Neurotensin (NT) stimulates growth of normal and atrophic small bowel mucosa; the mechanisms for this trophic effect of NT are not completely known. The purpose of this study was to (a) determine whether the trophic effect of NT is mediated by mechanisms involving luminal or nonluminal factors and (b) determine whether NT exerts a differential trophic effect on either jejunal or ileal mucosa. Twenty-eight male Sprague-Dawley rats underwent construction of either a jejunal or ileal Thiry-Vella fistula (TVF). After a 1-week recovery period, rats were further subdivided into groups to receive either saline (control) or NT (300 micrograms/kg). Rats were killed on day 6, and TVF as well as corresponding segments of intact jejunum or ileum were removed. Mucosa was scraped, weighed, and analyzed for DNA and protein content. In addition, representative sections of full-thickness bowel from each group were examined histologically. In the jejunal TVF group, NT increased mucosal growth measurements in both the TVF and the intact jejunum. However, in the ileal TVF group, NT stimulated proliferation of intact ileal mucosa only; it had no effect on ileal mucosa in the TVF. These results suggest that NT exerts a systemic effect independent of luminal factors on the proliferation of proximal gut mucosa in addition to an indirect effect produced by stimulation of endogenous luminal secretions. In contrast, an indirect mechanism appears to be the predominant action of NT on growth of distal gut mucosa.