Differential Protective Effect of Resveratrol and Its Microbial Metabolites on Intestinal Barrier Dysfunction is Mediated by the AMPK Pathway

The effectiveness of resveratrol (RES) on intestinal barrier dysfunction and colitis has been extensively studied. However, the specific effects of its microbial metabolites on gut barrier function remain unclear. Hence, we compared the protective effects of RES and its microbial metabolites dihydroresveratrol (DHR) and 3-(4-hydroxyphenyl)-propionic acid (4HPP) against intestinal barrier injury and colitis. Only 4HPP and RES significantly reduced paracellular permeability and the secretion of proinflammatory cytokines in lipopolysaccharides (LPS)-treated intestinal Caco-2 cells, which was consistent with the upregulation in tight junction (TJ) proteins. Furthermore, RES and 4HPP ameliorated intestinal barrier dysfunction and colonic inflammation in colitis mice, while DHR did not. In particular, the expressions of intestinal TJ proteins and Muc2 were restored by RES and 4HPP. The molecular mechanism involved the adenosine monophosphate-activated protein kinase (AMPK)-mediated activation of CDX2 and the regulation of the SIRT1/NF-κB pathway. These findings provide new insights into understanding the protective effects of RES against intestinal barrier damage and colitis.