Influence of Gut Microbiota-Derived Ellagitanninsʼ Metabolites Urolithins on Pro-Inflammatory Activities of Human Neutrophils

Abstract

Introduction !Ellagitannin-rich medicinal plant extracts and food products are currently commercialized and consumed due to their potential positive effects on diseases possessing inflammatory background. In inflammation-associated cardiovascular diseases, such products as nuts, pomegranate, blackberries, strawberries, and oak-aged red wine, were proven to exhibit beneficial effect in many human interventional studies [1][2][3][4][5][6]. A recent study conducted on people with a high cardiovascular risk has clearly shown, that regular nut intake (walnuts, almonds, and hazelnuts) significantly reduced the incidence of major cardiovascular events connected with excessive inflammatory response [7]. Although many in vitro studies conducted for extracts and single compounds deal with the explanation of the mechanism of action, the extrapolation of their results on in vivo processes raises many difficulties due to the not well-established bioavailability of ellagitannins [1]. Ellagitannins are hydrophilic, high-molecular-weight dietary polyphenols containing hexahydroxydiphenoyl subunits. They are subsequently transformed by intestinal microbiota to dibenzo [b,d]pyran-6-one derivatives, urolithins. It was established on human model that ellagitannins from strawberries, raspberries, oak-aged wine, pomegranate juice, and nuts could be transformed by intestinal microbiota to urolithins, which are the main biomarkers detected in human plasma following the intake of ellagitannin-rich food products and medicinal plants. These metabolites in contrary to ellagitannins are lipophilic compounds which have a good bioavailability and may be present in plasma in the range of 0.5 to 18.6 µM [8][9][10]. Because of their catechol-like structure after absorption they are a potential substrate for catechol-Omethyl transferase (COMT) enzyme, which increases lipophilicity and may lead to biological Abstract ! Ellagitannin-rich products exhibit beneficial influence in the case of inflammation-associated diseases. Urolithins, metabolites of ellagitannins produced by gut microbiota, in contrary to high molecular weight hydrophilic parental polyphenols, possess well established bioavailability. Because of the important role of neutrophils in progression of inflammation, the influence of urolithins on their pro-inflammatory functions was tested. Urolithin B at a concentration of 20 µM showed significant inhibition of interleukin 8 and extracellular matrix-degrading enzyme MMP-9 production. It was also significantly active in prevention of cytochalasin A/formyl-met-leuphenylalanine-triggered selectin CD62L shedding. Urolithin C was the only active compound towards inhibition of elastase release from cytochalasin A/formyl-met-leu-phenylalanine-stimulated neutrophils with 39.0 ± 15.9 % inhibition at a concentration of 5 µM. Myeloperoxidase release was inhibited by urolithins A and C (at 20 µM by 46.7 ± 16.1 and 63.8 ± 8.6 %, respectively). Urolithin A was the most potent reactive oxygen species release inhibitor both in formyl-met-leu-phenylalan...

Urolithins, gut microbiota‐derived metabolites of ellagitannins, inhibit LPS‐induced inflammation in RAW 264.7 murine macrophages

“…At a concentration of 20 M urolithin A, B, and C decreased LPS triggered production of IL-8 by 24.8, 31.6, and 19.4%, respectively. Moreover, inhibition of elastase, MPO and ROS release was also observed [36]. Urolithin A and B were previously shown to inhibit haemozoin-induced MMP-9 secretion in THP-1 cell line [37].…”

Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status

“…In these studies, the urolithins reduce the levels and expression of key molecules involved in the regulation of inflammation (TNF-␣, IL-1␤, IL-6, IL-8, MCP-1 (monocyte chemotactic protein 1), PAI-1, prostaglandins, etc.). In association with some of these anti-inflammatory molecular effects, these metabolites also appear to counteract fibroblasts and endothelial cell migration and monocyte adhesion [76,82], which are critical processes associated with inflammatory dysfunction [83,84]. Except for the studies looking at (19 of 35) 1500901…”

Urolithin A attenuates ox‐LDL‐induced endothelial dysfunction partly by modulating microRNA‐27 and ERK/PPAR‐γ pathway

“…The peak plasma levels of UA and its conjugates could reach to 4 ß 18 M after ingestion and persisted in systemic circulation for almost 72 h [25,26]. Compared with urolithin B and C, UA showed the strongest inhibition of TNF-␣ production in THP-1-derived (where THP-1 is human acute monocytic leukemia cell line) macrophages, indicating a strong anti-inflammatory activity [27]. Furthermore, it has been reported that UA exhibited more potent antioxidant activity than ellagitannins and other urolithins, supporting that UA is probably the key mediator of ellagitannin's beneficial effect in vivo [28,29].…”