Thursday, April 18, 2024
4/18/2024
ABSTRACT Food allergy (FA) has become a public health concern, affecting a sizeable segment of the population. Despite the alarming increase in its prevalence, efforts to contain the FA epidemic have been stymied by the limited understanding of disease pathogenesis, especially the role in this process of early life gut dysbiosis. In that regard, our studies have established a critical role for immunomodulatory Clostridiales and Bacteroidales species in enforcing immune tolerance to FA by inducing the differentiation of RORgt+ Treg cells, which act to suppress FA. Early life expansion of RORgt+ Treg cells is induced by the bloom in Clostridiales and Bacteroidales species during weaning from maternal milk to solid food. This expansion is counter-regulated by resistin-like molecule beta (RELMb), which is elevated in FA subjects and mice. Accordingly, the focus of this proposal is to elucidate the mechanisms by which early life dysbiosis promotes FA and its long-term implications in terms of disease persistence and response to microbial therapy. We hypothesize that the microbial and immunological changes ushered by weaning early in life provide a window of opportunity for tolerance induction to solid food in a process regulated by RELMb, whose dysregulation by dysbiosis promotes FA (Aim 1). We also hypothesize that the ineffective differentiation of RORgt+ Treg cell populations and the reciprocal emergence of Th2 cell-like Treg cells, an imbalance we have identified to play a fundamental role in FA, acts to promote disease pathogenesis by licensing IgE anti-food and anti-bacterial antibody responses (Aim 2). Finally, we hypothesize that products and metabolites of individual immunomodulatory bacterial strains, including Toll-like receptors activators, aryl hydrocarbon receptor ligands and secondary bile acids, act to enforce oral tolerance in FA by promoting RORgt+ Treg cell differentiation (Aim 3). The proposed studies will provide fundamental new insights relevant to the pathogenesis of FA and offers novel opportunities in early life disease intervention and therapy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
