1 Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
2 Biosystems and Biomaterials Division, National Institute of Standards and Technology, Gaithersburg, MD, USA.
3 Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA.
4 Concordia University, Montreal, Quebec, Canada.
5 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
6 Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology; Experimental Medicine Research Cluster (EMRC), and Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, Brazil.
7 Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, Ontario, Canada.
8 Centre for the Analysis of Genome Evolution and Function, University of Tor

Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies.