Scientists have given orally administered bacteria a "backpack" to improve their therapeutic effect

In a biological context, reactive oxygen species (ROS) are natural byproducts of normal oxygen metabolism and play an important role in cell signaling and homeostasis. Excess reactive oxygen species, on the other hand, can cause oxidative stress in the body, amplifying the inflammatory response and exacerbating inflammatory diseases. Excess reactive oxygen species in the intestine cause oxidative stress, which is thought to be a major factor in the development of inflammatory bowel disease (IBD).

Antioxidants are known to help relieve IBD symptoms by scavenging reactive oxygen species from the intestinal tract. However, the non-specific biodistribution of the drug after systemic administration, combined with the relatively low efficacy of scavenging reactive oxygen species, has resulted in an unsatisfactory therapeutic effect of antioxidants in IBD, as well as adverse reactions in normal tissues.

Nov. 11, 2022—A team of researchers from the University of Wisconsin-Madison developed polymeric nanoparticles that effectively scavenged reactive oxygen species and combined them with modified E. coli to safely and effectively target colon tissue in mouse experiments and significantly alleviate the animals' IBD symptoms, according to a recent study published in Science Advances. This research paves the way for potential clinical applications.

In healthy people, intestinal flora maintains ecological homeostasis and protects the host from pathogen invasion and colonization. Dysbiosis, on the other hand, causes a chronic inflammatory state, which increases toxin production and disrupts host metabolism. Scientists have discovered that IBD is associated with dysbiosis of the intestinal flora ecology in the colonic microenvironment, in addition to excess reactive oxygen species in the intestine.

Previously, the team developed a technique for encasing beneficial bacteria in a very thin protective shell to aid in their establishment and proliferation in the mouse intestine. Unfortunately, these therapeutic bacteria can be highly sensitive to the harsh environment in the gastrointestinal tract, limiting their activity and residence time in the intestine, resulting in suboptimal therapeutic effects.

In this new study, the team established a platform that selectively and sustainably scavenges reactive oxygen species from inflamed colon tissue. They synthesized a hyaluronic acid (HA)-PPS conjugate and self-assembled HA-PPS nanoparticles based on the amphiphilic nature present when HA and PPS are bound. Hyaluronic acid was used to modify PPS and construct nanoparticles because it can alleviate IBD symptoms by modulating the immune response. In addition, hyaluronic acid is usually found in synovial fluid and extracellular matrix, is biocompatible and biodegradable, and has been widely used in biomedicine.

Researchers wrapped modified E. coli Nissle 1917 (EcN) with norepinephrine (NE) to protect probiotic bacteria from external environmental attack by forming a polyNE film on the surface through autoxidation to improve the effective delivery of orally administered bacteria to the colon. Furthermore, the catecholamine moiety of NE is enriched with the highly adhesive mussel foot mucin, which provides strong mucosal adhesion to the engineered bacteria and can prolong their stay in the intestine, enhancing the therapeutic effect.

The researchers incorporated nanoparticles onto the surface of the engineered bacteria, which acted as a "backpack" for the bacteria based on the colonization properties of E. coli in colon tissue. This engineered E. coli backpack can effectively deliver to inflammatory colon tissue and normalize reactive oxygen levels while minimizing off-target side effects.

Finally, tests in mice revealed that engineered E. coli encased in a protective shell and equipped with a nanoparticle "backpack" were significantly better than their unarmed counterparts at relieving symptoms of inflammatory bowel disease. When compared to partially or untreated mice, fully treated mice lost less weight and had shorter colons.

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