During the past seven years we have defined many of the factors that regulate human proximal duodenal mucosa secretion in both health and duodenal ulcer (DU) disease. Of relevance, compared to normal subjects patients with DU disease have significantly diminished basal and stimulated duodenal bicarbonate secretion. Recent studies suggest altered anion transport in DU patients (a disease that affects about 4.5 million Americans annually). This abnormality is present in approximately 85 percent of DU patients, more prevalent than other pathophysiologic abnormalities. The duodenal mucosa is a unique functional portion of the small intestine due to its ability to secrete bicarbonate, a physiologic function that provides prompt neutralization of gastric acid and inactivation of pepsin, and thereby protects the duodenum from damage. We shall define the acid/base transport processes involved in duodenal bicarbonate secretion in humans and in a rabbit model. Furthermore, the localization and role of carbonic anhydrases, necessary for the hydroxylation of CO2 and present in high concentrations in duodenal enterocytes, will be determined. This closely integrated approach (from humans to isolated duodenal enterocytes) will provide both fundamental as well as clinically relevant physiologic and pathophysiologic findings regarding the mechanisms and neurohumoral mediators involved in duodenal mucosal bicarbonate transport. Three related areas will be systematically studied: 1. Normal subjects and patients with inactive DU (as well as comparison of duodenal versus jejunal acid/base transporters); 2. Paired duodenal mucosa from rabbit and human in Ussing chambers under short-circuited conditions; and, 3. Based upon the hypothesis that the transporters involved in bicarbonate secretion differ markedly in duodenal villous versus crypt cells, we shall employ dual fluorescent imaging with human (normal and DU) and rabbit duodenocytes to methodically identify exchangers, cotransporters and conductance pathways and their regulation. Although histological differences have not been identified between normal and DU patients, it is possible that ultrastructural abnormalities may account for the impaired bicarbonate secretion. We, therefore, will pursue studies to determine if indeed the altered bicarbonate secretion observed in ulcer patients is related to an ultrastructural counterpart.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine A Subcommittee 2 (GMA)
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University of California San Diego
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Sellers, Zachary M; Mann, Elizabeth; Smith, Anders et al. (2008) Heat-stable enterotoxin of Escherichia coli (STa) can stimulate duodenal HCO3(-) secretion via a novel GC-C- and CFTR-independent pathway. FASEB J 22:1306-16
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Tuo, Bi-Guang; Sellers, Zachary M; Smith, Anders J et al. (2004) A role for CagA/VacA in Helicobacter pylori inhibition of murine duodenal mucosal bicarbonate secretion. Dig Dis Sci 49:1845-52
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