Gut-liver crosstalk in bile-acid induced diarrhea

胆汁酸引起的腹泻中的肠肝串扰

• 批准号: 9750692
• 负责人: Waddah A. Alrefai
• 金额: $ 28.35万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750692
• 关键词: 3-Dimensional; Agonist; Applications Grants; Bile Acid Biosynthesis Pathway; Bile Acids; CYP7A1 gene; Caco-2 Cells; Cells; Clinical Research; Clinical Trials; Colitis; Crohn' s disease; Cultured Cells; Data; Development; Diagnosis; Diarrhea; Diet; Dimensions; Disease; Egg Yolk; Enterocytes; Enzymes; Epithelial; Epithelial Cells; Experimental Models; Expression Profiling; FGF19 gene; Fibroblast Growth Factor; Food; Future; Gel; Genes; Genetic Transcription; Hepatic; Homeostasis; Hormones; Human; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interferon Type II; Interleukin-1 beta; Intestinal Diseases; Intestines; Investigation; Ion Transport; Irritable Bowel Syndrome; Knockout Mice; Lead; Liver; Lysophosphatidic Acid Receptors; Mediating; Modeling; Molecular; Mus; Oral; Organoids; Pathogenesis; Patients; Phospholipids; Production; Regulation; Role; Severities; Signal Pathway; Signal Transduction; Small Intestines; TNF gene; TNFRSF5 gene; Therapeutic Agents; Therapeutic Intervention; Transgenic Mice; Treatment Efficacy; Up-Regulation; base; cytokine; design; ileum; in vitro Model; insight; lysophosphatidic acid; mRNA Expression; matrigel; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; p65; promoter; protein expression; public health relevance; response; soy

 DESCRIPTION (provided by applicant): Bile acid overproduction is implicated in diarrhea associated with several GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Bile acids in the ileum stimulate the expression and secretion of ileal Fibroblast Growth Factor 19 (FGF15 in mice), which circulates to the liver to suppress CYP7A1 enzyme that mediates the rate-limiting step of bile acid synthesis. Recent studies showed that the levels of FGF15/19 are decreased in mouse model of intestinal inflammation and in patients with IBD along with an increase in the rate of hepatic bile acid synthesis. These observations provided evidence for the key role of FGF15/19 in the pathogenesis of diarrhea during intestinal inflammation, albeit the mechanisms underlying this decrease are not fully understood. Our preliminary data provided evidence demonstrating a decrease in FGF15/19 expression and promoter activity by TNF suggesting a direct effect of proinflammatory cytokines on FGF15/19 expression. In this regards, dietary compounds that increase ileal FGF15/19 expression could be exploited to reduce the excessive production of bile acids. Our novel preliminary findings showed that lysophosphatidic acid (LPA), normally found in foods such as soy and egg yolk, induced the expression of FGF15/19 providing a new lead to novel therapeutic interventions to treat bile acid-induced diarrhea. Based on these data, we hypothesized that ileal FGF15/19 expression is decreased by pro-inflammatory cytokines via transcriptional mechanisms leading to subsequent increase in hepatic CYP7A1 and exacerbating diarrhea associated with intestinal inflammation. We further hypothesized that the activation of LPA-receptors in intestinal epithelial cells triggers specific signaling pathways that lead to an increase in FGF15/19 expression and could be exploited as a therapy for bile acid-induced diarrhea. The proposed studies will utilize advanced in vitro models including intestinal organoids and human epithelial Caco2 cells cultured in 3 dimensional matrigel. FGF15 knockout mice and transgenic mice with hepatic overexpression of CYP7A1 with overproduction of bile acids will be used to investigate the impact of disrupting FGF15/19-CYP7A1 axis on diarrhea and intestinal inflammation. Studies in Aim 1 will determine the molecular mechanisms involved in the inhibition of FGF15/19 by cytokines. Proposed studies in Aim 2 will investigate the mechanisms underlying the upregulation of FGF15/19 expression and secretion by LPA and determine the LPA receptor subtype involved utilizing LPA receptor knockout mice. Aim 3 is designed to investigate the effects of LPA on bile acid homeostasis and examine the contribution of disrupting ileal FGF15-hepatic CYP7A1 to diarrhea and deregulation of intestinal ion transport in mouse models of intestinal inflammation (DSS and TNBS-induced intestinal inflammation). Unraveling the molecular mechanisms controlling crosstalk between the gut and liver will provide the basis for future clinical studies to design novel therapy for bile acid-induced diarrhea.

 描述(申请人提供)：胆汁酸分泌过多与几种胃肠道疾病相关的腹泻有关，如炎症性肠病(IBD)和肠易激综合征(IBS)。回肠中的胆汁酸刺激回肠成纤维细胞生长因子19(FGF15)的表达和分泌，回肠成纤维细胞生长因子19(FGF15)循环到肝脏，抑制介导胆汁酸合成限速步骤的CYP7A1酶。最近的研究表明，在小鼠肠炎模型和IBD患者中，FGF15/19的水平随着肝脏胆汁酸合成速率的增加而降低。这些观察结果为FGF15/19在肠道炎症期间腹泻发病机制中的关键作用提供了证据，尽管这种下降的机制尚不完全清楚。我们的初步数据表明，肿瘤坏死因子降低了FGF15/19的表达和启动子活性，表明促炎细胞因子对FGF15/19的表达有直接影响。在这方面，可以利用增加回肠FGF15/19表达的饮食化合物来减少胆汁酸的过度产生。我们新的初步发现表明，溶血磷脂酸(LPA)，通常存在于大豆和蛋黄等食物中，诱导FGF15/19的表达，为治疗胆汁酸引起的腹泻提供了新的治疗措施。基于这些数据，我们假设促炎症细胞因子通过转录机制减少回肠FGF15/19的表达，从而导致肝脏细胞色素P7A1的表达增加，并加剧与肠道炎症相关的腹泻。我们进一步假设肠上皮细胞LPA受体的激活 细胞触发特定的信号通路，导致FGF15/19表达增加，可用于治疗胆汁酸引起的腹泻。拟议的研究将利用先进的体外模型，包括肠道类器官和在三维基质中培养的人上皮Caco 2细胞。利用FGF15基因敲除小鼠和肝脏过度表达CYP7A1并伴有胆汁酸过度产生的转基因小鼠，研究干扰FGF15/19-CYP7A1轴对腹泻和肠道炎症的影响。目标1的研究将确定细胞因子抑制FGF15/19的分子机制。在Aim 2中提出的研究将探讨LPA上调FGF15/19表达和分泌的机制，并确定利用LPA受体敲除小鼠所涉及的LPA受体亚型。目的研究LPA对胆汁酸稳态的影响，以及阻断回肠FGF15-肝脏细胞色素P7A1在肠炎症(DSS和TNBS诱导的肠炎)小鼠腹泻和肠道离子转运紊乱中的作用。解开控制肠道和肝脏之间串扰的分子机制将为未来的临床研究设计治疗胆汁酸引起的腹泻的新疗法提供基础。