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P-glycoprotein(P-gp)and breast cancer resistance protein(BCRP)are involved in intestinal barrier.Short-chain fatty acids(SCFAs)play important roles in maintaining intestinal barrier.In this study we explored how SCFAs affected the expression and function of intestinal P-gp and BCRP in rats.Rats received 150 mM acetate,propionate or butyrate in drinking water for 4 weeks.In SCFA-treated rats,the expression and function of intestinal P-gp were decreased,but those of intestinal BCRP were increased;intestinal p-p65 was also decreased,which was positively related to P-gp protein expression.Among the three SCFAs tested,butyrate exhibited the strongest induction or inhibitory effect,followed by propionate and acetate.Similar results were observed in mouse primary enterocytes and Caco-2 cells treated with acetate(5 mM),propionate(2 mM),or butyrate(1 mM).In Caco-2 cells,addition of butyrate,vorinostat,and valproate(two classic HDAC inhibitors),Bay1 17082(selective inhibitor of NF-κB activation)or NF-κB p65 silencing significantly decreased the expression of P-gp and the level of phosphorylated p65(p-p65).Furthermore,butyrate attenuated the expression of P-gp and p-p65 induced by TNF-a(NF-κB activator)and theophylline(HDAC activator).However,vorinostat,valproate,Bay1 17082,TNF-a or p65 silencing hardly affected BCRP protein expression.But GW9662(selective PPARy antagonist)or PPARy silencing abolished BCRP induction by butyrate and troglitazone(PPARy agonist).SCFAs-treated rats showed higher intestinal protein expression of PPARy,which was positively related to BCRP protein expression.Butyrate increased plasma exposure of fexofenadine but decreased that of rosuvastatin following oral dose to rats.In conclusion,SCFAs exert opposite effects on the expression and function of intestinal P-gp and BCRP;butyrate downregulated P-gp expression and function possibly via inhibiting HDAC/NF-κB pathways;butyrate induced BCRP expression and function partly via PPARy activation.