Self-tunable Engineered Yeast Probiotics for the Treatment of Inflammatory Bowel Disease

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2021 Jun 29

PMID 34183837

Citations 74

Authors

Benjamin M Scott

Cristina Gutierrez-Vazquez

Liliana M Sanmarco

Jessica A da Silva Pereira

Zhaorong Li

Agustin Plasencia

Patrick Hewson

Laura M Cox

Madelynn OBrien

Steven K Chen

Pedro M Moraes-Vieira

Belinda S W Chang

Sergio G Peisajovich

Francisco J Quintana

Affiliations

Soon will be listed here.

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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