Activation of granulocytes within the lamina propria by luminally derived bacterial products may represent an important mechanism in the pathogenesis of inflammatory bowel disease. The objective of this study was to determine the effects of luminal perfusion with N-formyl methionyl-leucyl-phenylalanine (FMLP), a bacterial product that attracts and activates granulocytes, on mucosal permeability in different regions of the rat small intestine and colon. Mucosal permeability was measured using blood-to-lumen clearance of 51Cr-ethylenediamine-tetraacetate during luminal perfusion with FMLP (10(-3) to 10(-8) M) dissolved in Tyrode's solution. Of the bowel segments studied, mucosal permeability was significantly increased by FMLP only in the distal 10 cm of ileum. The minimal FMLP concentration required to increase mucosal permeability was 10(-6) M. The increased mucosal permeability induced by FMLP could be prevented by depletion of circulating granulocytes with antineutrophil serum. The greater sensitivity of the distal ileum to FMLP did not correlate with a higher tissue myeloperoxidase activity, but it was associated with a higher basal ethylenediaminetetraacetate clearance. These observations indicate that a high basal mucosal permeability to solutes the size of FMLP (5-6 A radius), rather than a greater number of resident granulocytes in the lamina propria, predisposes the terminal ileum to the inflammatory actions of FMLP.