 It was observed that reduced intestinal JAK3 expression during human obesity or JAK3 knockout in mouse or siRNA-mediated β-catenin knockdown in human intestinal epithelial cells all result in significant loss of intestinal BCRP expression and compromised colonic drug efflux and barrier functions.These results uncover a mechanism of BCRP-mediated intestinal drug efflux and barrier functions and establish a role for BCRP in preventing CLGI-associated obesity both in humans and in mice.These studies have wider implications not only in our understanding of physiological and pathophysiological mechanisms of intestinal barrier functions and CLGI associated chronic inflammatory diseases but also in protein-mediated drug-efflux pharmacokinetic and pharmacodynamic characteristics of oral drug formulations.