Allergic diseases have reached epidemic proportions over the past decades, affecting millions of people worldwide and continuing to rise in prevalence in developing countries. Environmental and microbial exposures have been suggested to play a key role in this trend. In particular, the gut microbiota, which matures in parallel with the immune system early in life, influences immune profiles locally and systemically, mainly through metabolite production, and its disruption has been associated with allergy development. However, how microbial, metabolic, and immune factors are linked to allergic disease, whether these connections persist from early life into adulthood, and whether allergy treatment affects them is still not fully clear. This thesis aimed to provide a deeper understanding through mechanistic studies and analyses of patient samples.   

In Paper I, we showed that factors secreted by Staphylococcus aureus, a common commensal and opportunistic pathogen, promote the differentiation of T_H9 cells and IL-9 production, accompanied by a transcriptional program associated with allergic inflammation. Retinoic acid, a vitamin A-derived compound, attenuated this response, demonstrating that microbial and dietary metabolites can interact to influence allergy-relevant immune pathways.

In Paper II, we investigated the effects of peanut oral immunotherapy (OIT), an emerging allergy treatment, in young children, exploring a broad range of immunological parameters. OIT led to reduced T cell activation following peanut stimulation, suppressed T_H2- and T_H17-associated responses, shifts in peanut-specific antibody production from IgE to IgG4, and alterations in dendritic cell (DC) activation markers. Furthermore, changes at the transcriptional level, including immune and metabolic pathways, were observed. These interconnected shifts across adaptive and innate compartments may collectively counteract immune pathways characterizing allergy progression, which were observed in untreated children.

In Paper III, we explored gut microbiota and plasma metabolic changes in the same cohort and found that OIT is associated with increased microbial diversity and enrichment of taxa linked with healthy conditions, as well as distinct alterations in the metabolic profile, especially lipid-derived compounds. These findings suggest that microbial and metabolic shifts accompany immune modulation during treatment.

In Paper IV, we examined whether early-life immune and gut microbiota profiles are associated with allergic asthma in young adulthood. Twenty-year-old asthmatics differed from non-asthmatics in DC markers and circulating immune cell transcriptome profiles, particularly in RNA processing and immune signalling pathways, already at age two. Distinct bacterial trajectories were found from one week of life, suggesting that early gut microbiota alterations can have long-lasting consequences for allergic asthma susceptibility beyond genetic risk. 

In summary, combining immunological, microbial, and metabolic perspectives, this work provides novel insights into allergic disease development from early life to adulthood and into mechanisms of tolerance induction, highlighting opportunities for prevention and intervention measures.