regulated and the mechanisms involved are, for the most part, unknown. However, recent work suggests that one biological pathway that regulates permeability involves zonulin. This hormone appears to be secreted into the lumen and activates an apical receptor which initiates a cascade of events culminating in the opening of the tight junction. The identification of this pathway has also provided an opportunity for pharmacological manipulation of increased permeability associated with over-activity of this pathway. Because zonulin receptors are not present in colonic epithelium, 16 drugs that work via this mechanism should not have effects in the colon. To confirm that this was true in our mice, we tested whether a zonulin-mediated event could be elicited in the colon under conditions identical to those used in our experiments. We used AT-1002, a peptide very similar to AT-1001 but an agonist of the zonulin receptor, and found that at a high concentration it could only increase small intestinal permeability. Moreover, when both the agonist and antagonist were given together the change in small intestinal permeability was prevented, suggesting that they act through the same pathway. These data suggest that the zonulin receptor is not present in the colon of mice (as described in the rabbit) but we cannot exclude the possibility that the peptides were simply degraded during their transit of the small intestine. However, regardless of which explanation is correct, these data suggest that the attenuation of colitis observed in this study following treatment with AT-1001 was due to its effect