The world of microbes living in the human gut can have far-reaching effects on human health. Multiple diseases, including inflammatory bowel disease (IBD), are tied to the balance of these microbes, suggesting that restoring the right balance could help treat disease. Many probiotics -- living yeasts or bacteria -- that are currently on the market have been optimized through evolution in the context of a healthy gut. However, in order to treat complex diseases such as IBD, a probiotic would need to serve many functions, including an ability to turn off inflammation, reverse damage and restore the gut microbiome. Given all of these needs, researchers from Brigham and Women's Hospital have developed a "designer" probiotic -- a thoughtfully engineered yeast that can induce multiple effects for treating IBD. Preclinical results from their work are published in Nature Medicine.

"We've taken yeast -- the very yeast that's used to make beer -- and we've given it the ability to sense inflammation and secrete an anti-inflammatory molecule," said the corresponding author. "We call this new platform 'Y-bots' (yeast robots) and see the potential here for developing therapeutics that can treat diseases of the gut tissue and more."

Previous research from the lab has helped illuminate the connection between the gut and diseases that affect the brain, suggesting potential applications for engineering probiotics beyond IBD.

The authors developed their probiotic using Saccharomyces cerevisiae, a species of yeast used in winemaking, baking and brewing. 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, the authors developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. They 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.

The engineered yeast can secrete different levels of enzyme, depending upon how much of the inflammatory signal is present at a location in the gut. This means that the probiotic can have a highly localized response to inflammation. In mice, the engineered yeast successfully suppressed intestinal inflammation, reduced fibrosis and restored a balanced gut microbiome.

To bring this new therapeutic platform to bear on IBD and other diseases in humans, the authors will need to conduct safety studies. They also plan to further refine and test the engineered yeast to see if they can speed up tissue repair. Beyond IBD, the team plans to investigate the use of engineered probiotics for treating a common side effect of cancer immunotherapy, colitis.

"We want to use the tools of synthetic biology to engineer what can be found in nature," said the senior author. "By engineering probiotics, our goal is to create more personalized, localized and highly controlled medications for treating diseases of the gut and beyond."

https://www.nature.com/articles/s41591-021-01390-x