Microbiome Influences on Immune Development and Allergy Risk

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

During FY2025, we advanced our understanding of how specific gut microbiota communities, shaped by early-life diet, influence immune development and susceptibility to allergic airway inflammation. Our findings reveal a key role for microbial metabolism, particularly of dietary tryptophan, in regulating immune cell function during early infancy. Using a house dust mite (HDM)-induced allergic airway inflammation model, we discovered that a high abundance of Lactobacillus species associated with milk-based diets during the pre-weaning period enhances susceptibility to allergic sensitization. Mechanistically, this effect is mediated by the production of microbiota-derived indole metabolites, especially indole-3-aldehyde (IAld) and indolelactic acid (ILA). These metabolites activate the aryl hydrocarbon receptor (AhR) in classical monocytes, impairing their responsiveness to GM-CSF and inhibiting their differentiation into proinflammatory monocyte-derived dendritic cells (moDCs), a cell type that suppress Th2-driven allergic responses. Importantly, during FY2025 we also found that infant dietary supplementation with galacto-oligosaccharides (GOS), a class of non-digestible carbohydrates abundant in human milk, modifies microbial tryptophan metabolism. This shift enables the generation of inflammatory moDCs that effectively suppress Th2 responses and reduce allergic inflammation. Thus, the dietary ratio of tryptophan to GOS critically influences the composition and function of the gut microbiota and its downstream effects on immune regulation. Given that tryptophan and GOS levels naturally vary among lactating mothers and in infant formula, these findings raise the possibility that such variation may shape early-life microbial metabolism and immune development. This hypothesis provides a valuable framework for future studies investigating how early dietary influences modulate allergy risk. Together, these results offer new mechanistic insight into how early-life dietary and microbial factors interact to shape immune development and allergic disease susceptibility. A manuscript detailing these findings is currently in preparation for publication.