Scientists Reverse Food Allergies by Targeting the Microbiome



When exposed to foods that trigger their allergies, many people only have minor symptoms. Some, though, could suffer deadly consequences. In laboratory testing, the bacterial chemical butyrate, which healthy microbiomes produce, has showed promise in preventing allergic reactions. The issue is that it tastes bad when consumed orally. Today, researchers outline a more appealing method of administering this substance. Additionally, they claim that their "polymeric micelles" successfully treat mouse peanut allergies. One day, the medication might be able to treat various inflammatory disorders including food allergies.

The researchers will present their findings at the American Chemical Society's fall meeting (ACS). August 21–25 will see the hybrid ACS Fall 2022 meeting, with on-demand access available from August 26–September 9. Nearly 11,000 talks covering a wide range of science issues are included in the meeting.

The gut microbiome is made up of bacteria, some of which create substances like butyrate to support the growth of good bacteria and preserve the gut lining. Food particles that haven't fully digested can escape the stomach if the microbiome of the individual is sick and deficient in these butyrate-producing bacteria, which can then set off an allergic reaction.

Giving the missing bugs to allergy sufferers orally or by a fecal transplant is one method of treatment. However, according to Jeffrey Hubbell, Ph.D., one of the project's lead scientists, that hasn't been successful in the clinic (PIs). "So we reasoned, why not just deliver the metabolites that a healthy microbiome creates, like butyrate?"

Butyrate doesn't taste good and smells like rotten butter, so people wouldn't want to ingest it, claims Shijie Cao, Ph.D., who is presenting the findings at the team conference at the University of Chicago. And even if someone could manage to swallow it, butyrate would be broken down before it got to the lower intestines.

The researchers created a novel delivery mechanism to get around these difficulties, working with co-PI Cathryn Nagler, Ph.D., and Ruyi Wang, Ph.D. They combined methacrylic acid or hydroxypropyl methacrylamide with butanoyloxyethyl methacrylamide, which possesses a butyrate group as a side chain. The resultant polymers formed aggregates, or polymeric micelles, which tucked the butyrate side chains in their core, masking the compound's unpleasant taste and odor.

The digestive systems of mice lacking either healthy gut bacteria or an effective gut lining were given these micelles by the researchers. The inert polymers were removed in the feces when digestive processes in the lower intestine released the butyrate. Through increasing the production of peptides that eliminate bad bacteria and make place for beneficial butyrate-producing bacteria, the therapy was able to restore the gut's protective barrier and microbiota.

Most notably, it was shown that administering allergic mice with micelles prior to exposing them to peanuts prevented a potentially fatal anaphylactic reaction. According to Cao, "This kind of treatment is not antigen specific." Theoretically, by modifying gut health, it might be generally applicable to any food sensitivities.

Trials on larger animals are the next step, and then clinical trials. The micelles might be sold in little packets, which customers would tear open and stir into a glass of water or juice, if those studies are successful and the FDA in the United States approves the oral treatment. The research group is also using micelles to analyze data on the use of oral treatment to treat inflammatory bowel illnesses.

The use of injections for administration is also being studied by the researchers. Scientists have demonstrated that this technique enables micelles and their butyrate cargo to build up in lymph nodes, which are a component of the immune system. They discovered that this strategy works well for treating mouse peanut allergies, but it can also be utilized to decrease immunological activity locally rather than systemically. For individuals who have undergone organ transplantation or who suffer from a localized autoimmune and inflammatory disease like rheumatoid arthritis, injections may be beneficial.

The researchers thank the University of Chicago and their start-up company ClostraBio for their financial assistance.

Title Butyrate-prodrug polymeric micelles, a microbial metabolite, improve gut health and alleviate food sensitivities

Numerous factors impact the systemic and mucosal health of the gut microbiota. Because they produce short-chain fatty acids, especially butyrate, resident commensal bacteria are crucial for maintaining mucosal homeostasis. Although it is well established that butyrate regulates gut immunity and maintains epithelial barrier function, butyrate's clinical application is difficult due to its unpleasant odor and rapid absorption in the upper gastrointestinal tract. Here, we developed two block copolymers that self-assemble into water-soluble micelles and have a high butyrate content. These two copolymers combine a hydrophilic block, such as poly(N-(2-hydroxypropyl) methacrylamide) or poly(methacrylic acid), with a hydrophobic block, such as poly(N-(2-butanoyloxyethyl) methacrylamide), forming an ester link that connects a backbone sidechain to butyrate. These two copolymers can either form neutral (NtL-ButM) or negatively charged (Nt-ButM) micelles (Neg-ButM). Following intragastric delivery to mice, each micelle releases butyrate from its polymeric core in the ileum or cecum, as appropriate. These polymer compositions serve as carriers to gradually release the active ingredient (butyrate) as the micelles move through the GI tract while also masking the unpleasant taste and odor of butyrate. In germ-free (and hence butyrate-depleted) mice, treatment with NtL-ButM increased the expression of genes for antimicrobial peptides in the ileal epithelium. In mice treated with antibiotics or dextran sodium sulfate (DSS), a chemical perturbant that causes epithelial barrier dysfunction, we demonstrate that these butyrate-containing micelles, when given in combination, restored a barrier-protective response. Our butyrate-prodrug micelles, administered twice daily intragastrically, reduce the severity of the anaphylactic reaction to peanut challenge in mice with peanut allergy and boost the population of bacteria in a cluster (Clostridium Cluster XIVa) known to contain butyrate-producing taxa. These butyrate-prodrug polymeric micelles may serve as a novel, antigen-independent strategy for the treatment of food allergy by restoring microbial and mucosal homeostasis.                                                                                                                                                                       By AMERICAN CHEMICAL SOCIETY

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