Intestinal 5-HT Transporter: A novel therapeutic target for GI disorders

肠道 5-HT 转运蛋白：胃肠道疾病的新型治疗靶点

• 批准号: 10316170
• 负责人: Ravinder K Gill
• 金额: $ 45.63万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316170
• 关键词: AHR gene; Actinobacteria class; Affect; Agonist; Antiinflammatory Effect; Aryl Hydrocarbon Receptor; Attenuated; Bacteria; Bifidobacterium; Binding; Blood flow; CCL20 gene; CYP11A1 gene; CYP1A1 gene; Candidate Disease Gene; Cells; Chronic; Communities; Complex; Data; Diarrhea; Diet; Dietary Phytochemical; Disease; Down-Regulation; Drug Metabolic Detoxication; Effectiveness; Electrolytes; Enteral; Enterochromaffin Cells; Enzymes; Epithelial Cells; Event; Experimental Models; Functional disorder; Funding; Gastrointestinal tract structure; Gene Targeting; Genes; Genetic; Gut Mucosa; Health; Homeostasis; Hormones; Human; Ileitis; Immune; Immune response; Immunity; Impairment; Infection; Inflammation; Inflammatory Bowel Diseases; Intervention; Intestinal Motility; Intestines; Knock-out; Knockout Mice; Lead; Ligands; Link; Maintenance; Mediating; Microarray Analysis; Modeling; Molecular; Mus; Neurons; Neurotransmitters; Nuclear Receptors; Oral Administration; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Physiological Processes; Predisposition; Probiotics; Receptor Activation; Receptor Signaling; Resistance; Role; Serotonin; Severities; Signal Pathway; Small Intestines; Structure; Supplementation; Susceptibility Gene; Therapeutic Intervention; Tissue-Specific Gene Expression; Transport Process; Tryptophan; Up-Regulation; Wild Type Mouse; Xenobiotic Metabolism; Xenobiotics; absorption; antimicrobial peptide; aryl hydrocarbon receptor ligand; bacterial community; cruciferous vegetable; dietary; dysbiosis; efficacy evaluation; extracellular; gut inflammation; gut microbiota; ileum; in vivo Model; insight; intestinal epithelium; microbiota; microbiota metabolites; mouse model; new therapeutic target; novel; novel therapeutic intervention; overexpression; prevent; response; reuptake; serotonin receptor; serotonin transporter; uptake; villin

Serotonin transporter (SLC6A4; SERT) represents a primary mechanism to regulate 5-HT availability in the gut mucosa. A large body of evidence supports linkage of SERT to various GI disorders, however, the mechanisms are not well understood. Our recent studies and preliminary data demonstrated an entirely novel role of SERT and intracellular 5-HT in the activation of Aryl hydrocarbon receptor (AhR), a newly recognized IBD susceptibility gene. Interestingly, SERT KO mice fed with AhR agonist (β-naphthoflavone) showed impaired induction of CYP1A1, the canonical AhR gene target. Our preliminary data further showed that SERT was essential for the maintenance of healthy gut microbiota, as deletion of SERT in mice was associated with a reduction in actinobacteria, and altered community structure that may affect the availability of ligands known to activate AhR. Since AhR pathways regulate gut immunity, the decrease in SERT may contribute to the pathophysiology of intestinal inflammation by suppressing basal and agonist-induced AhR activity. However, the mechanisms linking this novel paradigm of the role of serotonergic machinery in dysbiosis and agonist induced AhR activation are not known. Interestingly, dietary AhR ligands such as those present in cruciferous vegetables have protective roles in ameliorating intestinal inflammation. However, a decrease in SERT expression associated with inflammation may dampen their effects and reduce effectiveness in the course of IBD. We hypothesize that SERT-mediated uptake of 5-HT is crucial for the activation of AhR in response to dietary ligands. We also hypothesize that agents which activate SERT and/or counteract its down regulation will confer novel anti-inflammatory effects via AhR dependent mechanisms. Proposed studies in Specific Aim 1 will: a) investigate cell specific mechanisms by which 5-HT activates intestinal AhR utilizing mouse and human enteroids; b) examine whether loss of SERT renders resistance to the beneficial effects of dietary AhR ligands in TNBS ileitis model; and; c) elucidate the effects of microbiota in the activation of AhR pathways utilizing fecal transfer and investigate the link between SERT and the ability of microbiota to produce AhR ligands. Given that SERT is consistently shown to be decreased in all models of inflammation and patients with IBD, proposed studies in Specific Aim 2 will examine the efficacy of natural AhR ligands present in the diet in preventing the onset of gut inflammation, when combined with agents that upregulate SERT, such as probiotic Bifidobacteria breve. In addition, the role of SERT upregulation on mechanisms of AhR activation will be investigated utilizing state-of-the-art mouse model of epithelial cell- specific inducible overexpression of SERT. Outcome of the proposed studies should define the molecular mechanisms by which 5-HT activates AhR and should establish this novel link of the host serotonergic machinery with gut inflammation via AhR and gut microbiota/metabolites. These studies should also establish the beneficial role of SERT up regulation as a novel interventional strategy for IBD.

