Enterococcus faecium HDRsEf1 Represses CYP3A29 Expression in the Intestine through the TLR1/2-induced A20 to attenuate the NF-κB/RXR-α Signaling

Abstract CYP3A29, like human CYP3A4 is crucial for drug metabolism in pigs and some probiotics can regulate the expression of CYP3A in mammals. Here, we show that Enterococcus faecium HDRsEf1 significantly reduces CYP3A29 expression in pig intestinal tissues and epithelial cells, dependent on cell-cell contact. In IPEC-J2 cells, HDRsEf1 decreased the CYP3A29 promoter activity, RXR-α expression and mitigated the RXR-α or PXR-increased CYP3A29 expression. Both RXR-α/PXR over-expression synergistically increased CYP3A29 expression while RXR-α or PXR silencing reduced CYP3A29 expression. Co-immunoprecipitation revealed that RXR-α directly interacted with PXR. HDRsEf1, like a NF-kB inhibitor, significantly decreased the NF-kBp65 activation, RXR-α and CYP3A29 expression, which were abrogated by RXR-α silencing. HDRsEf1 increased A20 expression dependent on TLR1/2 expression. Therefore, HDRsEf1 inhibits the expression of CYP3A29 through the TLR1/2-induced A20 to attenuate the NF-κB/RXR-α signaling in pig intestinal tissues. Our findings suggest potential risks in the clinical application of probiotics.