Targeted delivery of butyrate to the colon in mice

性状（由申请人提供）：丁酸盐通常在结肠腔中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并刺激分化和凋亡。在许多动物研究中，但不是全部，丁酸盐已被报道可以减少结肠肿瘤的大小和发病率。很可能文献中的不确定性是由于与尝试将已知量的丁酸盐递送至体内结肠相关的困难。与西南研究所合作，我们将开发一种克服这些困难的方法，允许丁酸盐对结肠疾病的影响在体内进行研究，并最终使用转基因动物，促进机制研究。在本申请中，我们提出开发可以掺入饮食中的丁酸酯加载的微胶囊，以受控和可量化的方式递送靶向小鼠的大肠。这些研究的具体目标是两个假设：通过时间释放微胶囊将丁酸盐直接递送到结肠可以增加结肠腔中的丁酸盐浓度，并且增加丁酸盐递送到结肠将降低结肠疾病包括癌症的风险。第一个具体目标是开发能够将丁酸盐靶向递送至小鼠结肠的微胶囊，将通过体外研究、随后的急性体内研究以及随后的小鼠慢性体内研究来实现。作为我们的第二个目标，我们将建立鲁米诺丁酸盐浓度和掺入饮食中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，并测试概念验证，我们以后将能够使用体内模型转基因和基因敲除小鼠模型研究丁酸盐降低结肠疾病风险的机制。这些结果将为人类疾病的治疗和预防提供信息。

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.