Bile Acids, Genetic Control and Colonic Function in Irritable Bowel Syndrome

描述（由申请人提供）：肠易激综合征（IBS）是一种与粘膜免疫激活、结肠运动和感觉功能障碍相关的下胃肠功能紊乱。影响所有这些功能的病因因素包括内源性物质，如胆汁酸（BA）。疏水di ？羟基BA，如chenodeoxycholic acid (CDC)，是内源性的表面活性剂，可改变粘膜功能，刺激血清素的释放，改变粘膜通透性，通过其清净作用诱导低度炎症和蛋白质损失，并增加结肠分泌和蠕动。20-75%的慢性腹泻患者报告BA吸收不良；据报道，BA缺乏在儿童便秘的罕见病例。我们之前已经使用微阵列和验证性qRT-PCR来量化肠易激综合征患者结肠粘膜SLC6A4（控制血清素[5-HT]再摄取的溶质载体蛋白，SERT）、p11（另一种溶质载体，修饰5-HT受体亚型的功能）和12个参与保护（如粘蛋白产生）和防御细菌（如活性氧的产生）的基因在结肠粘膜中的表达。在参与BA代谢的7个基因（ASBT、FGFR4、ost - α、ost - β、Klotho B [KLB] SHP和CYP7A1）的15个SNP和标记SNP中，我们发现KLB基因的SNP rs17618244（具有功能，影响蛋白质合成）与IBS-D患者的结肠转运有显著关联。我们已经确定了TGR5 SNP rs 11554825与小肠运输（特别是IBS-D）和结肠运输的可能关联。该基因编码G蛋白偶联受体（GPCR）超家族的一个成员，并作为BA的细胞表面受体。总体假设是BA动力学，BA调节蛋白和TGR5的遗传变异与IBS-D和IBS-C的表型相关，并通过控制5-HT和BA作用的因子的结肠黏膜表达变化介导。我们的目标是：首先，检查肠易激- d患者BA吸收不良（BAM）的患病率和病理生理学（结肠运输、粘膜通透性、血清FGF19和7alpha - ac4、粪便胆汁酸），以及与健康对照组相比，肠易激- c患者BA缺乏；第二，评估控制胆汁酸合成和吸收的分子机制以及单独的胆汁酸G-蛋白偶联受体TGR5的遗传变异在IBS和健康人群中的流行程度及其对结肠转运的影响；第三，比较合并和不合并BAM的IBS-D患者与健康对照者的粪便胆汁酸排泄、结肠粘膜通透性、张力、收缩以及黏膜5 -羟色胺能、胆汁酸转运体（FXR和ASBT）、TGR5、MUC20和PARM1的表达。意义：这些综合的、转化的研究将增强对BA动力学、粘膜通透性和结肠运动的理解，并将为相当大一部分以腹泻或便秘为表现的低功能胃肠道疾病患者带来新的治疗方法。

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a disorder of lower gastrointestinal function associated with mucosal immune activation, colonic motor and sensory dysfunctions. The etiological factors that impact on all these functions include endogenous substances, like bile acids (BA). Hydrophobic di ? hydroxyl BA, such as chenodeoxycholic acid (CDC), are endogenous, surface-active agents that may alter mucosal function, stimulate release of serotonin, alter mucosal permeability, induce low grade inflammation and protein loss through their detergency, and increase colonic secretion and motility. BA malabsorption is reported in 20-75% of patients with chronic diarrhea; BA deficiency is reported in rare cases of childhood constipation. We have previously used microarray and confirmatory qRT-PCR to quantify the expression in colorectal mucosa of SLC6A4 (the solute carrier protein that controls serotonin [5-HT] re-uptake, or SERT), p11 (another solute carrier, which modifies function of 5-HT receptor subtypes) and 12 genes involved in protection (e.g. mucin production) and defense against bacteria (e.g. generation of reactive oxygen species) in colonic mucosa from IBS patients. Among 15 SNPs and tag SNPs in the 7 genes involved in BA metabolism (ASBT, FGFR4, OST-alpha, OST-beta, Klotho B [KLB] SHP, and CYP7A1), we identified significant association of SNP rs17618244 (which is functional, influencing protein synthesis) in the KLB gene with colonic transit in patients with IBS-D. We have identified a possible association of TGR5 SNP rs 11554825 with small bowel transit, particularly in IBS-D, and with colonic transit. This gene encodes a member of the G protein-coupled receptor (GPCR) superfamily, and functions as a cell surface receptor for BA. The overarching hypothesis is that BA kinetics, and genetic variation of the BA modulating proteins and TGR5 are associated with the phenotypes of IBS-D and IBS-C, and mediated through changes in colonic mucosal expression of factors controlling 5-HT and BA actions. Our aims are: first, to examine the prevalence and pathophysiology (colonic transit, mucosal permeability, serum FGF19 and 7alphaC4, fecal bile acids) of BA malabsorption (BAM) in patients with IBS-D, and of BA deficiency in IBS-C compared to healthy controls; second, to evaluate prevalence and impact on colon transit of genetic variation in molecular mechanisms controlling bile acid synthesis and absorption, as well as the separate bile acid G- protein coupled receptor, TGR5, in IBS and health; third, to compare In patients with IBS-D with and without BAM and healthy controls, fecal bile acid excretion colonic mucosal permeability, tone, contractions, and mucosal expression of serotonergic, bile acid transporters (FXR and ASBT), TGR5, MUC20 and PARM1. Significance: These integrative, translational studies will enhance understanding of BA kinetics, mucosal permeability, and colon motility, and should usher in new treatment in a sizeable subset of patients with lower functional GI diseases presenting with diarrhea or constipation.