A breakthrough study reveals that food allergies can be reversed in mice August 21, 2022 by ved There are various treatments and methods for reducing severe reactions. There are paths to desensitize people via immunotherapy, wherein a small amount of an allergen is injected or delivered via tablets or drops. In one method, sufferers basically take very small amounts of what they are allergic to, building up a tolerance over time. But the stakes are high. Food allergies are responsible for sending someone to the emergency room every three minutes. A huge number of people — especially the 32 million people in the U.S. with food allergies — would love a permanent cure, including the ability to reverse an existing allergy, if possible. What was once considered a pipe dream may now be almost here. Researchers at the University of Chicago have developed a way to deliver a compound called “polymeric micelles” that targets the microbiome, and has been demonstrated to be effective in treating peanut allergies in mice. The breakthrough study could perhaps someday help counteract several types of food allergies and inflammatory diseases. The research was presented at a meeting of the American Chemical Society. Milk, eggs, peanuts, and shellfish account for most of all reactions. The most common types of food allergies are triggered by antibodies in the body called immunoglobulin E or IgE. “When someone has a food allergy, IgE is part of triggering a response when the immune system comes into contact with that food. It releases histamine and other inflammatory chemicals which causes the symptoms of food allergy,” Shijie Cao, Ph.D., who is part of the study, told IE in an interview. However, Cao also pointed out that the reason why the body acts differently towards such harmless substances is still largely a mystery. A turning point in the experiment was finding that the gut microbiome (the trillions of microorganisms that live in the digestive tract) is associated with food allergies. Some of the bacteria in the gut microbiome produce a bacterial compound called butyrate. This is a short-chain fatty acid produced through microbial fermentation of dietary fibers in the lower intestinal tract. It has been shown to have anti-inflammatory properties, as well as beneficial effects on intestinal homeostasis and energy metabolism, and has an important role in maintaining the the gut lining. If a person’s microbiome is unhealthy, it will have a lower number of these butyrate-producing bacteria, or may even be without them altogether. This could result in fragments of partially digested food leaking out of the gut and producing an immune reaction that results in an allergic response. The study researchers — Jeffrey Hubbell, Ph.D., one of the project’s principal investigators (PIs), co-PI Cathryn Nagler, Ph.D. Ruyi Wang, Ph.D., along with Cao — tried treating allergies by replacing mising microorganisms either orally or with a fecal transplant, which did not work well in the clinic. They then wondered if they could just deliver the metabolites directly, as in a healthy microbiome. Though butyrate showed promise in treating allergic reactions in lab tests, there were a number of issues with taking it orally. “Firstly, it has a very strong smell, quite rancid and stinky. Also, butyrate is produced at a large scale in the healthy gut, and we’ll have to develop a large amount to effectively treat food allergies,” says Cao. To overcome such challenges, the researchers polymerized butanoyloxyethyl methacrylamide — which has a butyrate group as a side chain — with methacrylic acid or hydroxypropyl methacrylamide. The resulting polymers self-assembled into aggregates, or polymeric micelles, that tucked the butyrate side chains in their core, hiding the compound’s foul smell and bad taste, according to a press release. These micelles were then administered to the digestive systems of mice that lacked either healthy gut bacteria or a properly functioning gut. Digestive juices released the butyrate in the lower gut, and inert polymers were eliminated in the feces. This treatment restored the gut’s protective barrier and microbiome by increasing the production of peptides that destroy harmful bacteria, which made room for butyrate-producing bacteria. Dosing the allergic mice with the micelles prevented a life-threatening anaphylactic response when they were exposed to peanuts. “These micelles, which can be formulated as powder, can even be added to drinking water or juice. The polymer also masks the smell and taste of butyrate,” says Cao. Most importantly, he adds, this therapy is not antigen-specific and can be applied to any other food allergies. “We have tested the efficacy of a peanut allergy model until now. But our goal is also to test several other food allergy models as theoretically, our system is not designed for just one particular food allergen. In other work, we’re also looking to treat inflammatory bowel diseases with oral therapy,” says Cao. Administration via injection is another method that is being investigated. This method allows the micelles and their butyrate cargo to accumulate in lymph nodes, which are part of the immune system. Though this approach is effective in treating peanut allergies in mice, it could also be used to suppress immune activation locally rather than throughout the body. For example, such injections could be helpful in patients who have had an organ transplant or a localized autoimmune and inflammatory condition. The team hopes to test their system on larger animals before proceeding to clinical trials. If those trials succeed and the U.S. Food and Drug Administration approves the oral treatment, the micelles could be marketed in small packets. “The micelles drug delivery system is a pretty robust platform that could also be used to deliver other microbial metabolites, in addition to butyrate. We’re also collaborating with several other labs to test data on different applications,” adds Cao. Study abstract: The gut microbiome has myriad effects on both mucosal and systemic health. Resident commensal bacteria play a critical role in the maintenance of mucosal homeostasis, in part through their production of short-chain fatty acids, especially butyrate. Although butyrate is known to play important roles in regulating gut immunity and maintaining epithelial barrier function, its clinical translation is challenging due to its offensive odor and quick absorption in the upper gastrointestinal tract. Here, we designed two block copolymers that contain a high content of butyrate and self-assemble into water-suspendible micelles. These two copolymers consist of a hydrophilic block, poly(N-(2-hydroxypropyl) methacrylamide) or poly(methacrylic acid), with a hydrophobic block, poly(N-(2-butanoyloxyethyl) methacrylamide), thus connecting a backbone sidechain to butyrate with an ester bond. These two copolymers form micelles with either a neutral charge (NtL-ButM) or a negative charge (Neg-ButM). Each micelle releases butyrate from their polymeric core in the ileum or the cecum, respectively, after intragastric administration to mice. These polymer formulations mask the foul smell and taste of butyrate and act as carriers to release the active ingredient (butyrate) over time as the micelles transit the GI tract. Treatment with NtL-ButM in germ-free (and thus butyrate-depleted) mice up-regulated genes expressing antimicrobial peptides in the ileal epithelium. We show that these butyrate-containing micelles, used in combination, restored a barrier-protective response in mice treated with either antibiotics or dextran sodium sulfate (DSS), a chemical perturbant that induces epithelial barrier dysfunction. Twice daily intragastric administration of our butyrate-prodrug micelles ameliorates an anaphylactic response to peanut challenge in a mouse model of peanut allergy and increases the abundance of bacteria in a cluster (Clostridium Cluster XIVa) known to contain butyrate-producing taxa. By restoring microbial and mucosal homeostasis, these butyrate-prodrug polymeric micelles may function as a new, antigen-agnostic approach to the treatment of food allergy.