Bile acids in intestinal homeostasis and allogeneic hematopoietic transplantation

胆汁酸在肠道稳态和同种异体造血移植中的作用

• 批准号: 10650323
• 负责人: Gabriel Nunez
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650323
• 关键词: Acute Graft Versus Host Disease; Address; Affect; Allogenic; Amino Acids; Anaerobic Bacteria; Antibiotics; Bacteria; Bile Acid Biosynthesis Pathway; Bile Acids; Blood Circulation; Cholesterol; Cholic Acids; Clinical; Deoxycholic Acid; Development; Dietary Fats; Duodenum; Enterococcus; Enterococcus faecalis; Enzymes; Food; GPBAR1 gene; Gallbladder; Generations; Genetic study; Glycine; Gnotobiotic; Growth; Hospitals; Human; Hydrolase; Infection; Ingestion; Integration Host Factors; Intestinal Absorption; Intestines; Liver; Mediating; Metabolism; Modeling; Modification; Mus; Patients; Physiological Processes; Plasmids; Production; Regulation; Role; Sepsis; Signal Induction; Taurine; United States; Vancomycin; Vancomycin Resistance; Vancomycin resistant enterococcus; bile acid metabolism; bile salts; dehydroxylation; fecal transplantation; genetic approach; graft vs host disease; gut colonization; hematopoietic cell transplantation; hematopoietic transplantation; in vivo; intestinal homeostasis; member; microbial; microbiota; mortality; mouse model; receptor; response; transmission process

PROJECT SUMMARY/ABSTRACT – PROJECT 2 Bile acids (BAs) are synthesized in the liver from cholesterol, conjugated with taurine or glycine, stored in the gallbladder and released into the duodenum in response to food ingestion. In the intestine, conjugated primary BAs undergo amino acid deconjugation by bacterial bile salt hydrolases (BSHs) followed by several modifications including 7α-dehydroxylation by anaerobic bacteria to produce secondary BAs. Although a main function of BAs is to promote the intestinal absorption and transport of dietary lipids, it is now recognized that BAs also regulate diverse physiological processes. Vancomycin- resistant enterococcus (VRE) is one of the leading causes of bloodstream infection in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in hospitals around the world including the United States. Dominant intestinal colonization in patients undergoing allo-HCT can lead to bloodstream VRE infection, high mortality rates, and patient-to-patient transmission in hospitals. Notably, VRE can be eradicated from the intestine by fecal transplantation and several symbiotic bacterial species have been shown to promote VRE intestinal clearance. However, the mechanism by which members of the microbiota inhibit VRE colonization remains unknown. To understand the mechanism that regulates VRE colonization by the microbiota and how VRE affects the intestine during allo-HCT, we have developed a VRE model in the mouse by transferring a vancomycin-resistance plasmid from a human VRE strain to a mouse Enterococcus fecalis strain by conjugation. Upon treatment with antibiotics, mouse VRE accumulated in the mouse intestine to levels comparable to human VRE in patients undergoing allo-HCT. Using the mouse VRE model, we have identified a role for BAs in the regulation of VRE colonization in the intestine. Deconjugation of glycine or taurine-conjugated BAs is the key rate-limiting step in BA metabolism which is mediated by bacterial BSH enzymes. We have identified mouse symbiotic bacteria that mediate BA deconjugation and promote the production of cholic acid (CA) and DCA from conjugated BAs which correlates with the generation of VRE-inhibitory activity. We also found that the amounts of primary and secondary BAs in the intestine are decreased after allo-HCT. The overreaching hypothesis is that specific BA-processing bacteria, BAs and host factors including the bile acid receptor FXR regulate VRE colonization and graft-versus-host disease (GVHD) after allo-HCT. To address these hypotheses, we propose three specific Aims to understand the role of BAs and BA-induced signaling in VRE colonization and GVHD.

项目摘要/摘要 – 项目 2 胆汁酸 (BA) 在肝脏中由胆固醇合成，与牛磺酸或甘氨酸结合，储存 在胆囊中并响应食物摄入而释放到十二指肠。在肠道内， 结合的初级 BA 通过细菌胆汁盐水解酶 (BSH) 进行氨基酸解结合 随后进行一些修饰，包括厌氧细菌的 7α-脱羟基作用以产生 二级学士学位。虽然BA的主要功能是促进肠道吸收和转运 膳食脂质，现在人们认识到 BA 还调节多种生理过程。万古霉素- 耐药肠球菌（VRE）是接受治疗的患者血流感染的主要原因之一 包括美国在内的世界各地医院均开展同种异体造血细胞移植 (allo-HCT) 国家。接受异基因 HCT 的患者肠道定植占主导地位可导致血流 VRE 感染、高死亡率以及医院内患者之间的传播。值得注意的是，VRE 可以 通过粪便移植从肠道中根除，并且一些共生细菌物种已被 显示可促进 VRE 肠道清除。然而，成员的机制 微生物群抑制 VRE 定植仍不清楚。了解调节 VRE 的机制 微生物群的定植以及 VRE 在异基因 HCT 期间如何影响肠道，我们开发了一种 通过将人 VRE 菌株的万古霉素抗性质粒转移至小鼠 VRE 模型 通过接合获得小鼠粪肠球菌菌株。使用抗生素治疗后，小鼠 VRE 在接受同种异体 HCT 的患者中，小鼠肠道中积累的 VRE 水平与人类 VRE 相当。 使用小鼠 VRE 模型，我们确定了 BA 在调节 VRE 定植中的作用 肠道。甘氨酸或牛磺酸结合的 BA 的解偶联是 BA 的关键限速步骤 由细菌 BSH 酶介导的代谢。我们已经鉴定出小鼠共生细菌 介导 BA 解结合并促进结合物产生胆酸 (CA) 和 DCA BA 与 VRE 抑制活性的产生相关。我们还发现，数量 allo-HCT 后肠道中的原发性和继发性 BA 均减少。过度假设 是特定的 BA 处理细菌、BA 和包括胆汁酸受体 FXR 在内的宿主因子调节 allo-HCT 后 VRE 定植和移植物抗宿主病 (GVHD)。为了解决这些假设， 我们提出了三个具体目标来了解 BA 和 BA 诱导的信号传导在 VRE 中的作用 定植和 GVHD。