New drug platforms are needed which enable the directed delivery of therapeutics to sites of disease to maximize efficacy and limit off-target effects. Here, we report the development of PROT3EcT, commensal Escherichia coli engineered for the direct secretion of proteins into their surroundings. PROT3EcT are composed of four modular components: an E. coli chassis, a modified bacterial protein secretion system, a regulatable transcriptional activator, and a secretable therapeutic payload. PROT3EcT that secrete functional single-domain antibodies, nanobodies (Nb), stably colonize and maintain a functional secretion system within the intestines of mice. A single prophylactic dose of PROT3EcT that secretes a tumor necrosis factor alpha (TNFα) neutralizing Nb is sufficient to ablate TNF levels and prevent the development of injury and inflammation in a chemically-induced model of inflammatory bowel disease. This work lays the foundation for the development of PROT3EcT as a therapeutic platform for the treatment of at least gastrointestinal-based diseases.