-20.

[4. Yang X, Tomás-Barberán FA. Tea Is a Significant Dietary Source of Ellagitannins and Ellagic Acid. J Agric Food Chem. 2019 May 15;67(19):5394-5404.

5. López de Felipe F, de Las Rivas B, Muñoz R. Bioactive compounds produced by gut microbial tannase: implications for colorectal cancer development. Front Microbiol. 2014 Dec 5;5:684.

6. Tomás-Barberán FA, González-Sarrías A, García-Villalba R, et al. Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol Nutr Food Res. 2017 Jan;61(1).

7. Singh A, D’Amico D, Andreux PA, et al. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Rep Med. 2022 May 17;3(5):100633.

8. Lewis, Margaret (1915). “Mitochondria (and other cytoplamic structures) in tissue cultures” (PDF). American Journal of Anatomy. 17 (3): 339–401.

9. Chen G, Kroemer G, Kepp O. Mitophagy: An Emerging Role in Aging and Age-Associated Diseases. Front Cell Dev Biol. 2020 Mar 26;8:200.

10. Ryu D, Mouchiroud L, Andreux PA, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016 Aug;22(8):879-88.

11. Andreux PA, Blanco-Bose W, Ryu D, et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019 Jun;1(6):595-603. https://www.researchgate.net/publication/333789099_The_mitophagy_activator_urolithin_A_is_safe_and_induces_a_molecular_signature_of_improved_mitochondrial_and_cellular_health_in_humans

12. Jayatunga DPW, Hone E, Khaira H, et al.Therapeutic Potential of Mitophagy-Inducing Microflora Metabolite, Urolithin A for Alzheimer’s Disease. Nutrients. 2021 Oct 23;13(11):3744. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617978/pdf/nutrients-13-03744.pdf

13. Liu S, D’Amico D, Shankland E, et al. Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jan 4;5(1):e2144279.

14. Singh A, D’Amico D, Andreux PA, et al. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Rep Med. 2022 May 17;3(5):100633. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133463

15. McCulloch JA, Davar D, Rodrigues RR, et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat Med. 2022 Mar;28(3):545-556.

16. Visconti A, Le Roy CI, Rosa F, et al. Interplay between the human gut microbiome and host metabolism. Nat Commun. 2019 Oct 3;10(1):4505.

17. Dekkers KF, Sayols-Baixeras S, Baldanzi G, et al. An online atlas of human plasma metabolite signatures of gut microbiome composition. Nat Commun. 2022 Sep 23;13(1):5370.

18. Sekikawa A, Wharton W, Butts B, et al. Potential Protective Mechanisms of S-equol, a Metabolite of Soy Isoflavone by the Gut Microbiome, on Cognitive Decline and Dementia. Int J Mol Sci. 2022 Oct 7;23(19):11921.

19. Fang Y, Zhang J, Zhu S, et al. Berberine ameliorates ovariectomy-induced anxiety-like behaviors by enrichment in equol generating gut microbiota. Pharmacol Res. 2021 Mar;165:105439. https://www.sciencedirect.com/science/article/pii/S1043661821000220?via%3Dihub

20. Swer NM, Venkidesh BS, Murali TS, Mumbrekar KD. Gut microbiota-derived metabolites and their importance in neurological disorders. Mol Biol Rep. 2023 Feb;50(2):1663-1675.

21. Luca SV, Macovei I, Bujor A, et al.. Bioactivity of dietary polyphenols: The role of metabolites. Crit Rev Food Sci Nutr. 2020;60(4):626-659.

Published June 29, 2024

About the Author

Jacob Schor, ND, now retired, had a general practice with a focus on naturopathic oncology in Denver, Colorado. He served as Abstract & Commentary Editor for the Natural Medicine Journal for several years (https://www.naturalmedicinejournal.com/) and posts blog articles on natural therapies,  nutrition, and cancer (https://drjacobschor.wordpress.com/). He was a board member of CoAND and past president of OncANP, and is someone who is happier outdoors than inside.