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

描述(申请人提供)：肠易激综合征(IBS)是一种下胃肠功能障碍，与粘膜免疫激活、结肠运动和感觉功能障碍有关。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)。疏水病？羟基BA，如鹅去氧胆酸(CDC)，是一种内源性表面活性物质，可改变粘膜功能，刺激5-羟色胺的释放，改变粘膜通透性，通过其去污作用诱导低度炎症和蛋白质丢失，增加结肠分泌和运动。据报道，20-75%的慢性腹泻患者存在BA吸收不良；在罕见的儿童便秘病例中，BA缺乏。我们已经使用微阵列和确认性QRT-PCR技术定量检测了SLC6A4(控制5-羟色胺再摄取的溶质载体蛋白，SERT)、p11(另一种溶质载体，修饰5-羟色胺受体亚型的功能)和12个参与IBS患者结肠黏膜保护(例如粘蛋白产生)和抵抗细菌(例如产生活性氧)的基因在大肠粘膜中的表达。在与BA代谢有关的7个基因(ASBT、FGFR4、OST-α、OST-β、Klotho B[KLB]SHP和CYP7A1)的15个SNPs和Tag SNP中，我们发现KLB基因中的SNP rs17618244(具有功能，影响蛋白质合成)与IBS-D患者的结肠运输显著相关。我们已经确定TGR5SNP rS 11554825可能与小肠运输有关，特别是在肠易激综合征-D中，以及与结肠运输有关。该基因编码G蛋白偶联受体(GPCR超家族)成员，作为BA的细胞表面受体。最重要的假设是BA的动力学、BA调节蛋白和TGR5的遗传变异与IBS-D和IBS-C的表型有关，并通过结肠粘膜控制5-羟色胺和BA作用的因子表达的变化来调节。我们的目标是：第一，检测IBS-D患者BA吸收不良(BAM)和IBS-C中BA缺乏的患病率和病理生理学(结肠转运、粘膜通透性、血清FGF19和7AlphaC4、粪便胆汁酸)；第二，评估控制胆汁酸合成和吸收的分子机制以及分离的胆汁酸G蛋白偶联受体TGR5的遗传变异在IBS和健康人群中的患病率和对结肠转运的影响；第三，比较有无BAM的IBS-D患者和健康对照组的粪胆酸排泄、结肠黏膜通透性、张力、收缩、5-羟色胺能、胆汁酸转运体(FXR和ASBT)、TGR5、MUC20和PARM1的表达。意义：这些综合性的翻译研究将加强对BA动力学、粘膜通透性和结肠动力的了解，并将在大量表现为腹泻或便秘的低功能性胃肠道疾病患者中引入新的治疗方法。

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.