Bacteria use quorum sensing molecules (QSMs) to communicate within as well as across species, however, the effects of QSM on eukaryotic host cells are less understood. We report that the quorum-sensing pentapeptide, competence and sporulation factor (CSF), of a Gram-positive bacterium Bacillus subtilis, activates key survival pathways including p38 MAP kinase and protein kinase B (Akt) in intestinal epithelial cells and also induces cytoprotective heat shock proteins (Hsps), the latter which prevent oxidant-induced intestinal epithelial cell injury and loss of barrier function. These effects of CSF depend on its uptake by an apical membrane organic cation transporter-2 (OCTN2). OCTN2-transported CSF therefore serves as an example of a unique mechanism of host-bacterial interactions allowing the host to monitor changes in colonic flora behavior or composition.