Bacterial regulation of lipid immuno-modulators in patients with ulcerative colitis

溃疡性结肠炎患者脂质免疫调节剂的细菌调节

• 批准号: 9374370
• 负责人: Beth A McCormick
• 金额: $ 20.94万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-23 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9374370
• 关键词: ATP-Binding Cassette Transporters; Acids; Acute; Address; Anti-Inflammatory Agents; Anti-inflammatory; Apical; Arachidonic Acids; Area; Automobile Driving; CASP3 gene; CNR2 gene; Cells; Chemotactic Factors; Clinical; Colitis; Data; Development; Dietary Component; Disease; Elements; Endocannabinoids; Environment; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Ethanolamines; Event; Feces; Gene Expression; Genetic Variation; Germ-Free; Homeostasis; Human; Immune; Immunity; Immunomodulators; Individual; Infectious Agent; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Injury; Intestinal Mucosa; Intestines; Invaded; Ions; Knowledge; Lipids; Mediating; Mediator of activation protein; Membrane; Metabolism; Metagenomics; Molecular; Movement; Multi-Drug Resistance; Mus; Neutrophil Infiltration; P-Glycoprotein; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Phospholipase A2; Physiology; Play; Process; Recruitment Activity; Regulation; Research; Role; Salmonella typhimurium; Severities; Signal Transduction; Signaling Molecule; Surface; System; Testing; Tight Junctions; Time; Tissues; Transplantation; Ulcerative Colitis; apical membrane; cannabinoid receptor; commensal microbes; design; efflux pump; emergency service responder; endocannabinoid signaling; feeding; gut microbiota; healing; immunoregulation; inflammatory milieu; intestinal epithelium; intestinal homeostasis; lipid transport; microbial; microbiome; microbiota; microbiota transplantation; microorganism; migration; neutrophil; novel; pathogenic bacteria; prevent; protein expression; response; sex; solute; therapeutic target; transcriptomics

SUMMARY Neutrophil influx into the intestinal lumen is critical in the response to infectious agents, but is also associated with intestinal damage observed in idiopathic inflammatory bowel disease (IBD). Our prior studies have shown that this influx is mediated by the chemoattractant actions of hepoxilin A3 (HXA3) secreted from the luminal surface of epithelial cells by the efflux pump MRP2. Preliminary studies herein provide evidence that epithelial cells export another class of bioactive lipids from their apical surface, N-acyl ethanolamine class endocannabinoids via the multidrug resistance transporter P- glycoprotein (P-gp), which counteract this inflammatory response. Loss of endocannabinoid signaling through CB2, the peripheral cannabinoid receptor, leads to increased pathology and neutrophil influx during acute intestinal inflammation, consistent with events of IBD. Such preliminary data underscore a key role for epithelial cells in balancing the secretion of pro- and anti-inflammatory lipids via surface efflux pumps in order to control neutrophil infiltration and maintain homeostasis in the healthy intestine. Thus, we have identified a new layer of regulation of neutrophil function in the intestine. Unlike other anti- inflammatory lipids, such as the specialized pro-resolving mediators that are produced by immune cells, we have discovered that epithelial cells constitutively produce and apically secrete endocannabinoids, which we refer to as AMEND (activity modulating epithelial-neutrophil discourse), to locally establish an anti-inflammatory environment to maintain intestinal homeostasis. Thus, it appears that there are two systems, an anti-inflammatory P-gp secretion of endocannabinoids pathway and a pro-inflammatory MRP2 secretion of HxA3 pathway, that function in a balanced and coordinated manner that can be used by epithelial cells to integrate signals from the local environment to maintain exquisite control over the initiation of intestinal inflammation. We seek to further understand the interaction between HXA3 and neutrophils, and to investigate the mechanisms by which AMEND regulates HXA3 activity during homeostasis and disease. Bridging this gap could help explain how commensal bacteria can stabilize a state of tolerance and how genetic variations in specific elements of either pathway might predispose individuals to development of IBD. To address these questions, we will determine whether P-gp/AMEND and MRP2/HXA3 pathways modulate the balance between microbial tolerance and inflammatory responses, and that disturbance of this balance leads to pathological inflammation. Thus, Aim 1 is designed to assess the imbalance between the Pgp/EC and MRP2/HXA3 pathways in patients who suffer from ulcerative colitis, and Aim 2 will examine whether dysbiotic vs. healthy human stool differentially modulates the P-gp and MRP pathways in the intestine.

概括 中性粒细胞流入肠腔对于对感染因子的反应至关重要，但 也与特发性炎症性肠病（IBD）中观察到的肠道损伤有关。我们的 先前的研究表明，这种流入是由赫泊西林 A3 的化学引诱作用介导的 (HXA3) 由外排泵 MRP2 从上皮细胞的管腔表面分泌。初步研究 本文提供的证据表明上皮细胞从其顶端输出另一类生物活性脂质 表面，N-酰基乙醇胺类内源性大麻素通过多药耐药性转运蛋白 P- 糖蛋白（P-gp），可以抵消这种炎症反应。内源性大麻素信号传导丧失 通过 CB2（外周大麻素受体）导致病理学和中性粒细胞流入增加 急性肠道炎症期间，与 IBD 事件一致。这些初步数据强调了 上皮细胞通过表面流出平衡促炎和抗炎脂质分泌的关键作用 泵以控制中性粒细胞浸润并维持健康肠道的稳态。因此， 我们已经确定了肠道中中性粒细胞功能的新调节层。与其他抗 炎症脂质，例如免疫细胞产生的专门的促消解介质， 我们发现上皮细胞组成性地产生并顶部分泌内源性大麻素， 我们称之为 AMEND（活性调节上皮-中性粒细胞对话），以局部建立一个 抗炎环境，维持肠道稳态。因此，似乎有两个 系统，内源性大麻素途径的抗炎 P-gp 分泌途径和促炎途径 MRP2分泌HxA3途径，该途径以平衡和协调的方式发挥作用，可用于 由上皮细胞整合来自局部环境的信号，以保持对细胞的精确控制 肠道炎症的启动。我们寻求进一步了解 HXA3 和 中性粒细胞，并研究 AMEND 在过程中调节 HXA3 活性的机制 体内平衡和疾病。弥合这一差距可能有助于解释共生细菌如何稳定细菌 耐受状态以及任一途径的特定元件的遗传变异如何可能诱发 IBD 的发展。为了解决这些问题，我们将确定 P-gp/AMEND 是否 MRP2/HXA3 通路调节微生物耐受性和炎症之间的平衡 反应，而这种平衡的紊乱会导致病理性炎症。因此，目标 1 是 旨在评估患者 Pgp/EC 和 MRP2/HXA3 通路之间的不平衡 溃疡性结肠炎，目标 2 将检查生态失调与健康人类粪便是否存在差异 调节肠道中的 P-gp 和 MRP 途径。