BACKGROUND AND AIMS: Functional dyspepsia in childhood is commonly triggered by food allergen in sensitised individuals. We investigated the topography of eosinophils and mast cells in gastric antral lamina propria, the interaction of mast cell products with mucosal nerve fibres, and changes in gastric antral muscle slow wave activity in children with atopy and non-atopy-related functional dyspepsia. PATIENTS AND METHODS: Open label study of gastric mucosal cow's milk challenge in 10 atopic and 6 nonatopic children (ages 2-12 years) investigated consecutively with gastroscopy for functional dyspepsia. Simultaneous surface electrogastrography and milk challenge were undertaken and laser scanning fluorescence microscopy used to examine the association of mast cell tryptase with mucosal nerves in the gastric mucosa before and after challenge. RESULTS: Eosinophils and mast cells within the lamina propria were increased in number in children with atopic functional dyspepsia and degranulated rapidly after cow's milk challenge in the atopic group. For degranulating eosinophils, median = 13.0% (interquartile range = 3.7-31.0) premilk versus 32.0% (12.0-42.0) after milk biopsies (P < 0.05); for degranulating mast cells, 5.35% (2.7-10.9) premilk biopsies versus 18.75% (12.9-22.1) after milk biopsies (P < 0.05). No such differences were seen in nonatopic patients. Mast cells were closely associated with mucosal nerve fibres and released tryptase, which colocalised with proteinase-activated receptors on mucosal nerve fibres. The gastric antral slow wave became abnormal within 2 minutes of antigen challenge in atopics with an increase in dominant frequency instability coefficient (P < 0.005), decrease in 3 cycles per minute myoelectrical activity (P < 0.01), and increase in bradygastria (P < 0.01). CONCLUSIONS: Early-onset neuroimmune interactions induced by cow's milk in the gastric mucosa of atopic children are associated with rapid disturbance of gastric myoelectrical activity and dyspeptic symptoms.