The gut microbiome in food allergy

Abstract

Objective: To review observational human, murine, and interventional trial studies that have examined the gut microbiome in food allergy, and to provide perspective on future investigations in this field.

Data sources: A review of the published literature was performed with PubMed, and clinical studies catalogued at ClinicalTrials.gov were also reviewed.

Study selections: The most recent relevant studies, seminal works, and topical clinical trials were selected.

Results: Gut dysbiosis likely precedes the development of food allergy, and the timing of such dysbiosis is critical. Gut microbiota associated with individual food allergies may be distinct. Murine models support the importance of gut microbiota in shaping immune maturation and tolerance. Gut microbiota may affect food allergy susceptibility by modulating type 2 immunity, influencing immune development and tolerance, regulating basophil populations, and promoting intestinal barrier function. Ongoing and future interventional trials of probiotics, prebiotics, synbiotics, and fecal microbiota transfer will help translate our understanding of the gut microbiome in food allergy to clinical practice. Future work in this area will include deepening of current research foci, as well as expansion of efforts to include the virome, mycobiome, and interactions between the microbiome, host, and environment. Robust and consistent study designs, multidimensional profiling, and systems biology approaches will enable this future work.

Conclusion: By advancing research on the microbiome in food allergy, we can further our understanding of food allergy and derive new approaches for its prevention and therapy.

Figure 1.. Mechanisms by which gut microbiota may affect food allergy susceptibility.

Murine models of food allergy have shown that gut microbiota interact with multiple aspects of the intestinal mucosa, innate immunity, and adaptive immunity. (1) Gut microbiota modulate type 2 immunity. In germ-free mice, expression of Th2-promoting cytokine IL-33 by epithelial cells is increased. In contrast, Th2-inhibiting RORγt+ Treg cells are profoundly reduced in both germ-free and antibiotic-treated mice. As a result, Th2-associated pathology is exacerbated and IgE levels are elevated in the absence of key microbial signals. (2) Gut microbiota influence immune development and tolerance. Microbial colonization promotes the expansion of Treg cells. Microbial signals promote IL-1β secretion by intestinal macrophages (mφ), which leads to GM-CSF release by type 3 innate lymphoid cells (ILC3). As a result, IL-10 and retinoid acid secretions by dendritic cells (DC) and mφ are elevated, which leads to the expansion of local Treg cells. Strain-specific Clostridia colonization of gnotobiotic mice stimulates the secretion of TGF- β from intestinal epithelial cells, leading to the expansion of colonic Treg cells. Strain-specific Clostridia colonization also induces key anti-inflammatory molecules (IL-10 and ICOS) in Treg cells. (3) Gut microbiota regulate basophil populations. Circulating basophil levels increase in antibiotic-treated mice. Conversely, the presence of microbial signals limits the proliferation of bone-marrow basophil precursors, and reduces basophil-mediated allergic inflammation. (4) Gut microbiota promote intestinal barrier function. Selective colonization of germ-free mice with certain strains of Clostridia and Bacteroides promotes intestinal IgA secretion, which can contribute to immune exclusion and reduce allergen uptake. Strain-specific Clostridia colonization of germ-free mice also induces IL-22 production by innate lymphoid cells (ILC) and CD4+ T cells. IL-22, in turn, promotes mucous secretion by goblet cells and reduces intestinal permeability to dietary allergens. Adapted from Ho and Bunyavanich, Curr Allergy Asthma Rep. 2018 Apr 5;18(4):27.

Figure 2.. Potential modalities for gut microbiome manipulation.

Potential modalities for gut microbiome manipulation include diet, probiotics, prebiotics, synbiotics, and fecal microbiota transplantation. Probiotics are live microorganisms that, when administered, confer a health benefit to the host. Prebiotics are non-digestible substrates that can be selectively utilized by host microorganisms. Synbiotics are products that contain both prebiotics and probiotics. Fecal microbiota transplantation (FMT) is the administration of fecal matter from a donor to a recipient. Examples of each based on existing or planned studies are provided.