Abstract
PurposeEllagitannins 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.MethodsThe 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.ResultsUrolithin 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.ConclusionComparative 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.
Highlights
Ellagitannins are high-molecular-weight polyphenols present in high quantities in various food products and medicinal plants
None of the tested compounds exhibited cytotoxic effect on THP-1 macrophages (MTT test, Fig. S1) and on human primary neutrophils
The incubation of cells with respective glucuronide conjugates GUA and GiUA did not result in any changes in this cytokine production
Summary
Ellagitannins are high-molecular-weight polyphenols present in high quantities in various food products and medicinal plants. Different health benefits and biological activities are attributed to these natural products being based on the dietary and clinical prospective and retrospective studies [1]. The impaired health conditions in which ellagitannin-containing products were shown to express preventive or curative effects are in particular diseases with the inflammatory background such as cardiovascular diseases and intestinal inflammations [2,3,4,5]. New light on the mechanisms standing behind the health benefits of ellagitannins has been put by the studies on their metabolism by human gut microbiota, which was shown to metabolize ellagitannins of different structures and origin to the series of low-molecular-weight postbiotic metabolites-urolithins [6]. In contrast to parental molecules, urolithins are highly lipophilic and can penetrate the biological barriers what was confirmed in human and on different animal models [7]. Urolithin A (UA) was consistently shown to possess strong and structure-specific anti-inflammatory properties [8,9,10,11,12,13,14,15,16]
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