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/文摘