Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

The pregnane-X-receptor ( PXR) is master gene overseeing detoxification of wide number of xenobiotics anti is critical for maintenance of intestinal integrity The intestinal expression of genes Involved in cellular detoxification is clown-regulated in patients with inflammatory bowel diseases (IBD) Rifaximin is a non-absorbable antibiotic endowed with a PXR agonistic activity In the present study we have investigated whether rifaximin activates PXR in primary human colon epithelial cells and human colon biopsies and assessed whether this antibiotic antagonizes the effect of tumor necrosis factor (TNF)-alpha on expression of PXR and PXR-related genes Present results demonstrate that primary colon epithelial cells express PXR and that their exposure to rifaximin induces the expression of genes involved in cellular detoxification Exposure to TNF alpha reduces the expression of PXR mRNA as well as expression of its target genes This inhibitory effect was prevented by that co-treatment with rifaximin. Knocking down the expression of PXR in colon epithelial cells by an anti-PXR si RNA, abrogated the counter-regulatory effects exerted by rifaximin on cell exposed to TNF alpha Finally, ex vivo exposure of colon biopsies obtained from ulcerative colitis patients to rifaximin increased the expression of genes involved in xenobiotics metabolism In aggregate, these data illustrate that rifaximin increases the expression of PXR and PXR-regulated genes Involved in the metabolism and excretion of xenobiotics and antagonizes the effects of TNF alpha in intestinal epithelial cells and colon biopsies These non-antibiotic effects of rifaximin could contribute to the maintenance of the intestinal barrier integrity against xenobiotics and products generated by luminal bacteria (C) 2010 Elsevier Inc. All rights reserved