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; 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胃肠道功能较低的疾病。影响所有这些功能的病因因素包括内源性物质，例如胆汁酸（BA）。疏水性DI？羟基BA，例如氯氧化胆酸（CDC），是内源性的，表面活性的剂，可能会改变粘膜功能，刺激5-羟色胺的释放，改变粘膜渗透性，诱导低级别的炎症和通过消除蛋白质损失，并增加殖民分泌和运动能力。据报道，有20％至75％的慢性腹泻患者据报道BA吸收不良。据报道，在极少数儿童便秘病例中，BA缺乏症。我们先前已经使用微阵列和验证性QRT-PCR来量化SLC6A4结直肠粘膜的表达（控制5-羟色胺[5-HT]重新摄取或Sert）P11（另一个溶质载体）（另一个修饰了5-HT受体子类型和12个基因的BACE）（E.G. M.G. M. M M，MM的溶质载体）（另一个溶质载体）（另一个溶质载体） IBS患者的结肠粘膜中的活性氧）。在参与BA代谢的7个基因中的15个SNP和TAG SNP中（ASBT，FGFR4，OST-ALPHA，OST-BETA，KLOTHO B [KLB] SHP和CYP7A1），我们确定了SNP rs17618244的显着关联，与protein col proctient col proctient in in kn in kn klbbsection col的转移相关。我们已经确定了TGR5 SNP卢比11554825与小肠过渡的可能关联，尤其是在IBS-D中，以及与结肠运输。该基因编码G蛋白偶联受体（GPCR）超家族的成员，并用作BA的细胞表面受体。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的表型有关，并通过控制5-HT和BA作用的因子的结肠粘膜表达来介导。我们的目标是：首先，检查IBS-D患者的BA吸收吸收不良（BAM）的患病率和病理生理学（结肠传播，粘膜渗透性，血清FGF19和7Alphac4，粪便胆汁酸）和IBS-C患者的BA缺乏症患者与健康对照相比；其次，为了评估控制胆汁酸合成和吸收的分子机制中遗传变异的患病率和影响，以及IBS和健康中的单独的胆汁酸G-蛋白偶联受体TGR5；第三，要比较具有和没有BAM和健康对照的IBS-D患者，粪便胆酸排泄结肠粘膜渗透性，张力，收缩和粘膜表达的血清素能，胆汁酸转运蛋白（FXR和ASBT），TGR5，MUC20和PARM1。意义：这些综合的转化研究将增强对BA动力学，粘膜渗透性和结肠运动的理解，并应在相当大的患有腹泻或便秘的功能性较低的GI疾病的患者中引入新治疗。