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

项目摘要/摘要 心血管疾病是全球主要的死亡原因。尽管外科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、支架植入和外科手术 搭桥失败是由于治疗动脉的新生内膜增生引起的再狭窄，这是一种细胞增殖过程。 因发炎而加重。预防和治疗新生内膜增生的新疗法迫在眉睫 需要的。然而，在理解环境的复杂贡献方面存在着重大的知识差距。 在这一过程中的效应器。PI使用无菌(GF)和抗生素治疗的令人信服的前期工作 小鼠模型已经证明了一种新的新生内膜增生易感性的元组织途径。我们 研究表明，与常规饲养的小鼠相比，GF小鼠的新生内膜增生程度有所减轻， 这是通过粪便移植恢复的。此外，抗生素治疗耗尽肠道微生物区系会导致 降低丁酸的水平，丁酸是一种短链脂肪酸，完全由微生物发酵膳食纤维产生， 伴随着加剧的新生内膜增生性易感性；这些影响被以下因素逆转 丁酸盐补充剂。丁酸受体，游离脂肪酸受体3(FFAR3)的动脉表达是 通过损伤和刺激FFAR3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生物微生物宿主 相互作用对血管手术后新生内膜增生的影响：益生素纤维增加肠道微生物 丁酸盐的产生，进而通过直接抑制动脉损伤引起的新生内膜增生。 FFAR3介导的对EC和炎症的影响。我们将在一个 使用GF和转基因小鼠、产酪酸菌和空间和 炎症反应的动态侧写。我们还将测试这一途径的翻译应用 在猪动脉损伤模型中使用丁酸盐前体三丁酸三丁酯的新配方。 总的来说，这些研究将测试这一途径的现象学、机械学和翻译学方面，因此 对接受血管手术的患者有潜在的变革性影响。

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.