Urolithin A: The Next Big Thing Or the Next Forgotten Fad?
Introduction
The supplement market is an ever-changing landscape, constantly evolving—or perhaps devolving—with the steady introduction of new molecules and substances touted as miracle solutions for various health concerns. One recent standout is Urolithin A, a gut microbiome metabolite derived from ellagitannins found in foods like pomegranates and walnuts. This compound has caught the attention of the scientific community, sparking the usual cascade of interest in the nutritional and functional medicine industries, alongside a frenzy among overzealous biohackers, health enthusiasts, and social media influencers.
But before diving headfirst into the hype surrounding Urolithin A, it's worth pausing to reflect on the history of supplement trends—many of which initially dazzled with potential only to fall short of expectations. History has a habit of repeating itself, after all.
Historical Context: Promises of the Past
Depending on ones age and time spent in this industry, the following brief list may ring some bells of familiarity in supplements gone by:
- Resveratrol: Once hailed as an anti-aging wonder, resveratrol's clinical outcomes failed to match the initial hype. While in vitro and animal studies showed promising results, human trials have been largely inconclusive [1].
- Beta carotene: Initially touted for cancer prevention, beta carotene supplements were later found to potentially increase lung cancer risk in smokers [2].
- Chromium picolinate: Claims of metabolism-boosting effects were largely debunked after extensive research showed minimal impact on weight loss or muscle gain [3].
- Conjugated linoleic acid (CLA): Despite initial promises of significant weight loss benefits, long-term studies have shown only modest effects, if any [4].
- DHEA: The anti-aging effects of DHEA proved less impressive in human studies than initially hoped, with potential side effects outweighing benefits for many individuals [5].
- And there are so many more littering the graveyard of once hopeful and promising supplements.
These examples serve as a cautionary tale as we delve into the potential of Urolithin A—or any new supplement that captures the attention of practitioners and the public alike. This article aims to provide a balanced exploration of Urolithin A, examining its mechanism of action, current research landscape, and broader context within gut health and metabolism. We'll consider both supplementation and whole food approaches, offering nutritional and functional medicine practitioners a comprehensive perspective to inform clinical decisions.
"While Urolithin A represents an exciting area of nutritional research, its place in clinical practice should be considered as part of a comprehensive approach to health that prioritizes dietary quality, gut health, and overall lifestyle factors."
The Chemical Structure and Properties of Urolithin A
Metabolism and Bioavailability
- Gut Microbiota Metabolism: The production of Urolithin A is largely dependent on the metabolic activities of gut microbiota. Different bacterial species play roles in this conversion process, with some being more efficient than others [30].
- Absorption: Once produced, Urolithin A is absorbed in the colon and enters the bloodstream.
- Liver Metabolism: In the liver, Urolithin A undergoes phase II biotransformation, resulting in various conjugated forms, primarily glucuronides and sulfates [28].
- Distribution: The conjugated forms of Urolithin A are then distributed throughout the body via the bloodstream.
- Excretion: Urolithin A and its metabolites are eventually excreted in urine and feces.
Foods Rich in Ellagitannins and Ellagic Acid
- Growing conditions
- Ripeness
- Storage conditions
- Processing methods
- Variety of the fruit/nut
- Analytical methods used to measure the compounds
- Pomegranates
- Amount: 150-300 mg of ellagic acid per 100g of fresh pomegranate seeds; high in punicalagins.
- Raspberries
- Amount: ~270 mg of ellagic acid per 100g of fresh raspberries; seeds are particularly high.
- Strawberries
- Amount: ~150-190 mg of ellagic acid per 100g of fresh strawberries.
- Blackberries
- Amount: ~150 mg of ellagic acid per 100g of fresh blackberries.
- Walnuts
- Amount: ~59 mg of ellagic acid per 100g of walnuts.
- Pecans
- Amount: ~33 mg of ellagic acid per 100g of pecans.
- Almonds
- Amount: ~33 mg of ellagic acid per 100g of almonds.
- Grapes (especially Muscadine)
- Amount: ~20-55 mg of ellagic acid per 100g of Muscadine grapes.
- Oak-aged wines
- Amount: Varies widely depending on the type and aging process, but generally lower than in fresh fruits.
- Guava
- Amount: ~20 mg of ellagic acid per 100g of guava.
- Cloudberries
- Amount: ~500 mg of ellagitannins per 100g; particularly sanguiin H-6.
