The Key Role of RELMβ in Food Allergy

Academic Background

Food allergy (FA) is a common immune system disorder, particularly prevalent among children. The occurrence of food allergy is associated with abnormal immune responses to food antigens, especially the dysregulation of type 2 immune responses. Type 2 immune responses are typically defense mechanisms against parasites and toxins, but their dysregulation can lead to pathological reactions such as food allergy and anaphylactic shock. Although the mechanisms of food allergy have been studied to some extent, the specific mechanisms underlying the maintenance and breakdown of immune tolerance remain unclear. In particular, the role of the gut microbiota in food allergy has not been fully elucidated.

This study aims to investigate the role of a protein secreted by intestinal goblet cells—Resistin-like molecule β (RELMβ)—in food allergy. RELMβ has been shown to play an important role in intestinal immunity and microbiota regulation, but its specific mechanism in food allergy remains unclear. By studying how RELMβ regulates the gut microbiota and immune tolerance, the researchers hope to reveal its key role in food allergy and provide new targets for the prevention and treatment of food allergy.

Source of the Paper

This paper was co-authored by Emmanuel Stephen-Victor, Gavin A. Kuziel, and other researchers from multiple institutions, including Boston Children’s Hospital and Harvard Medical School. The paper was published in Nature in 2024, titled “RELMβ sets the threshold for microbiome-dependent oral tolerance.” The study was supported by multiple grants, including those from the National Institutes of Health (NIH).

Research Process and Results

1. Expression of RELMβ in Food Allergy Models

The researchers first studied the expression of RELMβ in mouse models. They used a mouse model with enhanced type 2 immune responses (IL4RαF709 mice), which exhibited strong food allergy reactions after oral administration of ovalbumin (OVA) and staphylococcal enterotoxin B (SEB). Through quantitative PCR and ELISA experiments, the researchers found that the expression of RELMβ in the intestine and serum significantly increased after food allergy induction, while the expression of its homolog RELMα showed no significant change.

Results: The expression of RELMβ was significantly elevated in food allergy mouse models, suggesting its potential key role in food allergy.

2. Effect of RELMβ Deficiency on Food Allergy

To verify the function of RELMβ, the researchers constructed IL4RαF709 mice with RELMβ deficiency (IL4RαF709 Retnlb-/-). The results showed that RELMβ-deficient mice did not experience anaphylactic shock after food antigen challenge, and the levels of OVA-specific IgE and mucosal mast cell protease 1 (MMCP1) in the serum were significantly reduced. Additionally, RELMβ deficiency suppressed the expansion of intestinal mast cells and the expression of type 2 immune-related genes.

Results: RELMβ deficiency significantly inhibited food allergy reactions, indicating that RELMβ plays a key role in the development of food allergy.

3. RELMβ Regulates Immune Tolerance by Modulating the Gut Microbiota

The researchers further explored how RELMβ affects immune tolerance by regulating the gut microbiota. They found that the abundance of Lactobacilli and Alistipes in the intestines of RELMβ-deficient mice significantly increased, and these microbiota are closely related to the maintenance of immune tolerance. Through fecal microbiota transplantation (FMT) experiments, the researchers confirmed that the gut microbiota of RELMβ-deficient mice could protect other mice from food allergy.

Results: RELMβ regulates the composition of the gut microbiota, thereby influencing the maintenance of immune tolerance.

4. Role of Indole Metabolites in Immune Tolerance

The gut microbiota produces indole derivatives (such as indole-3-acetic acid, IAA) through tryptophan metabolism, which can activate the aryl hydrocarbon receptor (AHR) and promote the differentiation of regulatory T cells (Treg). The researchers found that the levels of indole metabolites in the intestines of RELMβ-deficient mice were significantly increased, and the increase in indole metabolites was closely related to the expansion of Treg cells and the suppression of food allergy.

Results: Indole metabolites produced by the gut microbiota activate AHR, promoting Treg cell differentiation and thereby maintaining immune tolerance.

5. Early Intervention with RELMβ Prevents Food Allergy

The researchers also explored the preventive effect of early intervention with RELMβ on food allergy. They found that treatment with anti-RELMβ monoclonal antibodies during the weaning period (2-4 weeks after birth) significantly increased the number of Treg cells and protected mice from food allergy in adulthood.

Results: Early intervention with RELMβ can prevent the development of food allergy, suggesting that RELMβ is a potential target for food allergy prevention.

Conclusions and Significance

This study reveals the key role of RELMβ in food allergy and elucidates its mechanism of influencing immune tolerance by regulating the gut microbiota and indole metabolites. The results indicate that RELMβ is an important regulator of food allergy, and its deficiency can promote Treg cell differentiation by increasing the levels of Lactobacilli and indole metabolites, thereby maintaining immune tolerance. Additionally, the study found that early intervention with RELMβ can prevent the development of food allergy, providing new insights for the prevention and treatment of food allergy.

Research Highlights

1. Key Role of RELMβ: For the first time, the study reveals the key role of RELMβ in food allergy and elucidates its mechanism of influencing immune tolerance by regulating the gut microbiota and indole metabolites.
2. Gut Microbiota and Immune Tolerance: The study reveals a new mechanism by which the gut microbiota produces indole metabolites, activates AHR, and promotes Treg cell differentiation.
3. Potential of Early Intervention: The study finds that early intervention with RELMβ can prevent the development of food allergy, providing a new strategy for food allergy prevention.

Other Valuable Information

This study also developed various experimental methods, such as fecal microbiota transplantation (FMT) and intestinal organoid culture, which provide new tools for studying the interaction between the gut microbiota and the immune system. Additionally, the study used advanced techniques such as RNA sequencing (RNA-seq) and mass spectrometry (MS) to deeply analyze the molecular mechanisms regulated by RELMβ.

This research not only reveals the key role of RELMβ in food allergy but also provides new targets and strategies for the prevention and treatment of food allergy, holding significant scientific and practical value.