Targeted delivery of butyrate to the colon in mice

描述(申请人提供)：丁酸盐通常是通过微生物发酵膳食纤维和未消化的淀粉在结肠腔中产生的。在培养的结肠腺癌细胞中，丁酸盐持续抑制生长，刺激分化和凋亡。在许多动物研究中，但不是所有的研究中，丁酸盐被报道可以减少结肠肿瘤的大小和发病率。文献中的不确定性很可能是由于在体内尝试将已知量的丁酸盐输送到结肠的相关困难造成的。与西南研究院合作，我们将开发一种克服这些困难的方法，允许在体内研究丁酸盐对结肠疾病的影响，并最终通过转基因动物促进机制研究。在这一应用中，我们建议开发可以被纳入饮食中的丁酸微囊，以受控和可量化的方式向小鼠的大肠递送。这些研究的具体目标背后有两个假设：通过时间释放的微囊将丁酸盐直接输送到结肠可以增加结肠腔中丁酸盐的浓度，增加丁酸盐输送到结肠将降低包括癌症在内的结肠疾病的风险。第一个具体目标是开发能够靶向将丁酸盐输送到小鼠结肠的微囊，将进行体外研究，然后是体内急性研究，然后是小鼠体内慢性研究。作为我们的第二个目标，我们将建立丁酸鲁米那浓度与饮食中微囊剂量之间的关系。在第三个目标中，我们将评估食用丁酸盐微囊对结肠癌风险的影响。通过开发这项技术，并测试概念的验证，我们稍后将能够使用体内模型转基因和基因敲除小鼠模型来研究丁酸盐降低结肠疾病风险的机制。这些结果将为人类治疗和预防疾病的应用提供信息。

DESCRIPTION (provided by applicant): Butyrate is normally produced in the colonic lumen via microbial fermentation of dietary fiber and undigested starch. In cultured colonic adenocarcinoma cells, butyrate consistently inhibits growth and stimulates differentiation and apoptosis. In many animal studies, but not all, butyrate has been reported to reduce the size and incidence of colonic tumors. It is likely that the uncertainty in the literature is accounted for by the difficulties associated with attempting to deliver known quantities of butyrate to the colon in vivo. In collaboration with the Southwest Research Institute, we will develop a method that overcomes these difficulties, allowing the influence of butyrate on colonic disease to be studied in vivo and, eventually, with genetically modified animals, facilitating mechanistic studies. In this application, we propose to develop butyrate-loaded microcapsules that can be incorporated into the diet, with delivery targeted to the large bowel of mice in a controlled and quantifiable manner. Underlying the specific aims of these studies are two hypotheses: butyrate concentrations in the colonic lumen can be increased by delivering butyrate directly to the colon via time-released microcapsules, and increasing butyrate delivery to the colon will reduce risk of colonic diseases including cancer. The first specific aim, to develop microcapsules able to target delivery of butyrate to the colon of mice, will be approached with in vitro studies, followed by acute in vivo, and then chronic in vivo studies in mice. As our second aim we will establish the relationship between luminal butyrate concentrations and dose of microcapsules incorporated into the diet. In the third aim, we will evaluate the effects on risk of colonic cancer of consuming butyrate-loaded microcapsules. By developing this technology, and testing proof of concept, we will later be able to study the mechanism by which butyrate reduces risk of colonic disease using in vivo models transgenic and knockout mouse models. These results will inform applications for treatment and prevention of disease in humans.