An engineered probiotic for diagnosis and mucosal healing in inflammatory bowel disease.

Early diagnosis and timely treatment of inflammatory bowel disease (IBD) are critical to limit disease progression, yet integrated diagnostic-therapeutic strategies remain limited. Here, we design a synthetic probiotic system that responds to reactive oxygen species (ROS) to enable noninvasive detection of intestinal inflammation. We further engineer EcN-IL22, a therapeutic strain that conditionally expresses interleukin 22-fragment crystallizable (IL-22-Fc) fusion protein in situ to mitigate colitis-associated tissue damage. Mechanistically, EcN-IL22 activates epithelial IL-22 receptor 1/signal transducer and activator of transcription 3 (IL-22R1/STAT3) signaling, promoting epithelial barrier restoration and intestinal stem cell proliferation. We identify thyroid hormone receptor-interacting protein 13 (Trip13) and fidgetin-like 1 (Fignl1) as IL-22R1-responsive candidate genes associated with epithelial repair. Importantly, replacing the diagnostic output of the ROS-responsive circuit with IL-22-Fc enables inflammation-triggered therapeutic delivery and significantly alleviates colitis. Finally, EcN-IL22 demonstrates robust protective efficacy in a piglet colitis model, supporting its translational potential. Together, this work establishes an integrated probiotic platform for IBD diagnosis and regenerative therapy.