Food allergy (FA) prevalence has significantly increased in recent decades 1. This marked rise has intensified interest in elucidating the complex interplay between different environmental factors and the immune system that contribute to the development of FA 2. Recent evidence suggests that impairment of the epithelial barrier can perturb the gut microbiome and subsequently interfere with the induction of regulatory T cells, ultimately compromising immune tolerance to dietary antigens 1, 2. Studies have identified several components of the intestinal environment capable of promoting the development of RORγt+ Treg cells and the induction of oral tolerance, including mucins, indole derivatives, retinoic acids, anti-inflammatory cytokines, CD103+ dendritic cells, and microbial metabolites such as short-chain fatty acids 3. However, the mechanisms by which molecular mediators and signals are integrated within the epithelial–microbiome–immune axis to either establish or impair oral tolerance to dietary antigens remain unclear 3. Resistin-like molecule β (RELMβ) is a goblet-cell-derived, highly cysteine-rich protein expressed in mice and human gastrointestinal tissues, whose expression is known to be upregulated by type 2 immune cytokines, including IL-4 and IL-13, and modulated by microbial dysbiosis in the intestinal epithelium 4. This protein is thought to maintain epithelial barrier integrity and regulate innate immune responses against parasites and inflammation 4. These regulatory functions are considered crucial for maintaining immune homeostasis at mucosal surfaces and for preventing allergic responses 4. Recently, Stephen-Victor et al. provided compelling evidence for a novel role for RELMβ as a molecular determinant of microbiome-dependent immune tolerance to dietary antigens 5. Their data demonstrate that RELMβ is markedly elevated in the sera of children with FA and in mouse models genetically prone to FA due to aberrant type 2 immunity, specifically those caused by a gain-of-function signaling of the IL-4 receptor (Il4raF709). RELMβ deletion in these models suppressed anaphylaxis, reduced serum food antigen-specific IgE levels, and increased levels of tolerogenic RORγt+ Treg cells. Together, they demonstrated that RELMβ is not only an important regulator of type 2 mediators but can suppress Treg-mediated immune regulatory responses and break tolerance to food antigens, uncovering a novel pathogenic role of RELMβ in FA. Additionally, Stephen-Victor et al. observed that RELMβ disrupted the gut microbiome in mice and reduced tryptophan-derived indole-metabolite-producing bacteria, key regulators of intestinal immune homeostasis, contributing to a depletion of protective Treg cells and loss of immune tolerance to food antigens 5. These findings highlight the suppression of tryptophan-derived gut microbiome indole metabolites as a relevant mechanism underlying the ability of RELMβ to drive FA. The authors extended their observations to a pediatric human cohort, in which patients with FA exhibited a depletion of Alistipes and Parabacteroides gut bacteria, which correlated with reduced levels of indole metabolites in faecal samples. However, interspecies differences between murine models and humans in environmental exposures, gut microbiome composition and the immune system may substantially limit the generalizability of these results. Furthermore, the authors found that indole derivatives reinforced oral tolerance by promoting tolerogenic RORγt+ Tregs via activation of the aryl hydrocarbon receptor (AhR) (Figure 1). These findings further support prior evidence indicating that AhR, a ligand-activated transcription factor that is activated by dietary and microbiota-derived indole metabolites, contributes to regulating certain immune cell differentiation, epithelial barrier function and mucosal homeostasis in experimental models 6, 7. Interestingly, during the weaning period, a critical developmental window for gut microbiota expansion and immune system maturation 8, RELMβ-driven microbiome dysregulation, combined with vertically transmitted genetic factors, promotes FA in adulthood by suppressing RORγt+ regulatory T cells. Notably, Stephen-Victor et al. demonstrated that treatment of Il4raF709 mice with anti-RELMβ monoclonal antibodies, both during early life and in adulthood, inhibited anaphylaxis and induced RORγt+ Treg cell differentiation. Although these results in murine models highlight RELMβ as a promising target for potential early-life strategies to prevent or reverse long-term FAs, their translational relevance in humans remains uncertain. While previous studies described a microbiome-epithelial-immune circuit in which chemosensory gut epithelial cells detect microbiome metabolites to promote type 2 responses, this study focuses on a specific molecular immune-epithelial-microbiome axis that orchestrates type 2 gut immunity in FA involving goblet-cell-derived RELMβ 5. This axis is distinguished by its sequential order of events: type 2 mediators first induce RELMβ production in gut epithelial cells, which then modulates the gut microbiota and regulates RORγt+ Treg cells via AhR signaling, sharpening antigen-specific responses to food and establishing a circuit in which innate immunity directs adaptive tolerance through microbiome editing 5. These findings offer novel insights into the mechanisms underlying FA, underscoring the central role of the microbiome and identifying potential targets for preventive and therapeutic strategies. Nonetheless, evidence about this immune-epithelial-microbiome axis in humans remains limited, underscoring the need for further studies to validate these observations and determine their translational relevance. Beatriz Moya: conceptualization, writing review and editing, and writing – original draft. Carmen Riggioni, Beatriz Cabanillas: conceptualization, writing review and editing, and supervision. All authors have read and agreed to the published version of the manuscript. The authors recognize Dr. Anna Globinska for graphical abstract design. The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report.
Moya et al. (Wed,) studied this question.