The Punicalagin Metabolites Ellagic Acid and Urolithin A Exert Different Strengthening and Anti-Inflammatory Effects on Tight Junction-Mediated Intestinal Barrier Function In Vitro

Abstract

Scope: Ellagitannins are polyphenols found in numerous fruits, nuts and seeds. The elagitannin punicalagin and its bioactive metabolites ellagic acid and urolithins are discussed to comprise a high potential for therapeutically or preventive medical application such as in intestinal diseases. The present study characterizes effects of punicalagin, ellagic acid and urolithin A on intestinal barrier function in the absence or presence of the proinflammatory cytokine tumor necrosis factor-α (TNFα).Methods and Results: Transepithelial resistance (TER), fluorescein and ion permeability, tight junction protein expression and signalling pathways were examined in Caco-2 and HT-29/B6 intestinal epithelial cell models. Punicalagin had less or no effects on barrier function in both cell models. Ellagic acid was most effective in ileum-like Caco-2 cells, where it increased TER and reduced fluorescein and sodium permeabilities. This was paralleled by myosin light chain kinase two mediated expression down-regulation of claudin-4, -7 and -15. Urolithin A impeded the TNFα-induced barrier loss by inhibition of claudin-1 and -2 protein expression upregulation and claudin-1 delocalization in HT-29/B6.Conclusion: Ellagic acid and urolithin A affect intestinal barrier function in distinct ways. Ellagic acid acts preventive by strengthening the barrier per se, while urolithin A protects against inflammation-induced barrier dysfunction.

Recovery from Food Waste—Biscuit Doughs Enriched with Pomegranate Peel Powder as a Model of Fortified Aliment

“…The integrity of the intestinal epithelium, formed by a single layer of cells, is of primary importance to prevent and avoid the entrance of toxic and noxious agent into the mucosa and bloodstream. Recent research has demonstrated that the ellagic acid is particularly effective in strengthening the intestinal epithelium by reducing the expression of the claudin-4, -7, and -15 pore-forming proteins in Caco-2 cells [49], thus contributing to the epithelium integrity. Furthermore, in Caco2 cells, urolithin A reinforced the barrier function of the colonic epithelium by upregulation of the expression of proteins involved in the tight junctions through activation of the Nrf2-dependent pathways.…”

A mechanistic insight into the biological activities of urolithins as gut microbial metabolites of ellagitannins

“…Due to the highly beneficial effects of pomegranate in inflammatory diseases of colon (Lynn S Adams et al, 2006; R. Zhao et al, 2019) and also the high concentration of urolithins in colon typically achieved after consumption of ellagitannin‐rich food (Espín et al, 2013), some recent researches focused on anti‐inflammatory activity of urolithin A in animal models of colon inflammation (Hering et al, 2021; Larrosa et al, 2010).…”

“…Because of their abundance in the human diet and direct impact on human health, several studies have investigated the various biological activities of urolithins (especially UroA) which include cardiovascular protection (Gao, Huang, Tong, & Jiang, 2020), nephroprotection (Chen, Lei, Chen, & Zhou, 2020), neuroprotection (H. J. Lee et al, 2021), anti‐inflammatory activity (Hering, Luettig, Jebautzke, Schulzke, & Rosenthal, 2021), anticarcinogenic properties, antidiabetic activity (Yang et al, 2020), antiobesity (Xia et al, 2020), and antioxidant and antibacterial properties. Here, we comprehensively review the potential role of urolithins as a new therapeutic agent and investigate the molecular pathways for their biological effects that have been reported in cell culture, animals, and humans using various in vitro models and in vivo evidence.…”

Promising Nutritional Fruits Against Cardiovascular Diseases: An Overview of Experimental Evidence and Understanding Their Mechanisms of Action

“… 85 Nevertheless, punicalagin has poor pharmacokinetic parameters including 1) low bioavailability, 2) ineffective absorption, 3) high metabolism, and 4) high systemic elimination. 134 , 135 Therefore, designing a novel molecule for the treatment of CVDs such as punicalagin is advantageous.…”