Inulin gel-based oral immunotherapy is effective in suppressing food allergy responses and anaphylactic shock

In a recent study published in Nature Materials, a team of researchers developed a novel oral immunotherapy platform that uses formulated inulin gel combined with food allergens to orally deliver dietary antigens to intestinal dendritic cells and modulate the microbiome-metabolites-immune axis in situ to establish an allergen-specific, sustained oral tolerance.

Study: Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy. Image Credit: Pixel-Shot/Shutterstock.com

Background

A growing health concern, especially in industrialized countries, is food allergies, with accidental exposure to food allergens leading to hypovolemic shock that can often become life-threatening.

The strategies and interventions to deal with food allergies have thus far consisted of strict avoidance of foods containing allergens, experimental therapy, and emergency treatment for anaphylaxis.

The first oral immunotherapy drug approved by the United States (U.S.) Food and Drug Administration (FDA) was Palforzia to lower the severity and incidence of peanut allergies. However, reports indicated close to 20% discontinuation of the treatment due to gastrointestinal adverse events.

The problems associated with dose intermittence and inadequate dose maintenance also contributed to a failure to develop long-term and persistent unresponsiveness to the allergen.

Many studies also report that food allergies might be linked to gut microbiome dysbiosis and the metabolites secreted by the gut microbes.

These findings are further supported by the allergen desensitization observed after probiotic therapy or fecal microbiota transplantation.

About the study

In the present study, the researchers aimed to address the problem of effective dietary allergen delivery into the small intestine to modulate the gut microbiomes in the small intestine and achieve allergen desensitization, given that most of the tolerance to food allergens and antigen priming occurs in the small intestine.

The inulin gel-based oral immunotherapy platform was designed to deliver the allergen or antigen directly to the dendritic cells of the small intestine that perform antigen sampling.

Inulin is a plant-derived prebiotic polysaccharide that is not absorbed or digested in the stomach and helps promote gut bacterial growth in the intestine.

Inulin was heated in phosphate-buffered saline (PBS), cooled to form the inulin gel, and blended with the protein allergen. The protein allergens tested in the study were ovalbumin from chicken egg whites, and casein from bovine milk.

Murine models that were intraperitoneally sensitized to the protein allergen were then treated with the inulin gel and protein allergen oral immunotherapy.

Occurrence of anaphylaxis and change in parameters such as body weight, complete blood count, body temperature, and biochemical measurements such as levels of immunoglobulin (Ig) E, interferon-gamma (IFNγ), mucosal mast cell protease (MMCP)-1, and various interleukins (IL) were measured to determine the safety profile of the oral immunotherapy.

The researchers also tested whether native inulin mixed with the protein allergen elicited similar responses.

Additionally, the immune landscape of the small intestinal lamina propria was examined using single-cell ribonucleic acid sequencing (scRNAseq) after the inulin gel and ovalbumin treatment.

To differentiate between the roles of cytokines and regulatory T cells induced by the inulin gel and ovalbumin treatment, the researchers used antibodies against cluster of differentiation (CD) 25, which is essential for the functioning of the regulatory T cells.

The researchers also replicated the dose escalation and therapeutic regimen used for Palforzia to determine if the inulin gel and protein allergen oral immunotherapy established sustained protection against the food allergen.

Results

The study found that oral immunotherapy consisting of formulated inulin gel and the protein allergen was retained in the small intestine for longer periods, enabling the antigen uptake by the dendritic cells in the small intestine.

Furthermore, the unresponsiveness to the allergen was sustained for more than 13 weeks after the therapy was discontinued.

The mice that were sensitized using ovalbumin were subsequently administered free ovalbumin, PBS, or formulated inulin gel with ovalbumin. Those who were treated with ovalbumin and PBS exhibited symptoms of anaphylactic shock, with a rapid decrease in body temperature.

However, the mice that were administered inulin gel with ovalbumin showed attenuated anaphylactic shock response, no systemic hypothermia, and a significantly lower occurrence of allergic diarrhoea.

The inulin gel and ovalbumin oral immunotherapy also resulted in elevated levels of regulatory T cells positive for IFNγ and IL-10, which are known to suppress allergic immune responses.

Administration of the inulin gel-based oral immunotherapy was also found to suppress the production of IL-13 and IL-4 by T helper 2 cells (T_H2), which are involved in allergic inflammatory responses.

Additionally, the researchers observed that the inulin gel-ovalbumin oral immunotherapy also normalized the microbiome dysregulation that occurred in the small intestine of the food allergy mouse models.

The abundance of Enterorhabdus and Eggerthellaceae, which were found to be lower in the ovalbumin sensitized mice in comparison to native mice, were restored after treatment with the formulated inulin gel and ovalbumin.

Conclusions

The study showed that an oral immunotherapy consisting of formulated inulin gel and a protein allergen such as ovalbumin or casein was successfully retained in the small intestine of food allergy mouse models.

The antigen uptake by the small intestinal dendritic cells elicited immune responses that suppressed allergic inflammation and anaphylactic shock.

These responses were also sustained well after the oral immunotherapy was discontinued.