Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Med ; 27(7): 1212-1222, 2021 07.
Article in English | MEDLINE | ID: mdl-34183837

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.


Subject(s)
Adenosine Triphosphate/metabolism , Apyrase/metabolism , Inflammatory Bowel Diseases/therapy , Probiotics/therapeutic use , Receptors, Purinergic P2Y2/metabolism , Saccharomyces cerevisiae/metabolism , Animals , Apyrase/genetics , CRISPR-Cas Systems/genetics , Disease Models, Animal , Dysbiosis/prevention & control , Female , Fibrosis/prevention & control , Gastrointestinal Microbiome/physiology , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/pathology , Humans , Inflammatory Bowel Diseases/pathology , Male , Mice , Mice, Inbred C57BL , Receptors, Purinergic P2Y2/genetics , Saccharomyces cerevisiae/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...