5-羟色胺转运体(SLC6A4；SERT)是调节肠道中5-羟色胺利用率的主要机制 粘膜。大量证据支持SERT与各种胃肠道疾病的联系，然而， 机制还不是很清楚。我们最近的研究和初步数据证明了一种全新的 SERT和细胞内5-羟色胺在新发现的芳香烃受体(AhR)激活中的作用 IBD易感基因。有趣的是，喂食AhR激动剂(β-萘黄酮)的SERT KO小鼠表现出 抑制了典型的AhR基因靶点--细胞色素P1A1的诱导。我们的初步数据进一步表明，SERT 对维持健康的肠道微生物区系至关重要，因为在小鼠中SERT的缺失与 放线菌的减少和群落结构的改变可能会影响已知配体的可用性 来激活AhR。由于AhR通路调节肠道免疫，SERT的减少可能有助于 通过抑制基础和激动剂诱导的AhR活性而引起的肠炎的病理生理学。然而， 5-羟色胺能机制在生物失调和激动剂中的作用这一新范例之间的联系机制 诱导的AhR激活尚不清楚。有趣的是，饮食中的AhR配体，如那些存在于十字花科的 蔬菜在减轻肠道炎症方面有保护作用。然而，SERT的下降 与炎症相关的表达可能会抑制它们的作用，并降低其在 IBD。我们推测，SERT介导的5-羟色胺摄取对AhR的激活至关重要 到饮食配基。我们还假设，激活SERT和/或抵消其下调的药物 调控将通过AhR依赖机制赋予新的抗炎效果。建议的研究 在特定的目标1中：a)研究5-羟色胺激活肠道AhR利用的细胞特定机制 小鼠和人类肠道；b)检查SERT的丢失是否对 膳食AhR配体在TNBS肠炎模型中的作用；以及；c)阐明微生物区系在AhR激活中的作用 利用粪便转移的途径，并调查SERT和微生物群生产能力之间的联系 AHR配体。鉴于SERT在所有炎症和炎症模型中一直被显示为降低 IBD患者，拟议的针对特定目标的研究2将检验天然AhR配体的疗效 在饮食中出现的预防肠道炎症的药物，当与促进妊娠的药物结合时 SERT、双歧杆菌等益生菌。此外，SERT上调在AhR机制中的作用 将利用最先进的上皮细胞特异性诱导的小鼠模型来研究激活 SERT的过度表达。建议的研究结果应通过以下方式定义分子机制 哪种5-羟色胺能激活AhR，并与宿主5-羟色胺能机制建立这种新的联系 通过AhR和肠道微生物区系/代谢产物引起的肠道炎症。这些研究还应确立 SERT上调作为一种新的IBD干预策略的有益作用。