Regulation of intestinal NaCl absorption

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The most common chronic diarrheal disease in this country and in veterans is inflammatory bowel disease (IBD; e.g. Crohn’s disease). Diarrhea is the most common and disabling morbidity of IBD. The available treatments for diarrhea of IBD are suboptimal, non-specific and fraught with many side effects. Diarrhea in these conditions is a result of electrolyte (e.g. Na, Cl) and fluid malabsorption by absorptive villus cells and enhanced secretion by secretory crypt cells. Immune inflammatory mediators (e.g. prostaglandins), known to be elevated in the mucosa of the chronically inflamed intestine, are paramount factors altering the activity of epithelial electrolyte transporters. While the concept of immune regulation of electrolyte transport in IBD is fairly well accepted, specifically which of the many immune inflammatory pathways may regulate coupled NaCl absorption to cause diarrhea in IBD is poorly understood. The existing paradigm is that coupled NaCl absorption occurs via the dual operation of Na:H (NHE3) and Cl:HCO3 exchange (DRA). But our studies in multiple IBD models showing that NHE3 is unaffected, raised an important question of what other Na absorptive pathway may be affected in tandem with DRA that results in coupled NaCl malabsorption leading to the most common and disabling symptom of IBD, diarrhea. Of the other potential major Na absorptive processes that may be coupled to Cl:HCO3 exchange is Na-glucose co-transport (SGLT1) on the villus cell BBM. SGLT1 is pivotal not only for the absorption of the major nutrient glucose, but also plays a critical role in maintaining overall fluid and electrolyte homeostasis by absorbing two Na for each glucose. Indeed, preliminary data in two animal models of IBD and in human IBD demonstrated inhibition of SGLT1, in parallel with DRA, albeit via different mechanisms. Further, preliminary studies showed that prostaglandins, key immune inflammatory mediators, may be specific modulators of SGLT1 during chronic enteritis. These observations, have led to the paradigm shifting conclusion, that in the chronically inflamed intestine it is not the conventional coupled NaCl absorption via NHE3/DRA that is affected, but rather a novel DRA/SGLT1 coupled absorptive pathway that may be inhibited to cause diarrhea in IBD. Given this background, the overall hypothesis of this competing renewal proposal is that altered novel DRA/SGLT1 coupled NaCl absorption, likely regulated by PGs, causes the diarrhea in IBD. Thus, the overall goal of this proposal is to elucidate the molecular mechanisms of regulation of SGLT1 and DRA by immune-inflammatory mediators in the chronically inflamed intestine. We will comprehensively and complementarily study molecular and physiological regulation of SGLT1 in vivo in rabbits with chronic enteritis and ex vivo in human small intestinal organoid 2-D monolayers. Outcome of the proposed studies will provide novel mechanistic insights into the cause of impaired absorption of both electrolytes (NaCl) and nutrient (glucose) in the IBD intestine and yield clinically relevant data which will be important to design effective and specific therapies for the most common complication of IBD, chronic diarrhea.