Engineered living glues secrete therapeutic proteins for treatment of inflammatory bowel disease

Engineering bacteria to secrete gut therapeutics has been limited by their poor autonomous sensing of pathological cues and inability to sustain localized, long-term therapeutic activity. Here we engineer nonpathogenic Escherichia coli with a blood-inducible gene circuit that secretes the barnacle-derived adhesive protein CP43K and the therapeutic gut-barrier-healing factor TFF3 in response to gastrointestinal bleeding, an indicator of severe inflammatory bowel disease (IBD). Adhesive production enables sustained bacterial attachment to inflamed tissues for up to 10 days or 7 days following a single rectal or oral administration, respectively. This effect depends on bleeding-induced adhesion. Using two mouse models of IBD, the colitis model induced by dextran sulfate sodium and the interleukin-10-knockout mouse model, we demonstrate improved weight recovery, reversed colonic shortening and reduced intestinal bleeding. Additionally, the treatment decreases intestinal inflammation, promotes mucosal repair and restores gut barrier integrity, demonstrating comprehensive therapeutic efficacy.