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.

项目总结/摘要 溃疡性结肠炎（UC）是一种以反复发作的结肠炎症为特征的破坏性疾病， 这给发达国家带来了巨大的健康和经济负担。目前， 部分UC患者接受TNFα抑制抗体治疗。这样的治疗是负担的， 医疗保健系统的财政和构成重大副作用的风险，并经常导致发展 抗药物抗体，以及随之而来的输液反应和治疗失败。因此，研究 治疗溃疡性结肠炎的新的成本有效的、低风险的方法应该是高度优先的。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，并导致随之而来的失调 局部宿主免疫途径，如中性粒细胞通过肠上皮的迁移， 已被证明有助于UC中粘膜炎症的起始及其持续， 破坏肠道屏障。UC患者结肠中的生态失调微生物已被证明 降低P-糖蛋白（P-gp）表达。在稳态条件下，P-gp抑制中性粒细胞迁移 通过维持内源性大麻素的跨上皮梯度， 炎症因此，肠上皮细胞（IEC）P-gp表达的增加有望限制炎症， UC通过防止中性粒细胞转胞吞作用。为此，我们必须了解肠道 P-gp是受管制的。虽然先前的工作已经显示了肠道P-gp表达的微生物组依赖性， 具体的微生物信号和潜在的代谢网络尚未被探索。本提案中 我将设计一种优化的微生物组合，以诱导IEC中的P-gp，并抑制结肠炎症。 溃疡性结肠炎此外，我还研究了诱导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潜力的候选细菌菌种。我会用这些 菌株，以设计和优化一种在转移到小鼠中时诱导P-gp的重组体。使用 将使用以下方法研究这种作为抑制肠道炎症的潜在细菌的聚生体： 小鼠炎症性肠病模型。在目标2中，我将研究微生物 与彼此和宿主上皮沟通以诱导P-gp。我会用一个有针对性的和公正的 确定上调P-gp的细菌信号和代谢产物并研究相互作用的方法 在细菌物种之间，促进IEC上的P-gp诱导。总的来说，这项研究将提供深入了解 人类微生物组如何调节中性粒细胞迁移并因此调节肠道炎症。的 该菌群的设计将作为研制细菌培养剂的第一步， 溃疡性结肠炎的治疗