- Persimmons
- Amount: ~20 mg of ellagic acid per 100g.
Urolithin Metabotypes
- Metabotype A: Individuals who efficiently produce Urolithin A as the main end-product of ellagitannin metabolism.
- Metabotype B: Individuals who produce Urolithin B and/or isourolithin A, with little or no Urolithin A production.
- Metabotype 0: Individuals who produce little to no urolithins.
The Role of Gut Microbiome in Urolithin A Production
Key findings from this study included:
- The researchers identified two main urolithin metabotypes based on the gut microbiota's ability to metabolize ellagitannins.
- These metabotypes correlated with cardiometabolic risk biomarkers, suggesting a potential link between urolithin production capacity and overall health.
- The study found differences in urolithin metabotypes among individuals with different body weight statuses (normal weight, overweight-obese, and metabolic syndrome).
Urolithin A Mechanism of Action
Lifespan Extension and mitophagy in C. elegans
Anti-inflammatory Properties
Antioxidant Effects
Muscle Function Enhancement
Gut Health Impact
The gut health effects of Urolithin A are particularly intriguing, given its origin as a gut metabolite. Some research suggests it may improve gut barrier function and reduce inflammation, but these findings are primarily from preclinical studies [18]. The potential for Urolithin A to positively influence the gut microbiome and overall digestive health warrants further investigation in human trials.
Cardiovascular Effects
Neuroprotective Potential
Paucity of Human Trials
Current Research Landscape
Key Human Studies
Study | Participants | Duration | Key Findings | Limitations |
Liu et al. (2022)[13] | 66 older adults | 4 months | Improved muscle endurance, no significant change in walking distance | Small sample size, short duration |
Andreux et al. (2019)[14] | 60 elderly individuals | 4 weeks | Improved mitochondrial gene expression in muscle | Short duration, limited functional outcomes |
Singh et al. (2022)[15] | 88 middle-aged adults | 4 months | Improved muscle strength and exercise performance | Industry-funded, limited long-term data |
Funding and Bias Concerns
Limitations of Current Human Clinical Evidence
- Small Sample Sizes: Most of the available human studies have involved relatively small numbers of participants, limiting the generalizability of their findings.
- Short Duration: Many of the studies have been relatively short-term, ranging from a few weeks to a few months. The long-term effects of Urolithin A supplementation remain unclear.
- Limited Population Diversity: Most studies have focused on older adults or middle-aged individuals. The effects of Urolithin A in younger populations or those with specific health conditions are less well-studied.
- Potential Conflicts of Interest: As discussed above, a significant portion of the human clinical research on Urolithin A has been sponsored by companies that produce Urolithin A supplements, which could potentially introduce bias.
- Lack of Diverse Health Outcomes: While muscle health and mitochondrial function have been relatively well-studied, there is a lack of human clinical evidence for many of the other potential benefits suggested by preclinical research, such as neuroprotective effects or anti-cancer properties.
- Variability in Dosage and Duration: The optimal dosage and duration of Urolithin A supplementation remain unclear, with studies using varying protocols.
Beyond Urolithin A
Urolithin Metabolites
- Urolithin B has shown promise in some studies for its anti-inflammatory and antioxidant properties [22].
- Urolithin C has demonstrated potential anticancer effects in preclinical models [23].
- The parent compound, ellagic acid, also possesses biological activities that may contribute to the overall health benefits of ellagitannin-rich foods [24].
Whole Food Complexity
Food Source | Key Bioactive Compounds | Potential Health Benefits |
Pomegranate | Punicalagins, anthocyanins, ellagic acid | Antioxidant, anti-inflammatory, cardioprotective |
Walnuts | Ellagitannins, omega-3 fatty acids, vitamin E | Cognitive function, heart health, anti-inflammatory |
Strawberries | Ellagitannins, vitamin C, anthocyanins | Antioxidant, immune support, cardiovascular health |
Raspberries | Ellagitannins, anthocyanins, quercetin | Anti-cancer, anti-inflammatory, metabolic health |
Table 1: Bioactive Compounds in Ellagitannin-Rich Foods
Prebiotic Effects
Matrix Effect
Comparative Analysis
Aspect | Urolithin A Supplementation | Dietary Sources of Ellagic Acid |
Dosage Control | High | Variable |
Concentration | Potentially Higher | Generally Lower |
Convenience | High | Moderate |
Whole Food Benefits | No | Yes |
Synergistic Effects | Limited | Potentially High |
Cost | Generally Higher | Generally Lower |
Safety Profile | Limited Long-Term Data | Well-Established |
Gut Microbiome Support | Limited | Potentially High |
Other Beneficial Compounds | Limited | Abundant |
Given these considerations, a balanced approach might involve focusing on a diet rich in ellagic acid-containing foods while simultaneously supporting overall gut health, rather than simply jumping to the latest isolated relatively untested molecule.
