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Engineering a human GPCR to create self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease
- Concordia University -
- Quebec, Canada -
Abstract
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.
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About Dr. Benjamin Scott
Benjamin Scott recently joined the Concordia University Genome Foundry as a Business Development & Partnerships Engagement Advisor. His post-doctoral and Ph.D. research focused on engineering cellular signaling to develop biosensors for industrially relevant compounds, and to create cell-based therapies. He founded SynBio Canada in 2017 to strengthen the national research community, advocate for trainee needs, and highlight their accomplishments.
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