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.
