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

项目总结/摘要 心血管疾病是全球主要的死亡原因。尽管手术方法有了进步， 心血管疾病，高达50%的血管手术，如球囊血管成形术，支架植入术和外科手术 由于治疗动脉中新生内膜增生（一种细胞增殖过程）导致的再狭窄， 通过炎症增强。新的预防和治疗新生内膜增生的治疗方法是迫切需要的 needed.然而，在理解环境影响的复杂贡献方面存在着重大的知识差距。 在这个过程中的影响力。PI使用无菌（GF）和经过抗菌处理的 小鼠模型已经证明了新内膜增生易感性的新的元生物途径。我们 已经表明，与常规饲养的小鼠相比，GF小鼠具有减弱的新生内膜增生， 可以通过粪便移植来修复此外，消耗肠道微生物群的抗生素治疗导致 丁酸盐水平降低，丁酸盐是一种短链脂肪酸，仅由膳食纤维的微生物发酵产生， 伴随着新生内膜增生易感性的加剧;这些作用通过以下方法逆转： 补充丁酸盐。丁酸受体，游离脂肪酸受体3（FFAR 3）的动脉表达， 损伤增加，刺激FFAR 3调节内皮细胞（EC），血管平滑肌细胞（VSMC）， 和炎症反应。综上所述，我们现在假设一个超有机体微生物宿主 相互作用影响血管手术后新生内膜增生：益生元纤维增强肠道微生物 丁酸盐的产生;而丁酸盐反过来又通过直接抑制动脉损伤诱导的新生内膜增生， 对由FFAR 3介导的EC和炎症的作用。我们将在一个 采用GF和转基因小鼠、产丁酸细菌以及空间和 炎症反应的动态特征。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包封的丁酸酯前体三丁酸甘油酯的新制剂。 总的来说，这些研究将测试这一途径的现象学，机械学和翻译方面， 对接受血管手术的患者具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.