Inulin Gel Oral Immunotherapy Suppresses Food Allergies

Researchers recently developed a novel oral immunotherapy platform that modulates the microbiome-metabolites-immune axis in situ to establish allergen-specific, sustained oral tolerance. The platform uses formulated inulin gel in combination with food allergens to deliver dietary antigens orally to intestinal dendritic cells.

Context
Food allergies are a rising health concern, particularly in developed nations where unintentional exposure to allergens can result in hypovolemic shock, which frequently poses a serious risk to life.

To date, the management of food allergies has involved the rigorous avoidance of foods containing allergens, experimental treatments, and immediate anaphylactic treatment.

Palforzia was the first oral immunotherapy medication authorized by the Food and Drug Administration (FDA) in the United States (US) to reduce the incidence and severity of peanut allergies. Nevertheless, investigations showed that gastrointestinal side effects caused nearly 20% of patients to stop their treatment.

The inability to acquire consistent and long-lasting unresponsiveness to the allergen was also influenced by issues with intermittent dosing and insufficient dose maintenance.

Numerous studies also suggest that the metabolites released by gut microorganisms and dysbiosis of the microbiome may be related to food allergies.

The allergy desensitization seen following fecal microbiota transplantation or probiotic therapy lends more credence to these conclusions.

About the Study

Since the small intestine is where most tolerance to food allergens and antigen priming occurs, the goal of the current study was to address the issue of effective dietary allergen delivery into the small intestine to modulate the gut microbiomes in the small intestine and achieve allergen desensitization.

The purpose of the inulin gel-based oral immunotherapy platform is to directly transport the allergen or antigen to the small intestine’s dendritic cells, which are responsible for antigen sampling.

A prebiotic polysaccharide generated from plants, inulin aids in the growth of gut bacteria in the intestine and is neither absorbed nor digested in the stomach.

The protein allergen was combined with heated inulin in phosphate-buffered saline (PBS), which was then chilled to produce an inulin gel. In the study, casein from cow’s milk and ovalbumin from chicken egg whites were evaluated for protein allergies.

Following intraperitoneal sensitization to the protein allergen, mice were treated with oral immunotherapy utilizing protein allergen and inulin gel.

The safety profile of the oral immunotherapy was assessed by measuring the incidence of anaphylaxis, changes in body weight, complete blood count, body temperature, and biochemical measurements such as immunoglobulin (Ig) E, interferon-gamma (IFNγ), mucosal mast cell protease (MMCP)-1, and different interleukins (IL).

The researchers also investigated the possibility of comparable reactions when native inulin and the protein allergen were combined.

Furthermore, following the inulin gel and ovalbumin therapy, the immunological landscape of the small intestinal lamina propria was investigated utilizing single-cell ribonucleic acid sequencing (scRNAseq).

Using antibodies against cluster of differentiation (CD) 25, which is necessary for regulatory T cell function, the researchers were able to distinguish between the roles of cytokines and regulatory T cells induced by the inulin gel and ovalbumin therapy.

To ascertain whether the inulin gel and protein allergen oral immunotherapy produced long-lasting protection against the food allergen, the researchers likewise duplicated the dose escalation and treatment plan utilized for Palforzia.

Outcomes
The study discovered that oral immunotherapy, which included a protein allergen and formed inulin gel, was able to keep the antigen in the small intestine for extended periods of time, facilitating its absorption by the intestinal dendritic cells.

Moreover, the insensitivity to the allergen persisted for over 13 weeks following the cessation of treatment.

After being sensitized with ovalbumin, the mice were given free ovalbumin, PBS, or an ovalbumin-infused designed inulin gel. Ovalbumin and PBS-treated animals showed signs of anaphylactic shock, including a sharp drop in body temperature.

On the other hand, the mice that received inulin gel with ovalbumin had a far decreased incidence of allergic diarrhea, no systemic hypothermia, and a diminished anaphylactic shock response.

Elevated levels of regulatory T cells positive for IFNγ and IL-10, which are known to dampen allergic immune responses, were also a result of the inulin gel and ovalbumin oral immunotherapy.

It was also shown that the administration of inulin gel-based oral immunotherapy inhibits T helper 2 cells’ (TH2) production of IL-13 and IL-4, which are involved in allergic inflammatory responses.

Furthermore, the researchers noticed that the microbiome dysregulation that took place in the small intestine of the food allergy mouse models was also corrected by the inulin gel-ovalbumin oral immunotherapy.

Following treatment with the manufactured inulin gel and ovalbumin, the quantity of Enterorhabdus and Eggerthellaceae, which had been observed to be reduced in the ovalbumin sensitized mice compared to native mice, was recovered.

In conclusion
The research demonstrated that oral immunotherapy, which included a protein allergen like ovalbumin or casein and made inulin gel, was effective in keeping food allergy mouse models’ small intestines intact.

The immunological responses that were triggered by the small intestine dendritic cells’ absorption of antigens inhibited allergic inflammation and anaphylactic shock.

Additionally, these effects persisted even after the oral immunotherapy was stopped.

For more information: Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy, Nature Materials, doi:10.1038/s4156302401909w