Technical Abstract: Probiotics are health-promoting bacteria which may protect the intestines from injury and inflammatory diseases but our understanding of the mechanisms for probiotic action are limited. In this study, we hypothesized that a protein, known as p40, which is derived from the probiotic bacteria, Lactobacillus rhamnosus GG (LGG), activates special receptors in the colon which ultimately helps prevent inflammation. To target these receptors in the colon, we constructed hydrogel bead capsules from two edible biopolymers: pectin, which is extracted from fruit peels, and zein, which is a protein isolated from corn, to contain the p40. In previous experiments, we have demonstrated that these capsules can deliver therapeutics to the colon via the oral route, showing great potential for use in colon-specific drug delivery. We demonstrated here for the first time that the encapsulated water-soluble protein p40, was active at the colonic site, as it reduced the chronic inflammation in colitis using mouse models. This collaborative research is also significant, because it is the last step in testing the pectin/zein drug delivery system prior to clinical testing in humans.