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道功能障碍。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）。疏水二？羟基BA如鹅去氧胆酸（CDC）是内源性表面活性剂，其可以改变粘膜功能、刺激5-羟色胺释放、改变粘膜渗透性、通过其去污力诱导低度炎症和蛋白质损失，并增加结肠分泌和运动性。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报告了BA缺乏症。我们之前已经使用微阵列和验证性qRT-PCR来定量SLC 6A 4在结直肠粘膜中的表达。（控制5-羟色胺再摄取的溶质载体蛋白，或SERT），p11（另一种溶质载体，它改变5-HT受体亚型的功能）和12个参与保护的基因在来自IBS患者的结肠粘膜中的抗细菌（例如粘蛋白产生）和抗细菌（例如活性氧物质的产生）的能力。在涉及BA代谢的7个基因（ASBT、FGFR 4、OST-α、OST-β、Klotho B [KLB] SHP和CYP 7A 1）中的15个SNP和标签SNP中，我们确定了KLB基因中SNP rs 17618244（具有功能性，影响蛋白质合成）与IBS-D患者的结肠转运显著相关。我们已经确定了TGR 5 SNP rs 11554825与小肠转运，特别是在IBS-D中，以及与结肠转运的可能关联。该基因编码G蛋白偶联受体（GPCR）超家族的成员，并作为BA的细胞表面受体发挥作用。总体假设是BA动力学和BA调节蛋白和TGR 5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作用的因子的结肠粘膜表达的变化介导。我们的目标是：第一，检查患病率和病理生理学（结肠运输、粘膜渗透性、血清FGF 19和7 α C4、粪便胆汁酸），与健康对照相比，IBS-D患者中BA吸收不良（BAM）和IBS-C中BA缺乏;第二，评估控制胆汁酸合成和吸收的分子机制中遗传变异的流行率和对结肠转运的影响，以及单独的胆汁酸G-蛋白偶联受体TGR 5;第三，在患有和不患有BAM的IBS-D的患者和健康对照中，比较粪便胆汁酸排泄、结肠粘膜渗透性、张力、收缩和结肠激素能胆汁酸转运体（FXR和ASBT）、TGR 5、MUC 20和PARM 1的粘膜表达。重要性：这些综合性、转化性研究将增强对BA动力学、粘膜渗透性和结肠动力学的理解，并将在相当大的伴有腹泻或便秘的低功能GI疾病患者亚组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.