Bacterial targeting of the P-glycoprotein/endocannabinoid axis for reducing intestinal inflammation in ulcerative colitis

细菌靶向 P-糖蛋白/内源性大麻素轴以减少溃疡性结肠炎的肠道炎症

• 批准号: 10537517
• 负责人: Benjamin Fidelius Sallis
• 金额: $ 3.15万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537517
• 关键词: ABCB1 gene; Affect; Age; Antibiotics; Antibodies; Automobile Driving; Bacteria; Bacterial Infections; Biochemical Pathway; Colitis; Colon; Colonic inflammation; Data; Databases; Dependence; Development; Disease; Disease model; Economics; Endocannabinoids; Enterocytes; Epithelial; Epithelial Cells; Equilibrium; Feces; Financial Hardship; Functional disorder; Genes; Health; Healthcare Systems; Human Microbiome; Immune; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Infusion procedures; Injury; Intestines; Lead; Life; Maintenance; Mediating; Metabolic; Metagenomics; Methods; Microbe; Modeling; Morbidity - disease rate; Mucositis; Multi-Drug Resistance; Mus; Neutrophil Infiltration; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Population; Prevalence; Publishing; Pump; Reaction; Regulation; Relapse; Research; Research Priority; Risk; Signal Transduction; Single Nucleotide Polymorphism; Spontaneous colitis; Stratification; System; TNF gene; TRIP10 gene; Testing; Tissues; Treatment Failure; Ulcer; Ulcerative Colitis; Work; Xenograft Model; base; commensal bacteria; commensal microbes; cost effective; design; dysbiosis; economic cost; experimental study; gut inflammation; gut microbiota; immune activation; improved; in vivo; inhibiting antibody; insight; intestinal barrier; intestinal epithelium; intestinal homeostasis; mathematical model; microbial; microbial community; microbiome; microbiota; microorganism interaction; migration; mortality; mouse model; neutrophil; novel; novel strategies; prevent; response; sex; side effect; standard of care; systemic inflammatory response; therapeutic target; transcytosis

Project Summary/Abstract Ulcerative Colitis (UC) is a devastating disease characterized by recurring episodic inflammation of the colonic mucosa that imposes a significant health and monetary burden on the developed world. Currently a significant portion of patients with UC are treated with TNFα inhibiting antibodies. Such treatments are burdensome on the healthcare system financially and pose the risk of significant side effects and frequently lead to the development of anti-drug antibodies, and consequent infusion reactions, and treatment failure. Consequently, researching novel cost effective, low risk approaches for treating ulcerative colitis should be of high priority. One approach is to leverage the microbiome to restore and maintain a non-inflammatory state in the colon, instead of targeting the systemic immune system. Dysbiosis is a hallmark of ulcerative colitis and leads to consequent dysregulation of local host immune pathways such as neutrophil transmigration through the intestinal epithelium, which has been shown to be instrumental in the initiation of mucosal inflammation in UC and its perpetuation through disruption of the intestinal barrier. The dysbiotic microbes in the colon of patients with UC have been shown to decrease P-glycoprotein (P-gp) expression. Under homeostatic conditions P-gp inhibits neutrophil transmigration through maintenance of a transepithelial gradient of endocannabinoids, thereby preventing aberrant inflammation. Thus, increases in intestinal epithelial cell (IEC) P-gp expression promises to limit inflammation in UC by preventing neutrophil transcytosis. To this end we must understand the mechanisms by which intestinal P-gp is regulated. While previous work has shown the microbiome dependence of intestinal P-gp expression, the specific microbial signals and the underlying metabolic networks have not yet been explored. In this proposal I will design an optimized microbial consortium to induce P-gp in IECs and dampen colonic inflammation in ulcerative colitis. Additionally, I study the microbial signals and underlying microbial dynamics that induces P-gp. In Aim 1 I will determine candidate bacterial species with the potential to regulate IEC P-gp. I will then use these strains to design and optimize a commensal consortium to induce P-gp when transferred into mice. The use of such a consortium as a potential bacteriotherapeutic for dampening intestinal inflammation will be studied using murine inflammatory bowel disease models. In Aim 2 I will study the mechanisms by which microbes communicate with each other and the host epithelium to induce P-gp. I will use a targeted and an unbiased approach to determine the bacterial signals and metabolites that upregulate P-gp and study the interactions between bacterial species that encourage P-gp induction on IECs. Overall, this study will provide insight into how the human microbiome regulates neutrophil transmigration and consequently intestinal inflammation. The design of the commensal consortium will serve as a first step in the development of a bacteriotherapeutic for treatment of ulcerative colitis.

项目概要/摘要 溃疡性结肠炎（UC）是一种破坏性疾病，其特征是结肠反复发作的炎症 粘膜给发达国家带来了巨大的健康和货币负担。目前一个重要的 部分 UC 患者接受 TNFα 抑制抗体治疗。这样的治疗对患者来说是一种负担 医疗保健系统在财务上存在重大副作用的风险，并经常导致发展 抗药物抗体，以及随后的输注反应和治疗失败。因此，研究 应高度重视治疗溃疡性结肠炎的新的成本有效、低风险的方法。一种方法是 利用微生物组来恢复和维持结肠的非炎症状态，而不是靶向 全身免疫系统。菌群失调是溃疡性结肠炎的一个标志，并导致随后的失调 局部宿主免疫途径的影响，例如中性粒细胞通过肠上皮的迁移， 已被证明有助于 UC 粘膜炎症的引发及其持续存在 肠道屏障破坏。 UC 患者结肠中的菌群失调已被证明 减少 P-糖蛋白 (P-gp) 表达。稳态条件下 P-gp 抑制中性粒细胞迁移 通过维持内源性大麻素的跨上皮梯度，从而防止异常 炎。因此，肠上皮细胞 (IEC) P-gp 表达的增加有望限制炎症 UC 通过阻止中性粒细胞转胞吞作用。为此，我们必须了解肠道的机制。 P-gp 受到监管。虽然之前的工作已经表明肠道 P-gp 表达的微生物组依赖性， 特定的微生物信号和潜在的代谢网络尚未被探索。在这个提案中 我将设计一个优化的微生物联盟来诱导 IEC 中的 P-gp 并抑制结肠炎症 溃疡性结肠炎。此外，我还研究诱导 P-gp 的微生物信号和潜在的微生物动力学。 在目标 1 中，我将确定具有调节 IEC P-gp 潜力的候选细菌种类。然后我将使用这些 菌株设计和优化共生联盟，以在转移到小鼠体内时诱导 P-gp。使用 将使用这种联合体作为抑制肠道炎症的潜在细菌治疗剂进行研究 小鼠炎症性肠病模型。在目标 2 中，我将研究微生物的机制 彼此和宿主上皮细胞通讯以诱导 P-gp。我将使用有针对性且公正的 确定上调 P-gp 的细菌信号和代谢物并研究相互作用的方法 促进 P-gp 对 IEC 诱导的细菌物种之间的差异。总的来说，这项研究将深入了解 人类微生物组如何调节中性粒细胞迁移并进而调节肠道炎症。这 共生联盟的设计将作为开发细菌治疗药物的第一步 治疗溃疡性结肠炎。