Engineered yeast can transport drugs and reduce inflammation

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Genetic engineering of S. boulardii to express cell surface mSA handle for attachment of ECM-specific targeting ligands. Credit: Nature communication (2024). DOI: 10.1038/s41467-024-48128-0

Inflammatory bowel disease (IBD) is a complex condition that requires individualized care to meet the needs of the patient’s current disease state. Because available medications sometimes cause serious side effects or lose effectiveness over time, many researchers have explored new, more targeted ways to deliver medications or other beneficial substances, such as probiotics.

To address pitfalls in IBD treatment and drug delivery, the laboratories of Juliane Nguyen, Ph.D., professor and vice chair of pharmacoengineering and molecular pharmaceuticals at the UNC Eshelman School of Pharmacy, and Janelle Arthur, Ph.D. .D., associate professor of microbiology and immunology at the UNC School of Medicine, have developed a genetically engineered probiotic strain of Saccharomyces boulardii.

In their new study published in Nature communicationNguyen, Arthur and colleagues used mouse models to demonstrate that their engineered drug delivery system increases probiotic concentrations and extends the survival time of probiotic yeasts in the intestines. The improved absorption of probiotics has also been proven to inhibit and even reverse inflammation.

“We can now use this knowledge to better engineer probiotics so that they are more potent and have more control over their function,” says Nguyen, who is also a member of the UNC Lineberger Comprehensive Cancer Center and the UNC McAllister Heart Institute. “Our long-term goal is to develop an oral live biotherapeutic that can secrete specific therapies so that patients with IBD do not require painful injections or antibody infusions.”

The human gut is a surprisingly difficult environment for oral probiotics due to its enhanced microbiome. When new probiotics are introduced into the intestines, it can be difficult for them to live and grow alongside established bacterial colonies. This challenge led Nguyen and Arthur to develop a living biotherapeutic delivery system that can survive and thrive in the gut.

For their targeted approach, researchers first had to select a drug delivery vehicle for the study. They chose a yeast called Saccharomyces boulardii, which has been proven to be safe and well tolerated by IBD patients, has anti-inflammatory properties and is resistant to antibiotic use.

Mairead Heavey, Ph.D., the paper’s first author and former Ph.D. candidate in Nguyen’s lab, developed a platform surface display system. The method inserts surface proteins into the cell walls of the yeast that are able to identify and target the proteins expressed by an IBD-affected colon.

The researchers focused specifically on proteins expressed by the extracellular matrix, the complex cellular network that is constantly worn down by ulcers and rebuilds itself to form new intestinal tissue. When the extracellular matrix works overtime to heal itself, it produces a greater number of proteins.

Using the upregulated proteins to their advantage, Nguyen and Arthur genetically modified the yeast with surface proteins that could target and bind to the extracellular matrix proteins for extended periods of time. Now that the system is allowed to linger in the colon for a while, the probiotic effects of the yeast have plenty of time to take effect, providing some anti-inflammatory relief.

“What we’re trying to do is give this system the ability to target ulceration and regions of increased extracellular matrix growth,” says Arthur, who is also a member of the UNC Lineberger Comprehensive Cancer Center. “We want to force it to stick around and colonize the intestines so it has enough time for proper treatment and anti-inflammatory effects.”

Over the course of 48 hours, researchers examined how well the surface display system stuck in the colon. After 24-48 hours of probiotic intestinal residence time, there was a 100-fold increase in probiotic concentrations in the colon in preclinical models of ulcerative colitis, compared to their controls. As the residence time of probiotics in the intestines increased, researchers found that colon length and inflammation improved and were ultimately restored to healthy levels.

Although the yeast has anti-inflammatory properties, it is not enough to provide relief to patients with IBD. Researchers have engineered the yeast to produce antibodies and peptides that can target extracellular matrix proteins and provide treatment. Antibodies, which are a common anti-inflammatory treatment for IBD, can be replaced with other compounds that can be administered through the drug delivery system.

“We can easily exchange and bundle connections in the system,” Arthur said. “Different compounds are needed depending on whether a patient is having a flare-up or is in remission. We have the ability to actually swap out the compound to tailor it to the patient and their disease progression,” Nguyen added.

Later, Nguyen and Arthur will explore how their system can be used to treat other gastrointestinal diseases, such as Clostridium difficile and colitis-associated colorectal cancer. Although their system is far from clinical trials on humans, the researchers are expanding their team with clinical experts who can help move their research from the laboratory to the clinic.

“I hope this work will spark further innovations in the field of probiotic engineering,” Heavey said. “I see so much potential as we continue to develop new bioengineering methods and uncover the role of the microbiome in health and disease progression.”

More information:
Mairead K. Heavey et al., Targeted delivery of the probiotic Saccharomyces boulardii to the extracellular matrix improves intestinal residence time and recovery in colitis in mice, Nature communication (2024). DOI: 10.1038/s41467-024-48128-0

Provided by UNC Lineberger Comprehensive Cancer Center

Quote: A potential treatment for inflammatory bowel disease: Engineered yeast could transport drugs and reduce inflammation (2024, May 7) retrieved May 7, 2024 from disease.html

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