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（由适用提供）：胆汁酸过量生产是在与多种GI疾病有关的腹泻中实施的，例如炎症性肠病（IBD）和肠易激综合征（IBS）。回肠中的胆汁酸刺激了卵子成纤维细胞生长因子19（小鼠中的FGF15）的表达和分泌，该因子向肝脏圆圈以抑制CYP7A1酶，从而介导胆汁酸合成的速率限制步骤。最近的研究表明，在肠道炎症和IBD患者的小鼠模型中，FGF15/19的水平降低，以及肝胆汁酸合成率的提高。这些观察结果证明了FGF15/19在肠道炎症期间腹泻发病机理中的关键作用，尽管尚未完全了解这种降低的机制。我们的初步数据提供了证据，表明TNF通过TNF降低了FGF15/19表达和启动子活性，这表明促炎细胞因子对FGF15/19表达的直接作用。在这方面，可以探索增加回肠FGF15/19表达的饮食化合物，以减少胆汁酸的过量产生。我们的新型初步发现表明，通常在大豆和蛋黄等食物中发现的溶物磷脂酸（LPA）诱导FGF15/19的表达，为治疗胆汁酸诱导的腹泻的新型治疗干预提供了新的铅。基于这些数据，我们假设回肠FGF15/19的表达通过促炎性细胞因子通过转录机制降低，从而导致随后增加肝CYP7A1的增加，并加剧与肠道炎症相关的腹泻。我们进一步假设肠上皮中LPA受体的激活 细胞会触发特定的信号通路，从而导致FGF15/19表达的增加，并可以作为胆汁酸诱导的腹泻的治疗探索。拟议的研究将利用先进的体外模型，包括在3维矩阵中培养的肠癌和人上皮CACO2细胞。 FGF15敲除小鼠和转基因小鼠具有CYP7A1的肝过度表达，胆汁酸过多，用于研究破坏FGF15/19-CYP7A1轴对腹泻和肠道感染的影响。 AIM 1中的研究将确定细胞因子抑制FGF15/19的分子机制。 AIM 2中的拟议研究将研究LPA对FGF15/19表达和分泌的上调的基础机制，并确定使用LPA受体敲除小鼠涉及的LPA受体亚型。 AIM 3旨在研究LPA对胆汁酸稳态的影响，并检查破坏回肠FGF15-肝脏CYP7A1对腹泻的贡献，并在肠道感染的小鼠模型（DSS和TNBS诱导的肠道感染）中对肠离子转运的影响。阐明控制肠道和肝脏之间串扰的分子机制将为将来的临床研究提供基础，以设计胆汁酸诱导的腹泻的新型治疗。