Gut microbiota has a wide variety of metabolic activities. I would like to rephrase that, more than activities, they are responsibilities. Nowadays, we know that the gut microbiota metabolizes what we used to believe to be “undigestible,” creating microflora-derived metabolites. Consequently, these metabolites promote the growth of beneficial bacteria leading to healthier wellbeing. Nevertheless, the central mediator to this phenomenon relies on the host’s dietary intake of “undigestible” fibers, phytonutrients, and other bioactive components found in different foods. Recently, the identification of beneficial compounds has shed some light on ellagitannins (ET). Ellagitannins (ET) promote the formation of gut-derived metabolites associated with lower cardiovascular risk, body composition improvement, thermogenesis, and aging. 

Ellagitannins 

Ellagitannins (ET) are found in pomegranate juice, walnuts, red berries, and strawberries. If we see these foods from an evolution point of view, humans have consumed these fruits since the hunter-gatherer days. 

In the digestive tract, ET is rapidly metabolized to ellagic acid (EA). Nevertheless, the gut’s microbiota is responsible for the remaining metabolic processes in which EA is converted to urolithin. Furthermore, urolithin has five different isoforms:

• urolithin A (UA)
• urolithin B (UB)
• urolithin C (UC)
• urolithin D (UD)
• iso-urolithin A (iso-UA)

High levels of ET can be detected in serum after 40 minutes of pomegranate juice ingestion but undetectable after just five hours of its consumption. On the other hand, urolithins can be seen in urine after 48h of pomegranate juice consumption. Urolithin has higher anti-inflammatory and antioxidant properties than those found in ET However, studies show that these levels of urolithin can be detectable in some patients, but not in all of them. Consequently, this is highly dependent on the variety and interaction between different bacterial strains and the metabolites that they produce. 

ET and obesity.

Recent studies have reported the effects of obesity-associated bacteria and the production of urolithin isoforms. Indeed, a study in obese individuals converted pomegranate and walnut-derives ET into UA, iso-UA, and UB, and other individuals only produced UA. Conversely, those individuals who made high UA levels had a lower risk of developing cardiometabolic disease.

Aging is also a crucial predictor of lower species-specific formation of urolithins from ET. This phenomenon is highly coincidental with the interindividual and age-related differences in gut microbiome composition. 

Not all urolithins are the same…

Up to date, we know that the UA isomer is associated with anti-cancer effects, is anti-inflammatory, and also anti-aging properties. Indeed, UA’s anti-cancer effects are related to its preventive action by reducing cell proliferation and metastasis in prostate and colorectal cancer cells.

Also, UA production by the gut microbiota has coincided with the inhibition of lipopolysaccharide-induced inflammation in macrophages. This last statement was tested in murine models.

UA mitochondrial function, longevity, and body composition.

UA has recently gained an FDA certificate of approval thanks to the results of a fascinating clinical trial. Researchers tested UA’s efficacy on skeletal muscle function and safe use of this bioactive component in their clinical trial. Furthermore, 36 patients were intervened with a single dose of 1000mg of UA for 28 days and then followed by multiple dosing for another 28 days. After this trial period, the patients were tested for mitochondrial gene expression and plasma acylcarnitine. Consequently, the researchers reported an improvement of mitochondrial function on skeletal muscle without any side effects.

UA, UC, and UD: lipid metabolism

Another outstanding research paper reported reduced triglyceride accumulation and fatty acid oxidation associated with higher circulating UA, UC, and UD levels. In fact, UA inhibits triglyceride accumulation in adipocytes, which associates with a reduced expression of adipogenesis-related genes.

UA supplementation’s foundation relies on its anti-inflammatory effects that enhance insulin sensitivity and the thermogenesis effect it stimulates. UA enhances adipose tissue production of T3 from a genetic point of view, leading to an upregulation of thermogenic genes: PCG1a and UCP-1. Consequently, the upregulation of these genes increases energy expenditure and improves body composition by lowering body fat mass.

Finally, the benefits of gut-derived metabolite UA are coincidental with an improvement in body composition. However, studies show that the main result of UA supplementation is a reduction in body fat mass. Ultimately, this results in lower levels of pro-inflammatory markers and better mitochondrial function. Also, UA promotes mitochondrial metabolism of dietary fat, improving energy utilization and skeletal muscle function. All of these mechanisms of action position ET and UA as potent mediators of overall health, reflecting in better body composition, ultimately ensuring longevity and mobility.

Human UA studies are scarce. However, the information reported by mouse models is promising. Nevertheless, UA’s benefits and production depend on a healthy and varied microbiota and the ingestion of foods like strawberries, pomegranate, red berries, and walnuts. Furthermore, the production of this metabolite provides a wide array of benefits that mainly focus on the production of energy by dietary fat in the mitochondria and less synthesis of adipocytes. In turn, this reflects improved muscular function, which enhances mobility and overall higher quality of living. – Ana Paola Rodríguez Arciniega, MS

References:

Xia, Bo et al. “Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice.” PLoS biology vol. 18,3 e3000688. 27 Mar. 2020, doi:10.1371/journal.bio.3000688

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