Targeted delivery of butyrate to the colon in mice

描述（由申请人提供）：丁酸盐通常在结肠内通过膳食纤维和未消化淀粉的微生物发酵产生。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，但不是全部，丁酸盐被报道可以减小结肠肿瘤的大小和发生率。文献中的不确定性很可能是由于试图将已知数量的丁酸盐输送到体内结肠的困难所致。通过与西南研究所的合作，我们将开发一种克服这些困难的方法，使丁酸盐对结肠疾病的影响能够在体内进行研究，并最终在转基因动物身上进行研究，从而促进机制研究。在这个应用中，我们建议开发装载丁酸盐的微胶囊，这种微胶囊可以加入到饮食中，并以可控和可量化的方式靶向递送到小鼠的大肠。这些研究的具体目的是基于两个假设：通过定时释放的微胶囊将丁酸盐直接输送到结肠，可以增加结肠腔内丁酸盐的浓度；增加丁酸盐输送到结肠，可以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将丁酸盐输送到小鼠结肠的微胶囊，将在体外研究中进行，然后是小鼠的急性体内研究，然后是慢性体内研究。作为我们的第二个目标，我们将建立肠道丁酸盐浓度与纳入日粮的微胶囊剂量之间的关系。在第三个目标中，我们将评估食用丁酸盐微胶囊对结肠癌风险的影响。通过开发这项技术，并测试概念证明，我们将能够在体内模型、转基因和敲除小鼠模型中研究丁酸盐降低结肠疾病风险的机制。这些结果将为治疗和预防人类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.