Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions

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Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions Aneta Bobowska1 · Sebastian Granica1 · Agnieszka Filipek1 · Matthias F. Melzig2 · Thomas Moeslinger3 · Jürgen Zentek4 · Aleksandra Kruk1 · Jakub P. Piwowarski1,2,4  Received: 7 April 2020 / Accepted: 10 September 2020 © The Author(s) 2020

Abstract Purpose  Ellagitannins are high molecular weight polyphenols present in high quantities in various food products. They are metabolized by human and animal gut microbiota to postbiotic metabolites-urolithins, bioavailable molecules of a low molecular weight. Following absorption in the gut, urolithins rapidly undergo phase II metabolism. Thus, to fully evaluate the mechanisms of their biological activity, the in vitro studies should be conducted for their phase II conjugates, mainly glucuronides. The aim of the study was to comparatively determine the influence of urolithin A, iso-urolithin A, and urolithin B together with their respective glucuronides on processes associated with the inflammatory response. Methods  The urolithins obtained by chemical synthesis or isolation from microbiota cultures were tested with their respective glucuronides isolated from human urine towards modulation of inflammatory response in THP-1-derived macrophages, RAW 264.7 macrophages, PBMCs-derived macrophages, and primary neutrophils. Results  Urolithin A was confirmed to be the most active metabolite in terms of LPS-induced inflammatory response inhibition (TNF-α attenuation, IL-10 induction). The observed strong induction of ERK1/2 phosphorylation has been postulated as the mechanism of its action. None of the tested glucuronide conjugates was active in terms of pro-inflammatory TNF-α inhibition and anti-inflammatory IL-10 and TGF-β1 induction. Conclusion  Comparative studies of the most abundant urolithins and their phase II conjugates conducted on human and murine immune cells unambiguously confirmed urolithin A to be the most active metabolite in terms of inhibition of the inflammatory response. Phase II metabolism was shown to result in the loss of urolithins’ pharmacological properties. Keywords  Ellagitannins · Inflammation · Urolithins · Phase II metabolism · Postbiotics

Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s0039​4-020-02386​-y) contains supplementary material, which is available to authorized users. * Jakub P. Piwowarski [email protected] 1



Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02‑097 Warsaw, Poland

2



Department of Pharmaceutical Biology, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany

3

Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

4

Institute of Animal Nutrition, Freie Universität Berlin, Berlin, Germany





Abbreviations iUA Iso-urolithin A UA Urolithin A UB Urolithin B Genist Genistein GiUA Iso-