Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is a gastric metaplastic lineage associated with the development of intestinal-type gastric adenocarcinoma. To study the etiology of this potential neoplastic precursor metaplasia, we used surgical rat models of remnant gastric adenocarcinoma studied with and without exposure to nitroso carcinogen. Animals with truncal vagotomy without duodenogastric reflux procedures demonstrated normal mucous neck cell spasmolytic polypeptide (SP) immunostaining. In these animals, anti-proliferating cell nuclear antigen (PCNA)-labeled nuclei were found in the normal midgland progenitor zone. Rats that received anatomic alterations that augmented the degree of duodenogastric reflux, however, revealed expansion of basally placed SP immunoreactive cells with early phenotypic changes of SPEM. Seventy percent of animals with antrectomy and carcinogen (with or without vagotomy) developed SPEM at the base of the gastric mucosa. In association with the appearance of this metaplastic lineage, a distinct second zone of PCNA-labeled nuclei developed in the deepest portion of the mucosa. Of interest, three animals demonstrating these changes developed intestinal-type gastric adenocarcinoma. Finally, we studied the immunostaining pattern of intrinsic factor, normally a chief cell marker in rat fundic mucosa. In animals with SPEM, we observed coexpression of SP and intrinsic factor in SPEM cells at the base of the mucosa. These findings support our hypothesis that SPEM develops from a second progenitor cell population, reflecting either the unmasking of a cryptic zone or transdifferentiation of chief cells.