Isovaleric acid alleviates food allergy-related constipation in mice via repairing serotonin synthesis in serotonergic neurons.

Abstract

BACKGROUND: Functional constipation is the most common diagnosis of gastrointestinal disease in pediatric clinics. Food allergy has been shown to be associated with functional constipation in children. However, the causal relationship has not been well established. METHODS: We observed food allergy-like intestinal immune responses and decreased intestinal motility in a mouse model that mimics the atopic march. Consequently, we utilized this model to investigate the role and regulatory mechanisms of the atopic march-induced food allergy on intestinal motility. Pathological features related to weakened intestinal motility were analyzed by RNA sequencing and metabolomics analyses. The role of metabolite deficiency on atopic march-induced constipation in mice was confirmed by supplementation in vivo. RESULTS: Elevated Th2/Th17 inflammation and decreased serotonin level were found in intestine of atopic march mice. Serotonin synthesis in enterochromaffin cells and enteric serotonergic neurons was found to be impaired. Clinical evidence further supports a reduction in serum serotonin in atopic dermatitis children with food allergies. Based on altered microbiota and disordered lipid metabolism, we identified insufficient isovaleric acid generation contributing to impaired serotonin synthesis in model mice. Isovaleric acid supplementation repaired serotonin synthesis in enteric serotonergic neurons and partially restored intestinal motility of atopic march-induced food allergy mouse model. CONCLUSION: Our study provided evidence for the regulatory mechanism of constipation related to atopic march-induced food allergy and suggested targets for its diagnosis and treatment. IMPACT: The atopic march murine model induces a food allergy-like intestinal immune response, characterized by diminished gastrointestinal motility. Enterogenic serotonin synthesis was impaired in atopic march model mice. Isovaleric acid supplementation repaired serotonin synthesis of enteric serotonergic neurons and restored intestinal motility of atopic march model mice.