The role of β-glucuronidase in disposition and anti-inflammatory effects of urolithins- gut microbiota-derived metabolites of ellagitannins.

The gut microbiota metabolism of orally applied natural products has been in recent years indicated as an important factor significantly influencing their therapeutic effects. One of the most extensively studied groups of compounds are ellagitannins, which are metabolized to urolithins- compounds having good bioavailability and being detected in plasma and urine at micromolar concentrations following oral intake of ellagitannin-containing products. In vivo studies conducted for these natural products clearly indicate beneficial health effects towards inflammation-related diseases, which are associated with the formation of urolithins. However, since the majority of in vitro experiments was conducted for urolithin aglycones, they occur incongruent with the results of recent pharmacokinetic studies clearly indicating that glucuronide conjugates are the dominant metabolites present in plasma, tissue and urine [1].

Fig. 1

The aim of this study was to isolate and structurally characterize urolithin conjugates from the urine of volunteers ingesting ellagitannin-containing natural products and to evaluate the potential role of human β-glucuronidase in urolithin disposition. Glucuronides of urolithin A, iso-urolithin A and urolithin B were isolated and shown to be cleaved by the β-glucuronidase released by neutrophils from azurophilic granules upon f-MLP stimulation. The comparative studies of urolithins and their glucuronides on bone marrow derived macrophages and BV2 microglial cells have shown, that urolithins were significantly more active than respective conjugates towards inhibition of LPS-induced nitric oxide production and iNOS mRNA and protein synthesis.

These results justify the hypothesis that the selective activation of urolithin glucuronides by β-glucuronidase, which is present at high abundance at inflammation site, could locally increase the concentration of biologically active urolithin aglycones.

The project was financially supported by a Polish Ministry of Science and Higher Education research grant, Iuventus Plus [IP2015 062274] and Foundation for Polish Science scholarship [START 84.2016].

[1] Tomas-Barberan F.A, Mol Nutr Food Res 2017, doi: 10.1002/mnfr.201500901