The morbidity of inflammatory bowel disease (IBD) stems from its effect on electrolytes, nutrients and fluid absorption; thus, patients with IBD sustain malabsorption and diarrhea with attendant malnutrition and weight loss. It has long been held that once chronic intestinal inflammation has occurred, malabsorption and diarrhea are the inevitable results. However, in the previous funding cycle of this proposal we demonstrated that malabsorption and diarrhea are not the irrevocable end results of chronic intestinal inflammation, but actively regulated processes. We focused on the regulation of Na-glucose co-transport (SGLT1) and Na-amino acid co-transport (NAcT), which are not only important for nutrient assimilation, but also the absorption of Na. We determined that upstream mast cells, inducible nitric oxide, and arachidonic acid were common pathways of extra cellular regulation of these 2 co-transporters. However, further downstream while prostaglandin E2 (PGE2) mediated the inhibition of SGLT1, leukotriene D4 (LTD4) mediated the inhibition of NAcT. We also demonstrated that the mechanism of inhibition of SGLT1 was secondary to a decrease in co-transporter numbers while that of NAcT was secondary to altered co-transporter affinity during chronic enteritis. Having demonstrated the unique extra cellular regulation of SGLT1 and NAcT in the chronically inflamed intestine, the next logical step is the overall aim of this proposal: Determine the intracellular mechanism of regulation and the molecular alterations of SGLT1 and NAcT during chronic enteritis. Specifically, we will determine intracellular G protein, 2nd messenger and protein kinase pathways, which regulate SGLT1 and NAcT during chronic enteritis. Then we will decipher the unique molecular alterations of SGLT1 and NAcT mediated by the respective intracellular pathways in the chronically inflamed intestine. Successful completion of these studies will provide novel and valuable information for the overall hypothesis of this proposal: Unique intracellular mechanisms of regulation result in the unique changes in SGLT1 and NAcT in the chronically inflamed intestine. This knowledge will provide the basis for new and more efficacious treatment modalities for the most common morbidities of IBD specifically, malabsorption, diarrhea and malnutrition. ? ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
West Virginia University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Singh, Soudamani; Arthur, Subha; Talukder, Jamilur et al. (2015) Mast cell regulation of Na-glutamine co-transporters B0AT1 in villus and SN2 in crypt cells during chronic intestinal inflammation. BMC Gastroenterol 15:47
Saha, Prosenjit; Manoharan, Palanikumar; Arthur, Subha et al. (2015) Molecular mechanism of regulation of villus cell Na-K-ATPase in the chronically inflamed mammalian small intestine. Biochim Biophys Acta 1848:702-11
Manoharan, Palanikumar; Gayam, Swapna; Arthur, Subha et al. (2015) Chronic and selective inhibition of basolateral membrane Na-K-ATPase uniquely regulates brush border membrane Na absorption in intestinal epithelial cells. Am J Physiol Cell Physiol 308:C650-6
Arthur, Subha; Sundaram, Uma (2015) Inducible nitric oxide regulates intestinal glutamine assimilation during chronic intestinal inflammation. Nitric Oxide 44:98-104
Arthur, Subha; Coon, Steven; Kekuda, Ramesh et al. (2014) Regulation of sodium glucose co-transporter SGLT1 through altered glycosylation in the intestinal epithelial cells. Biochim Biophys Acta 1838:1208-14
Arthur, Subha; Sundaram, Uma (2014) Protein kinase C-mediated phosphorylation of RKIP regulates inhibition of Na-alanine cotransport by leukotriene D(4) in intestinal epithelial cells. Am J Physiol Cell Physiol 307:C1010-6
Kekuda, Ramesh; Manoharan, Palanikumar; Baseler, Walter et al. (2013) Monocarboxylate 4 mediated butyrate transport in a rat intestinal epithelial cell line. Dig Dis Sci 58:660-7
Saha, Prosenjit; Arthur, Subha; Kekuda, Ramesh et al. (2012) Na-glutamine co-transporters B(0)AT1 in villus and SN2 in crypts are differentially altered in chronically inflamed rabbit intestine. Biochim Biophys Acta 1818:434-42
Arthur, Subha; Saha, Prosenjit; Sundaram, Shanmuga et al. (2012) Regulation of sodium-glutamine cotransport in villus and crypt cells by glucocorticoids during chronic enteritis. Inflamm Bowel Dis 18:2149-57
Coon, Steven; Kekuda, Ramesh; Saha, Prosenjit et al. (2011) Reciprocal regulation of the primary sodium absorptive pathways in rat intestinal epithelial cells. Am J Physiol Cell Physiol 300:C496-505

Showing the most recent 10 out of 23 publications