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 and is critical for maintenance of intestinal integrity. The intestinal expression of genes involved in cellular detoxification is down-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)-α 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 TNFα 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 siRNA, abrogated the counter-regulatory effects exerted by rifaximin on cell exposed to TNFα. 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 TNFα 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.
Mencarelli
Andrea
A
Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori, no. 1 S. Andrea delle Fratte, 06132 Perugia, Italy.
Migliorati
Marco
M
Barbanti
Miriam
M
Cipriani
Sabrina
S
Palladino
Giuseppe
G
Distrutti
Eleonora
E
Renga
Barbara
B
Fiorucci
Stefano
S
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000502:physiology*; D012294:Rifamycins / Q000493:pharmacokinetics / Q000494:pharmacology*; D000078262:Rifaximin; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012294:Rifamycins; D000078262:Rifaximin