Encapsulated Probiotics Equipped with Nanoparticle Backpacks Show Promise for IBD Therapy

Researchers at the University of Wisconsin (UW)–Madison have combined gut-friendly, encapsulated probiotic bacteria with nanoparticle technology to help improve the treatment of inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis.

Headed by Quanyin Hu, PhD, a biomedical engineer and professor in the UW–Madison School of Pharmacy, the research builds on technology the team had previously designed that encases beneficial bacteria in a thin protective shell that shields them from attack by stomach acid and competing microbes until they can establish in the gastrointestinal tract of mice. The newly reported development in addition harnesses specialized nanoparticles to scavenge and neutralize the reactive oxygen species (ROS) molecules implicated in IBD. The team has devised a way to attach these nanoparticle “backpacks” to the beneficial bacteria after encasing them in the protective coating.

Reported in Science Advances, the team’s studies in mice showed that probiotic bacteria encased in the protective poly-norepinephrine (NE) shell and kitted out with the hyaluronic acid-polypropylene sulfide (HA-PPS) polymer nanoparticle (HPN) backpacks were significantly better at relieving IBD symptoms than their counterparts without the additional backpack nanoparticles.

Hu and colleagues described their developments in a paper titled, “Mucoadhesive probiotic backpacks with ROS nanoscavengers enhance the bacteriotherapy for inflammatory bowel diseases,” in which they commented, “In this study, we established a platform that can selectively and sustainably scavenge ROS in inflamed colon tissues while also improving probiotic delivery for gut microbiota homeostasis modulation. This platform could help to restore a normal gut microenvironment and address the fundamental issues for effective IBD therapy.”

While the root causes of IBD are complex and still being studied, the overproduction of reactive oxygen species is one culprit. These molecules are crucial for certain human body functions, but their overproduction can fuel damaging inflammation along the lining of the intestines. “Excessive ROS-induced oxidative stress in the intestine is thought to be a major factor in the pathogenesis and progression of IBDs,” the authors wrote.

In addition to excessive ROS in the intestines, IBD is linked with an imbalance in gut microbiota in the colon, the authors continued. In healthy people the gut microbiota provide essential nutrients and fatty acids, and protect against invasion by pathogens, but “a disordered microbiota induces a chronic inflammatory state, increases toxic production, and disrupts the host’s metabolism,” the investigators noted. Their prior studies had shown that probiotics can help to restore a normal gut microbiome for treating GI tract-related diseases, but probiotics don’t survive well in the harsh environment of the GI tract, so their therapeutic effects are also limited.

Quinyan Hu, PhD, in his lab. [Sally Griffith-Oh]
The team had previously developed a technology that encases beneficial bacteria within a very thin protective shell that helps them to survive in the harsh environment of stomach acids and competing microbes in mice, for long enough to become established and multiply. “… EcN was encapsulated with an NE layer to protect the bacteria from the harsh environmental conditions presenting in the GI tract and to extend retention time of EcN in the intestine,” they wrote. While that technology did make orally administered probiotics more effective, it didn’t address other aspects of IBD. “IBD is a complicated disease, and you need to attack it at different angles,” said Hu.

To do this, Hu and his colleagues generated specialized nanoparticles that were designed to neutralize the ROS molecules implicated in IBD. They also figured out a way of attaching these nanoparticle “backpacks” to beneficial bacteria after encasing them in the protective coating. “

The tiny HPN backpacks are part sulfide and part hyaluronic acid. The acid acts as a powerful anti-inflammatory, and the sulfide directly targets the reactive oxygen species. In combination with the probiotic microorganisms, these nanoparticle backpacks could feasibly improve—and simplify—IBD treatments. “Previous research has shown that the addition of supplementary commensal bacteria is beneficial for regulating microbiota homeostasis in the GI tract for IBDs. Therefore, conjugating the ROS scavenger HPN onto the surface of probiotics has the potential to exhibit synergy for enhanced therapeutic efficacy in the setting of IBDs,” they stated.

The team’s newly reported research in mice demonstrated that probiotic bacteria Escherichia coli Nissle 1917 (EcN) encased in the protective NE shell and outfitted with the nanoparticle backpacks were significantly better at relieving IBD symptoms than the encapsulated bacteria without the backpacks.

Like humans, mice with IBD commonly experience weight loss and colon shortening as the disease progresses. The researchers measured changes in weight and also changes in the colon length of mice with IBD that did and did not receive the treatment. They found that animals receiving the encapsulated, nanoparticle backpack-equipped probiotic (HPN-NE-EcN) therapy experienced the least amount of weight loss and much less colon shortening than their counterparts that received only partial or no treatment.

“In the dextran sulfate sodium–induced mouse colitis models, HPN-NE-EcN showed substantially enhanced prophylactic and therapeutic efficacy,” they wrote. “Furthermore, the abundance and diversity of gut microbiota were increased after treatment with HPN-NE-EcN, contributing to the alleviation of IBDs.”

Current treatment options for IBD depend on the stage and severity of disease, but Hu and colleagues say they have sought a more holistic treatment that could be effective at any stage. “That’s the most exciting part of this research for me,” Hu stated. “We didn’t want to target a specific IBD stage. We wanted to select the most important factors that contribute to curing or treating the disease at whatever stage.”

Reporting on their published studies, the authors concluded, “This platform not only has the ability to prolong the retention time of probiotics in the intestine for enhanced bacteriotherapy, but it can also specifically deliver and slow-release HPN in the intestine for improved ROS-scavenging capabilities.” The HPN-NE-EcN probiotics are also administered orally, which could make it a palatable alternative to other more invasive forms of IBD treatment such as partial or complete removal of the colon.

Hu and the team next want to continue testing, to check the safety of the approach, and also to evaluate the nanoparticle backpacks with other probiotic bacteria species. Simplifying the process of creating and attaching the nano-backpacks will also be crucial for making the treatments clinically feasible.

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