Personalized Approach
Gut Health Optimization
Certain bacterial species, for example, particularly those belonging to the Gordonibacter genus, have been identified as key players in the conversion of ellagitannins to Urolithin A [30]. However, the presence of these bacteria alone does not guarantee efficient Urolithin A production. Factors such as overall microbial diversity, the presence of competing bacteria, and the overall gut environment all play roles in determining Urolithin A production efficiency.
- Increasing dietary diversity: Particularly focusing on plant-based foods rich in fiber and polyphenols [31].
- Regular consumption of fermented foods: To introduce beneficial bacteria and support microbial diversity [32].
- Stress reduction and adequate sleep: Which have been shown to positively impact gut microbiome composition [33].
- Regular physical activity: Which can enhance microbial diversity and overall gut health [34].
- Minimizing exposure to negative factors: Such as excessive alcohol consumption and certain medications that can disrupt gut health [35].
Strategies for Gut Health Optimization
Conclusion
The best and most reasonable approach appears to be a whole food approach that emphasizes ellagitannin-rich foods like pomegranates, berries, and nuts, while also supporting gut health. This approach offers several advantages. First, it provides not only the precursors for Urolithin A but also a complex array of other beneficial compounds and nutrients that may work together synergistically. Second, this approach also aligns with broader principles of gut health optimization, which has wide reaching benefits, as well as being crucial for optimal Urolithin A production.
Ultimately, while Urolithin A represents an exciting area of nutritional research, its place in clinical practice should be considered as part of a comprehensive approach to health that prioritizes diet quality, gut health, and overall lifestyle factors. As research continues to evolve, maintaining a critical and evidence-based perspective will be essential in determining whether Urolithin A truly represents the next big thing in nutritional science or if it will join the ranks of past supplement trends that failed to live up to their initial promise.
References
- Berman, A.Y., Motechin, R.A., Wiesenfeld, M.Y. et al. The therapeutic potential of resveratrol: a review of clinical trials. npj Precision Onc 1, 35 (2017). https://doi.org/10.1038/s41698-017-0038-6
- The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330(15):1029-1035.
- Vincent JB. The biochemistry of chromium. J Nutr. 2000;130(4):715-718.
- Whigham LD, Watras AC, Schoeller DA. Efficacy of conjugated linoleic acid for reducing fat mass: a meta-analysis in humans. Am J Clin Nutr. 2007;85(5):1203-1211.
- Nair KS, Rizza RA, O'Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med. 2006;355(16):1647-1659.
- 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;22(8):879-888.
- Sun N, Youle RJ, Finkel T. The Mitochondrial Basis of Aging. Mol Cell. 2016;61(5):654-666.
- Larrosa M, González-Sarrías A, Yáñez-Gascón MJ, et al. Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism. J Nutr Biochem. 2010;21(8):717-725.
- Espín JC, Larrosa M, García-Conesa MT, Tomás-Barberán F. Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far. Evid Based Complement Alternat Med. 2013;2013:270418.
- 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;3(5):100633.
- Cortés-Martín A, Selma MV, Tomás-Barberán FA, González-Sarrías A, Espín JC. Where to Look into the Puzzle of Polyphenols and Health? The Postbiotics and Gut Microbiota Associated with Human Metabotypes. Mol Nutr Food Res. 2020;64(9).
- Giménez-Bastida JA, González-Sarrías A, Larrosa M, Tomás-Barberán F, Espín JC, García-Conesa MT. Ellagitannin metabolites, urolithin A glucuronide and its aglycone urolithin A, ameliorate TNF-α-induced inflammation and associated molecular markers in human aortic endothelial cells. Mol Nutr Food Res. 2012;56(5):784-796.
- 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;5(1).
- 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;1(6):595-603.
- 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;3(5):100633.
- Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019;22(3):401-412.
- Spigoni V, Mena P, Cito M, et al. Effects of 6-week Urolithin A supplementation on cardiovascular risk factors in healthy overweight older adults: A randomized, double-blind, placebo-controlled trial. Eur J Nutr. 2021;60(5):2537-2550.
