Microbial metabolism of food allergens determines the severity of IgE-mediated anaphylaxis

Keywords

• Food allergy

• Microbiota

• Anaphylaxis

Main Findings

The role of the gut microbiota  in shaping food allergy outcomes has long been of interest, as bacteria  could influence allergen availability or create a pro-inflammatory  environment licensing a Th2 response. In this preprint by  Sánchez-Martínez et al., the  authors explore a novel connection between microbial metabolism and its  ability to modulate anaphylaxis — a life-threatening complication and  the most severe manifestation of food allergy triggered by accidental  allergen exposure. The study focuses on peanut allergy, one of the most  severe and persistent food allergies, with a rising global incidence. In  their initial experiments, the authors demonstrate that the gut  microbiota is able to degrade peanut protein, Enterococcus species appears to be primarily responsible in specific pathogen-free (SPF) mice.

Using a C3H-HeN SPF mouse model,  which is susceptible to Th2-driven allergic inflammation, the authors  show that the gut microbiota plays a protective role in peanut allergy -  induced anaphylaxis. Specifically, mice with diverse microbiota exhibit  lower serum levels of mucosal mast cell protease-1 (mMCP-1) and reduced  body temperature drop — both indicators of less anaphylactic severity.  Bridging their findings to human relevance, the authors examined the  oral microbiota of healthy volunteers for peanut-degrading capabilities.  They identified Staphylococcus and Rothiaspecies as the most efficient peanut degraders ex vivo. Subsequent in vitro experiments revealed that peanut extracts pre-digested by these  bacteria has less Ara h 1 and Ara h 2 proteins (key peanut allergens) as  seen via SDS-PAGE. The digested extract also reduced mast cell  activation in the presence of allergen-specific IgE in vitro. A central finding of the preprint shows that colonizing C3H-HeN mice with three Rothia strains (R1, R2, and R3), which were previously identified in humans,  has a mild protective effect upon allergenic challenge, as evidenced by  lower serum mMCP-1 levels compared to the non-colonized control. Adding  further clinical relevance, the study reports that peanut-allergic  individuals with higher tolerance thresholds (able to consume more than  40 mg of peanut protein) have a greater abundance of Ara h 2-degrading  bacteria in their oral microbiota.

In summary, this study presents  an intriguing mechanism by which microbial metabolism can modulate  allergen bioavailability, potentially reducing the severity of allergic  reactions such as anaphylaxis.

Limitations & Suggestions

• How  long does it take the bacteria to degrade the peanut proteins? Would be  interesting to better understand timing of peanut digestion, and how  physiologically relevant it would be in the end. Can chewing peanut  longer reduce chances of anaphylaxis, if there is a “proper”  peanut-degrading bacterial community in the oral cavity?

• It  would be very interesting to understand what metabolism pathway in  bacteria is responsible for peanut degradation, and how common it is.

• The key figure on Rothia colonization would benefit from showing temperature changes in mouse anaphylaxis.

• The  Fig. 2 should include Fig. S3 on body temperature reduction upon  anaphylaxis, and that mice with microbiota are protected from that.

• Bacterial digestion of peanut protein by Rothia and Staphylococcus could be moved to the supplementary, and experiments with in vitro stimulation of mast cells with degraded peanut extract + IgE would  benefit from flow cytometry analysis and a figure to visualize the  experimental design.

• In  Fig. 7H, there is no correlation of peanut threshold tolerance and Ara h  2 levels, but overall, with a larger sample size that would be  expected; people with severe peanut allergy cannot tolerate even low  doses of peanut.

• Technical point: indicate how many replicates of mouse experiments were performed, and plot data points on bar charts.

• In  general, and perhaps outside of the scope of this preprint, to have a  more ecological understanding how microbial community regulates peanut  digestion. This will also help to understand how it can be improved /  designed into a therapeutic.

Significance/Novelty

This preprint presents a novel  mechanism that may influence anaphylaxis outcomes in humans. However,  important questions remain regarding its physiological relevance in  humans. Nevertheless, the study inspires future investigations into  potential dietary or therapeutic interventions. One of potential  application is, for example, combination of specific probiotic with an  oral immunotherapy to achieve tolerance to food.

Credit

Reviewed by anonymous as part of a cross-institutional journal club between the Max-Delbrück  Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard),  the University of Virginia, the Medical University of Vienna and other  life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.