**5. Metabolism of ellagic acid**

Ellagitannins produce ellagic acid when exposed to basic or acidic environments. Ellagic acid was discovered to have antifungal, antiviral, anti-inflammatory, hepatoprotective, and cardioprotective effects [27].

Ellagic acid and ellagitannins are polyphenols found in berries, nuts, pomegranates, wines, and a range of medicinal herbs. Gut flora is necessary for the conversion of ellagitannins and ellagic acid to anticarcinogenic and anti-inflammatory metabolite urolithins (**Figure 2**).

#### **Figure 2.**

*Metabolism of ellagitannin/ellagic acid by human gut microbiota. Population genotypes have a significant influence on the metabolic pathway [28–30].*

Ellagic acid and ellagitannins are classified under polyphenols and can be obtained from various natural sources such as pomegranates, nuts, wines, berries, and several medicinal plants. Gut bacteria are crucial in the conversion of both ellagitannins and ellagic acid to urolithin A and its glucuronide conjugate, urolithin B and its glucuronide conjugate, isourolithin A, and its glucuronide conjugate, which are anticarcinogenic and anti-inflammatory metabolites. These metabolites are highly bioavailable [27–29].

Recently, the metabolic conversion of ellagitannin/ellagic acid to urolithins was investigated in three distinct phenotypic populations. The criteria used to distinguish the population were age, body mass index, gender, and quantity of consumed ellagitannin. Subjects were given walnut and pomegranate extracts, and their urine profiles were analyzed carefully [30]. According to the study, population group A only displayed conjugates of urolithin A. Isourolithin A, urolithin A, and/or urolithin B were among the metabolites discovered in population group B. Metabolites were not identified in population group C. This study demonstrates that differences in human microbiota have a major influence in metabolite synthesis. The outcomes of the study were based on the excretion patterns of three different patient morphologies.

Ellagitannin is a phytochemical found in pomegranate juice, peel, and extracts. Microbial and human enzymes aid in the biotransformation of these phytochemicals. Pomegranate juice contains phytochemicals that have anti-inflammatory, anticancer, and anti-aging effects [31].

After injecting pomegranate juice into healthy volunteers, researchers discovered a maximum concentration of ellagic acid of about 0.06 micromolar in their blood circulation [32].

The gut microbiota of humans transforms ellagic acid into urolithins before its absorption by the intestinal cells. Ellagitannin metabolites were detected in human plasma, and some can be seen in urine for up to 48 hours [33]. One of the studies had confirmed that the plasma concentration of urolithin peaked at 18.6 micromolar in healthy volunteers after consumption of pomegranate juice on consecutive 5 days [34].

Similar studies were also performed using raspberry juice and blackberry juice. Urolithin metabolites were discovered and the urolithin excretion pattern was examined between patients with gut dysbiosis and healthy subjects [34, 35]. The

primary metabolites observed throughout the metabolic process are isourolithin A, urolithin B, urolithin A glucuronide, isourolithin A glucuronide, and urolithin B glucuronide [31, 36].
