Regulation of intestinal NaCl absorption

在这个国家和退伍军人中最常见的慢性肠道疾病是炎症性肠病 (IBD;例如克罗恩病）。腹泻是IBD最常见和致残的发病率。可用 IBD腹泻的治疗是次优的、非特异性的并且充满了许多副作用。腹泻 这些病症是电解质（如Na、Cl）和吸收性绒毛细胞对液体吸收不良的结果， 分泌腺细胞分泌增强。免疫炎症介质（例如，白藜芦醇），已知 在慢性炎症肠粘膜中升高，是改变 上皮电解质转运蛋白。而炎症性肠病电解质转运的免疫调节的概念是公平的 广泛接受，特别是许多免疫炎症途径中的哪一个可以调节偶联NaCl 对IBD中引起腹泻的吸收知之甚少。现有的范例是， 吸收通过Na：H（NHE 3）和Cl：HCO 3交换（NO3）的双重操作发生。但是我们的研究 多个IBD模型显示NHE 3不受影响，提出了一个重要的问题，即其他Na 吸收途径可能与导致偶联NaCl吸收不良的NaCl吸收途径同时受到影响， IBD最常见的致残症状是腹泻。其他潜在的主要钠吸收 可能与Cl：HCO 3交换偶联的过程是绒毛细胞上的Na-葡萄糖共转运（SGLT 1 BBM。SGLT 1不仅对主要营养物质葡萄糖的吸收至关重要，而且在以下方面也起着关键作用： 通过对每一种葡萄糖吸收两个Na来维持总体液体和电解质的体内平衡。的确， 在两种IBD动物模型和人IBD中的初步数据表明，SGLT 1的抑制平行 尽管是通过不同的机制。此外，初步研究表明， 免疫炎症介质可能是慢性肠炎期间SGLT 1的特异性调节剂。这些 观察，已经导致了范式转变的结论，即在慢性炎症的肠道中， 通过NHE 3/DRA的传统耦合NaCl吸收受到影响，但新型DRA/SGLT 1耦合 在IBD中，可能抑制吸收途径以引起腹泻。在这种背景下， 这种竞争性更新提议的假设是改变的新的NCL 1/SGLT 1偶联的NaCl吸收， 可能受PGs调节，导致IBD腹泻。因此，本提案的总体目标是阐明 免疫炎症介质调节慢性胰腺炎患者SGLT 1和SGLT 2的分子机制 肠道发炎我们将全面、互补地研究分子和生理调控 慢性肠炎家兔体内和人小肠类器官2-D中离体SGLT 1的 单层。拟议研究的结果将为以下原因提供新的机制见解： IBD肠道中电解质（NaCl）和营养物质（葡萄糖）的吸收受损， 相关数据，这些数据对于设计最常见的有效和特异性治疗非常重要 IBD并发症慢性腹泻

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.