Fructooligosaccharides alleviate early-life antibiotic-exposed food allergy via the Indole-3-propionic acid-AhR-Nrf2 Axis: A multi-omics prospective cohort study

Background: Gut microbiota is critical in food allergy (FA) development. While early-life Antibiotics increase FA risk, the mechanism is unclear, and current treatments cannot correct underlying immune defects.

Objective: To investigate how early-life Antibiotics exacerbate FA and whether fructo-oligosaccharides (FOS) can restore gut-immune balance.

Methods: We linked early-life Antibiotic use to gut dysbiosis and metabolites in a birth cohor, modeled mechanisms and FOS intervention in antibiotic-exposed FA mice, and validated FOS efficacy in a pediatric trial.

Results: Early-life Antibiotics caused persistent gut dysbiosis (notably Lactobacillus depletion) and disrupted tryptophan metabolism, ultimately resulting in oxidative stress, barrier damage, and T-cell imbalance. FOS restored Lactobacillus and the tryptophan metabolite indole-3-propionic acid (IPA). IPA alleviates mitochondrial dysfunction and Reactive Oxygen Species accumulation via activation of the Aryl Hydrocarbon Receptor (AhR)-nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 (HO-1) antioxidant pathway, and enhances intestinal barrier integrity, ultimately rebalancing T-cell homeostasis and attenuating FA. In a pediatric trial, metagenomic Sequencing revealed that FOS enriches both Lactobacillus johnsonii and Clostridium sporogenes, synergistically promoting IPA production-which correlates with reduced SCORAD scores and improved weight gain.

Conclusions: Early-life Antibiotics cause lasting disruptions in gut microbiota and metabolism that worsen FA. FOS mitigates FA by boosting microbiota-derived IPA to activate the protective AhR-Nrf2-HO-1 pathway, highlighting its therapeutic potential for FA, particularly in patients with prior Antibiotic exposure.