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.

项目摘要/摘要 溃疡性结肠炎（UC）是一种毁灭性疾病，其特征是结肠的反复发作发作 粘膜不可能在发达国家拥有巨大的健康和货币伯恩。目前是重要的 UC患者的一部分用TNFα抑制抗体治疗。这种治疗在 医疗保健系统在财务上，构成重大副作用的风险，并经常导致发展 抗药物抗体，随之而来的输注反应和治疗失败。因此，研究 新颖的成本有效，低风险方法治疗溃疡性结肠炎的优先级应高。一种方法是 利用微生物组来恢复和维持结肠中的非炎症状态，而不是靶向 系统性免疫系统。营养不良是溃疡性结肠炎的标志，导致失调 局部宿主的免疫途径，例如中性粒细胞通过肠上皮的迁移， 事实证明，UC中粘膜注射的主动性及其通过 肠屏障的破坏。 UC患者结肠中的不良生物微生物已显示为 降低P-糖蛋白（P-GP）表达。在稳态条件下，P-gp抑制中性粒细胞转移 通过维持内源性大麻素的经层梯度，从而防止异常 炎。这是肠上皮细胞（IEC）P-gp表达的增加有望限制 通过预防嗜中性粒细胞的UC。为此，我们必须了解肠道的机制 P-gp受调节。虽然先前的工作显示了肠P-gp表达的微生物组依赖性，但 尚未探索特定的微生物信号和潜在的代谢网络。在此提案中 我将设计一个优化的微生物财团，以在IEC中诱导P-gp，并在Damen结肠注入中 溃疡性结肠炎。此外，我研究了影响P-gp的微生物信号和潜在的微生物动力学。 在AIM 1中，我将确定具有调节IEC P-gp的潜力的候选细菌。然后我将使用这些 当转移到小鼠中时，要设计和优化共生财团诱导P-gp的菌株。使用 这样的财团是一种潜在的细菌治疗剂，用于染色的肠炎症 鼠炎症性肠病模型。在AIM 2中，我将研究微生物的机制 相互交流，主机上皮诱导P-gp。我将使用目标和公正 确定上调P-gp并研究相互作用的细菌信号和代谢产物的方法 在鼓励对IEC诱导P-gp诱导的细菌物种之间。总体而言，这项研究将提供有关 人类微生物组如何调节嗜中性粒细胞的迁移和肠炎。这 共生财团的设计将作为开发细菌治疗性的第一步 治疗溃疡性结肠炎。