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

胆汁酸、遗传控制和肠易激综合症的结肠功能

• 批准号: 8536669
• 负责人: MICHAEL L. CAMILLERI
• 金额: $ 33.1万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536669
• 关键词: Address; Adverse effects; Affect; Apical; Bacteria; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; CYP7A1 gene; Carrier Proteins; Cell Surface Receptors; Cells; Chenodeoxycholic Acid; Childhood; Chronic; Colon; Colorectal; Constipation; Coupled; Data; Diarrhea; Disease; Enteral; Epithelium; Excretory function; FGFR4 gene; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Health; Homeostasis; Hydroxyl Radical; Inflammation; Inflammation Mediators; Inflammatory disease of the intestine; Irritable Bowel Syndrome; Kinetics; Link; Malabsorption Syndromes; Measures; Mediating; Metabolism; Molecular; Motor; Mucins; Mucous Membrane; Nitrergic Neurons; Nuclear Receptors; Patients; Permeability; Pharmaceutical Preparations; Phenotype; Population; Prevalence; Production; Protein Biosynthesis; Proteins; Public Health; Reactive Oxygen Species; Reporting; Sensory; Serotonin; Serum; Small Intestines; Sodium; Surface; Symptoms; absorption; base; bile acid transporter; cell motility; gastrointestinal function; immune activation; improved; member; protein expression; receptor; reuptake; solute; translational study; uptake

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.

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包括内源性物质，如胆汁酸 (BA)。疏水性二？羟基BA，例如鹅去氧胆酸（CDC），是内源性表面活性剂，可以改变粘膜功能，刺激血清素的释放，改变粘膜通透性，通过其去污力诱导轻度炎症和蛋白质损失，并增加结肠分泌和蠕动。据报道，20-75% 的慢性腹泻患者存在 BA 吸收不良；据报道，BA 缺乏症见于罕见的儿童便秘病例。我们之前使用微阵列和验证性 qRT-PCR 来量化结直肠粘膜中 SLC6A4（控制血清素 [5-HT] 再摄取或 SERT 的溶质载体蛋白）、p11（另一种溶质载体，其修饰5-HT 受体亚型）和 12 个涉及结肠保护（例如粘蛋白产生）和防御细菌（例如活性氧簇生成）的基因来自 IBS 患者的粘膜。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 和标签 SNP 中，我们发现了 SNP rs17618244（功能性、影响蛋白质合成）在 KLB 基因中与 IBS-D 患者的结肠转运有关。我们已经确定 TGR5 SNP rs 11554825 与小肠转运（特别是 IBS-D）以及结肠转运可能存在关联。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 动力学以及 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 作用的因子的结肠粘膜表达的变化来介导。我们的目标是：首先，检查 IBS-D 患者中 BA 吸收不良 (BAM) 的患病率和病理生理学（结肠传输、粘膜通透性、血清 FGF19 和 7αC4、粪便胆汁酸），以及与 IBS-C 患者中 BA 缺乏情况进行比较。健康控制；其次，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 和健康中的普遍性和对结肠运输的影响；第三，比较有或没有 BAM 的 IBS-D 患者和健康对照的粪便胆汁酸排泄、结肠粘膜通透性、张力、收缩以及 5-羟色胺能、胆汁酸转运蛋白（FXR 和 ASBT）、TGR5、MUC20 和 PARM1 的粘膜表达。意义：这些综合性、转化性研究将增强对 BA 动力学、粘膜通透性和结肠运动的理解，并为相当大一部分患有腹泻或便秘的低功能性胃肠道疾病患者带来新的治疗方法。