Technical Abstract: The use of genetically modified bacteria to deliver biologically active molecules directly to the gut has become an increasingly attractive area of investigation. The challenge of regulation of production of the therapeutic molecule and colonization of the bowel led us to investigate Bacteroides ovatus for the production of these molecules, due to its ability to colonize the colon and xylan utilization properties. The anaerobic nature of B. ovatus provides an inherent biosafety feature. B. ovatus strains expressing human keratinocyte growth factor-2 that plays a central role in intestinal epithelial homeostasis and repair (BO-KGF) were generated by homologous recombination and evaluated using the dextran sodium sulphate (DSS)-induced model of intestinal epithelial injury and colitis. In response to xylan BO-KGF produced biologically active KGF both in vitro and in vivo. In DSS-treated mice administration of xylan and BO-KGF had a significant therapeutic effect in reducing weight loss, improving stool consistency, reducing rectal bleeding, accelerating healing of damaged epithelium, reducing inflammation and neutrophil infiltration, reducing expression of pro-inflammatory cytokines, and accelerating production of goblet cells. BO-KGF and xylan treatment also had a marked prophylactic effect limiting the development of inflammation and disruption of the epithelial barrier. This novel diet-regulated, live bacterial drug delivery system may be applicable to treating various bowel disorders.