Targeting the Meta-organismal Butyrate Pathway to Prevent Arterial Restenosis after Vascular Surgery

靶向元生物体丁酸途径预防血管手术后动脉再狭窄

• 批准号: 10591598
• 负责人: KAREN J. HO
• 金额: $ 50.32万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591598
• 关键词: Agonist; Angioplasty; Antibiotic Therapy; Antibiotics; Arterial Injury; Arteries; Attenuated; Bacteria; Balloon Angioplasty; Biological; Biological Assay; Biology; Blood Vessels; Butyrates; Bypass; Cardiovascular Diseases; Cause of Death; Cell physiology; Cells; Complex; Cyclodextrins; Data; Development; Devices; Diet; Dietary Fiber; Encapsulated; Endothelial Cells; Endothelium; Environment; Family suidae; Fermentation; Fiber; Food; Formulation; Genetic; Germ-Free; Hyperplasia; Inflammation; Inflammatory Response; Injury; Institution; Intestines; Knockout Mice; Knowledge; Ligands; Link; Mediating; Microbe; Microbiology; Modeling; Molecular; Morbidity - disease rate; Mus; Nonesterified Fatty Acids; Nutritional Science; Operative Surgical Procedures; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Predisposition; Prevention therapy; Procedures; Process; Prodrugs; Production; Publications; Receptor Activation; Research; Rodent Model; Series; Small Interfering RNA; Smooth Muscle Myocytes; Stents; Supplementation; Surgical Injuries; Surgical Models; Testing; Transgenic Mice; Translating; Translations; Vascular Smooth Muscle; Volatile Fatty Acids; Work; absorption; arterial remodeling; attenuation; dietary manipulation; fecal transplantation; food science; gut microbes; gut microbiota; host-microbe interactions; iliac artery; improved outcome; in vivo; in vivo evaluation; innovation; microbial; microbiota; mortality; mortality risk; mouse model; novel; novel diagnostics; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; phenomenological models; porcine model; prebiotics; prevent; receptor; response; response to injury; restenosis; therapeutic development; translational applications; tributyrin; vascular injury

PROJECT SUMMARY/ABSTRACT Cardiovascular disease is a leading cause of death globally. Despite advancements in surgical approaches for cardiovascular disease, up to 50% of vascular procedures such as balloon angioplasty, stenting, and surgical bypass fail due to restenosis from neointimal hyperplasia in the treated artery, a cell proliferative process potentiated by inflammation. New therapies for prevention and treatment of neointimal hyperplasia are urgently needed. However, there are major knowledge gaps in understanding the complex contribution of environmental effectors in this process. Compelling preliminary work by the PI using germ-free (GF) and antibiotic-treated mouse models has demonstrated a novel meta-organismal pathway for neointimal hyperplasia susceptibility. We have shown that GF mice have attenuated neointimal hyperplasia compared to conventionally-raised mice, which is restored by fecal transplantation. Furthermore, antibiotic treatment to deplete gut microbiota results in reduced levels of butyrate, a short chain fatty acid produced exclusively by microbial fermentation of dietary fiber, which is accompanied by exacerbated neointimal hyperplasia susceptibility; these effects are reversed by butyrate supplementation. Arterial expression of the butyrate receptor, free fatty acid receptor 3 (FFAR3), is increased by injury, and stimulation of FFAR3 modulates endothelial (EC), vascular smooth muscle cell (VSMC), and inflammatory responses. Taken together, we now hypothesize that a meta-organismal microbe-host interaction impacts neointimal hyperplasia following vascular surgery: prebiotic fiber augments gut microbial production of butyrate; and butyrate, in turn, attenuates arterial injury-induced neointimal hyperplasia by direct effects on EC and inflammation that are mediated by FFAR3. We will test this innovative hypothesis in a comprehensive series of studies employing GF and transgenic mice, butyrogenic bacteria, and spatial and dynamic profiling of the inflammatory response. We will also test the translational application of this pathway using a novel formulation of encapsulated tributyrin, a butyrate precursor, in a pig model of arterial injury. Collectively, these studies will test phenomenological, mechanistic, and translational facets of this pathway, thus having a potentially transformative impact on patients undergoing vascular surgery.

项目概要/摘要 心血管疾病是全球死亡的主要原因。尽管手术方法取得了进步 心血管疾病，高达 50% 的血管手术，如球囊血管成形术、支架置入术和外科手术 由于接受治疗的动脉新生内膜增生导致再狭窄，搭桥失败，这是一种细胞增殖过程 因炎症而增强。预防和治疗新生内膜增生的新疗法刻不容缓 需要。然而，在理解环境的复杂贡献方面存在重大知识差距 这个过程中的效应器。 PI 使用无菌 (GF) 和抗生素处理进行的引人注目的初步工作 小鼠模型已经证明了新内膜增生易感性的新元有机体途径。我们 研究表明，与传统饲养的小鼠相比，GF 小鼠的新内膜增生有所减弱， 通过粪便移植可以恢复。此外，消除肠道微生物群的抗生素治疗会导致 降低丁酸盐的水平，丁酸盐是一种仅由膳食纤维微生物发酵产生的短链脂肪酸， 伴随着新内膜增生易感性加剧；这些影响被逆转 丁酸盐补充。丁酸受体、游离脂肪酸受体 3 (FFAR3) 的动脉表达是 因损伤而增加，刺激 FFAR3 可调节内皮细胞 (EC)、血管平滑肌细胞 (VSMC)、 和炎症反应。综上所述，我们现在假设一种元有机体微生物宿主 相互作用影响血管手术后的新内膜增生：益生元纤维增强肠道微生物 丁酸盐的生产；反过来，丁酸盐通过直接作用减弱动脉损伤引起的新内膜增生 对 FFAR3 介导的 EC 和炎症的影响。我们将在以下方面测试这一创新假设： 使用 GF 和转​​基因小鼠、产丁酸细菌以及空间和 炎症反应的动态分析。我们还将测试该途径的转化应用 在猪动脉损伤模型中使用封装的三丁酸甘油酯（丁酸盐前体）的新配方。 总的来说，这些研究将测试该途径的现象学、机制和转化方面，因此 对接受血管手术的患者具有潜在的变革性影响。