- García-Villalba R, Vissenaekens H, Pitart J, et al. Gastrointestinal Simulation Model TWIN-SHIME Shows That Urolithin A and Its Phase II Metabolites Are Absorbed and Metabolized by the Intestine and Liver. J Agric Food Chem. 2020;68(26):7281-7290.
- Tomás-Barberán FA, García-Villalba R, González-Sarrías A, Selma MV, Espín JC. Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J Agric Food Chem. 2014;62(28):6535-6538.
- Savi M, Bocchi L, Mena P, et al. In vivo administration of urolithin A and B prevents the occurrence of cardiac dysfunction in streptozotocin-induced diabetic rats. Cardiovasc Diabetol. 2017;16(1):80.
- González-Sarrías A, García-Villalba R, Núñez-Sánchez MÁ, et al. Identifying the limits for ellagic acid bioavailability: A crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts. J Funct Foods. 2015;19:225-235.
- Larrosa M, González-Sarrías A, García-Conesa MT, Tomás-Barberán FA, Espín JC. Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. J Agric Food Chem. 2006;54(5):1611-1620.
- González-Sarrías A, Giménez-Bastida JA, García-Conesa MT, Gómez-Sánchez MB, García-Talavera NV, Gil-Izquierdo A, Sánchez-Álvarez C, Fontana-Compiano LO, Morga-Egea JP, Pastor-Quirante FA, Martínez-Díaz F, Tomás-Barberán FA, Espín JC. Occurrence of urolithins, gut microbiota ellagic acid metabolites and proliferation markers expression response in the human prostate gland upon consumption of walnuts and pomegranate juice. Mol Nutr Food Res. 2010;54(3):311-322.
- Landete JM. Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health. Food Res Int. 2011;44(5):1150-1160.
- Tomás-Barberán FA, González-Sarrías A, García-Villalba R, Núñez-Sánchez MA, Selma MV, García-Conesa MT, Espín JC. 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;61(1):1500901.
- Selma MV, González-Sarrías A, Salas-Salvadó J, Andrés-Lacueva C, Alasalvar C, Örem A, Tomás-Barberán FA, Espín JC. The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome. Clin Nutr. 2018;37(3):897-905.
- Williamson G, Clifford MN. Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols. Biochem Pharmacol. 2017;139:24-39.
- García-Villalba R, Beltrán D, Espín JC, Selma MV, Tomás-Barberán FA. Time course production of urolithins from ellagic acid by human gut microbiota. J Agric Food Chem. 2013;61(37):8797-8806.
- Cortés-Martín A, García-Villalba R, González-Sarrías A, Romo-Vaquero M, Loria-Kohen V, Ramírez-de-Molina A, Tomás-Barberán FA, Selma MV, Espín JC. The gut microbiota urolithin metabotypes revisited: The human metabolism of ellagic acid is mainly determined by aging. Food Funct. 2018;9(8):4100-4106.
- Selma MV, Beltrán D, García-Villalba R, Espín JC, Tomás-Barberán FA. Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species. Food Funct. 2014;5(8):1779-1784.
- Heiman ML, Greenway FL. A healthy gastrointestinal microbiome is dependent on dietary diversity. Mol Metab. 2016;5(5):317-320.
- Marco ML, Heeney D, Binda S, et al. Health benefits of fermented foods: microbiota and beyond. Curr Opin Biotechnol. 2017;44:94-102.
- Karl JP, Hatch AM, Arcidiacono SM, et al. Effects of Psychological, Environmental and Physical Stressors on the Gut Microbiota. Front Microbiol. 2018;9:2013.
- Monda V, Villano I, Messina A, et al. Exercise Modifies the Gut Microbiota with Positive Health Effects. Oxid Med Cell Longev. 2017;2017:3831972.
- Engen PA, Green SJ, Voigt RM, Forsyth CB, Keshavarzian A. The Gastrointestinal Microbiome: Alcohol Effects on the Composition of Intestinal Microbiota. Alcohol Res. 2015;37(2):223-236.
- Henning SM, Summanen PH, Lee RP, Yang J, Finegold SM, Heber D, Li Z. Pomegranate ellagitannins stimulate the growth of Akkermansia muciniphila in vivo. Anaerobe. 2017;43:50-60. doi:10.1016/j.anaerobe.2016.12.003
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