Scientists reverse food allergies by targeting the microbiome

The scientists report that their “polymeric micelles” are effective against peanut allergens in mice. Treatment may one day combat many types of food allergies and inflammatory diseases.

Many people with food allergies experience only mild symptoms when exposed to trigger foods. However, some face potentially fatal consequences. A bacterial compound called butyrate, made by healthy microbiomes, has shown promise against allergic reactions in laboratory tests. The problem is that taking it orally is bad. Today, scientists describe a more palatable way to deliver this compound. They also report that their “polymeric micelles” are effective against peanut allergens in mice. Someday treatment can combat many types of food allergies and inflammatory diseases.

The scientists will present their results at the fall meeting of the American Chemical Society (ACS). ACS Fall 2022 is a hybrid meeting being held onsite and in person August 21-25, with on-demand access available June 26-September 9. The meeting features nearly 11,000 presentations on a wide range of science topics.

Some of the bacteria that make up the gut microbiome produce compounds like butyrate that promote the growth of beneficial bacteria and maintain the gut lining. If a person’s microbiome is unhealthy and lacks these butyrate-producing bacteria, partially digested food particles can escape from the gut and trigger an immune response that results in an allergic reaction.

One way to treat those with allergies is to provide them with missed bugs orally or with fecal implants. However, it hasn’t worked well in the clinic, according to Jeffrey Hubbell, PhD, one of the project’s principal investigators (PIs). “So we thought, why don’t we provide metabolites—like butyrate—that are produced by a healthy microbiome?”

“But butyrate has a very bad smell, like dog poop and rancid butter, and it tastes bad, so people don’t want to ingest it,” says Shijie Cao, Ph.D., who is presenting the results at the meeting. For the team, it’s in June[{” attribute=””>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

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.

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