Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far

Abstract

The health benefits attributed to pomegranate have been associated with its high content in polyphenols, particularly ellagitannins. This is also the case for other ellagitannin-containing fruits and nuts including strawberry, raspberry, blackberry, walnuts, and muscadine grapes. The bioavailability of ellagitannins and ellagic acid is however very low. These molecules suffer extensive metabolism by the gut microbiota to produce urolithins that are much better absorbed. Urolithins circulate in plasma as glucuronide and sulfate conjugates at concentrations in the range of 0.2-20 μ M. It is therefore conceivable that the health effects of ellagitannin-containing products can be associated with these gut-produced urolithins, and thus the evaluation of the biological effects of these metabolites is essential. Recent research, mostly based on in vitro testing, has shown preliminary evidence of the anti-inflammatory, anticarcinogenic, antiglycative, antioxidant, and antimicrobial effects of urolithins, supporting their potential contribution to the health effects attributed to pomegranate and ellagitannin-rich foods. The number of in vivo studies is still limited, but they show preventive effects of urolithins on gut and systemic inflammation that encourage further research. Both in vivo and mechanistic studies are necessary to clarify the health effects of these metabolites. Attention should be paid when designing these mechanistic studies in order to use the physiologically relevant metabolites (urolithins in gut models and their conjugated derivatives in systemic models) at concentrations that can be reached in vivo.

Figures

Figure 1

Chemical structure of urolithin A, a benzocoumarin.

Figure 2

Gut microbiota metabolism of ellagitannins and ellagic acid.

Figure 3

Sequential production of urolithins in the gut.

Figure 4

UV characteristic spectra of urolithins.

Figure 5

Common top ten functions and diseases identified by functional analysis (IPA, Ingenuity Pathways Analysis; Ingenuity Systems, Redwood City, CA, USA) and that were most significant to gene expression altered by the intake of pomegranate extract or Urolithin A in the colon mucosa of a rat model of ulcerative colitis (gene expression data from Larrosa et al. [29]). Black bars: pomegranate extract. Grey bars: urolithin A. A Fischer's exact test was used to calculate a P-value determining the probability that each function or disease assigned to the data was due to chance. We set a threshold at P value ≤ 0.05 (dashed line) which corresponds to a False Discovery Rate (FDR) ≤ 5% of false positives. Note: On the y-axis, the significance is expressed as the minus log (10-based) of the P values. The higher the bar, the lower the P value and hence the more significant for the enrichment of the function/disease.

Figure 6

Graphical representation of main genes involved in signaling pathways, transcription regulation, cell growth, cell cycle, and apoptosis for which deregulation has been implicated in cancer development. Genes depicted in red color were upregulated and genes represented in green color were downregulated in the colon mucosa of rats following the consumption of urolithin A, (Larrosa et al. [29]). Analyses were carried out using the Canonical Pathways Analysis tool of Ingenuity Pathways Analysis (Ingenuity Systems, Redwood City, CA, USA).