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

SCOPE

Urolithins (Uro), gut microbial metabolites derived from ellagic acid (EA), reach significant concentrations in the human colon. Uro-A exerts anti-inflammatory activity in animal models of inflammatory bowel diseases (IBDs). It is hypothesized that Uro can 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-B (LTB ), prostaglandin E (PGE ), and hemiketals (HKE and HKD ).

METHODS AND RESULTS

Leukocytes, obtained from six healthy donors, are stimulated with lipopolysaccharide and calcium ionophore A23187. Uro, at concentrations found in the human colon (1-15 µm), decrease eicosanoid biosynthesis and COX-2 levels in the activated leukocytes. In contrast, EA and conjugated Uro (glucuronides and sulfates) are inactive. Uro-A and isourolithin-A reduce the formation of the 5-LOX/COX-2 products HKE and HKD through the COX-2 pathway (down-regulation of COX-2 and PGE2), whereas Uro-C reduces 5-HETE and LTB via inhibition of 5-LOX.

CONCLUSIONS

The results show that physiologically relevant colonic Uro target eicosanoid biosynthetic pathways. The effect on HKs and LTB formation is unprecedented and expands the knowledge on anti-inflammatory mechanisms of Uro against IBDs.