Scientists report that their “polymeric micelles” are efficient towards peanut allergy symptoms in mice. The remedy might sometime counteract many forms of meals allergy symptoms and inflammatory illnesses.
Many individuals with dietary allergy symptoms solely expertise delicate signs when uncovered to triggering meals. However, some face doubtlessly deadly penalties. A bacterial compound referred to as butyrate that’s made by wholesome microbiomes has proven promise towards allergic reactions in lab assessments. The drawback is that it’s nasty to take orally. Today, scientists describe a extra palatable solution to ship this compound. They additionally report that their “polymeric micelles” are efficient towards peanut allergy symptoms in mice. Someday the remedy might counteract many forms of meals allergy symptoms and inflammatory illnesses.
The scientists will current their outcomes on the fall assembly of the American Chemical Society (ACS). ACS Fall 2022 is a hybrid assembly being held just about and in-person August 21–25, with on-demand entry out there on August 26-September 9. The assembly options practically 11,000 shows on a variety of science subjects.
Some of the micro organism that make up the intestine microbiome produce compounds, resembling butyrate, that promote the expansion of useful micro organism and preserve the liner of the intestine. If an individual’s microbiome is unhealthy and lacks these butyrate-producing micro organism, fragments of partially digested meals can leak out of the intestine and set off an immune response that ends in an allergic response.
One solution to deal with these with allergy symptoms could be to offer the lacking bugs to them orally or with a fecal transplant. However, that hasn’t labored nicely within the clinic, in keeping with Jeffrey Hubbell, Ph.D., one of many venture’s principal investigators (PIs). “So we thought, why don’t we just deliver the metabolites — like butyrate — that a healthy microbiome produces?”
“But butyrate has a very bad smell, like dog poop and rancid butter, and it also tastes bad, so people wouldn’t want to swallow it,” says Shijie Cao, Ph.D., who’s presenting the outcomes on the assembly for the workforce, which is on the University of Chicago. And even if people could manage to choke it down, butyrate would be digested before reaching its destination in the lower gut.
To overcome these challenges, the scientists, including co-PI Cathryn Nagler, Ph.D., and Ruyi Wang, Ph.D., designed a new delivery system. They 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, thus cloaking the compound’s foul taste and smell.
The researchers administered these micelles to the digestive systems of mice that were lacking either healthy gut bacteria or a properly functioning gut lining. After digestive juices released the butyrate in the lower intestine, the inert polymers were eliminated in the feces. The treatment restored the gut’s protective barrier and microbiome, in part by increasing the production of peptides that kill off harmful bacteria, which made room for helpful butyrate-producing bacteria.
Most importantly, dosing allergic mice with the micelles was shown to prevent a life-threatening anaphylactic response when they were exposed to peanuts. “This type of therapy is not antigen specific,” Cao notes. “So theoretically, it can be broadly applied to any food allergies through the modulation of gut health.”
Next up are trials in larger animals, followed by clinical trials. If those trials succeed and the U.S. Food and Drug Administration (FDA) approves the oral treatment, the micelles could be marketed in small packets; consumers would tear open a packet and stir the contents into a glass of water or juice. In other work with the micelles, the research team is analyzing data on treating inflammatory bowel diseases with the oral therapy.
The scientists are also investigating administration via injection. The researchers have shown that this method allows the micelles and their butyrate cargo to accumulate in lymph nodes, which are part of the immune system. They found that this approach is effective in treating peanut allergies in mice, but it could also be used to suppress immune activation locally — rather than throughout the body. For instance, injections could be helpful in patients who have had an organ transplant or who have a localized autoimmune and inflammatory condition, such as rheumatoid arthritis.
The researchers acknowledge support and funding from their start-up company, ClostraBio, and the University of Chicago.
Title
Microbial metabolite butyrate-prodrug polymeric micelles promote gut health and treat food allergies
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.
