Inhibition of 5-Lipoxygenase Derived Leukotrienes and Hemiketals as a Novel Anti-Inflammatory Mechanism of Urolithins.

Urolithins, gut microbial metabolites derived from ellagic acid (EA), reach significant concentrations in the human colon. Urolithin-A (Uro-A) exerts anti-inflammatory activity in animal models of inflammatory bowel diseases (IBDs). We hypothesized that urolithins could modulate the biosynthesis of leukocyte-derived inflammatory eicosanoids from the 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2) and 5-LOX/COX-2 pathways, relevant in the onset and progression of IBDs, including 5-hydroxyeicosatetraenoic acids (5-HETEs), leukotriene-B₄ (LTB₄ ), prostaglandin E₂ (PGE₂ ) and hemiketals (HKE₂ and HKD₂ ).

Leukocytes, obtained from six healthy donors, were stimulated with lipopolysaccharide and calcium ionophore A23187. Urolithins, at concentrations found in the human colon (1-15 μM), decreased eicosanoid biosynthesis and COX-2 levels in the activated leukocytes. In contrast, EA and conjugated urolithins (glucuronides and sulfates) were inactive. Uro-A and isourolithin-A (IsoUro-A) reduced the formation of the 5-LOX/COX-2 products HKE₂ and HKD₂ through the COX-2 pathway (down-regulation of COX-2 and prostaglandin E₂ ), whereas urolithin C reduced 5-HETE and LTB₄ via inhibition of 5-LOX.

Our results show that physiologically relevant colonic urolithins target eicosanoid biosynthetic pathways. The effect on HKs and LTB₄ formation is unprecedented and expands the knowledge on anti-inflammatory mechanisms of urolithins against IBDs. This article is protected by copyright. All rights reserved.