Exosome-mediated cross-species miRNA regulation: Bovine Milk-derived miR-320a attenuates ovalbumin-induced food allergy by suppressing STAT3.

Abstract

Food allergy (FA) is characterized by an imbalance in T helper cell responses, specifically a dysregulation of the Th17 and Treg cells. While bovine milk exosomes (BMEs) are known to possess immunomodulatory properties, their role in modulating Th17/Treg balance in FA remains unclear. This study aimed to investigate whether BMEs could alleviate FA by restoring Th17/Treg balance and to identify the key miRNA mediators involved, particularly focusing on the STAT signaling pathway. An OVA-sensitized mouse model of FA was established. Mice were treated with varying doses of BMEs. Symptoms, immune parameters, cytokine levels, and relevant signaling pathways were assessed. High-throughput sequencing and bioinformatics were used to identify miRNA candidates. Functional validation was performed using gain- and loss-of-function experiments in splenic lymphocytes. The results showed that BMEs administration significantly alleviated FA symptoms in a dose-dependent manner, restored Th17/Treg balance, and suppressed STAT3/p-STAT3/RORγt activation. High-throughput sequencing revealed miR-320a as a key BME-derived miRNA that targets the STAT pathway. Functional experiments demonstrated that miR-320a overexpression in OVA-sensitized lymphocytes significantly reduced specific antibody production, promoted Treg cell differentiation, and downregulated the STAT3/p-STAT3/RORγt pathway. Conversely, miR-320a knockdown yielded opposing effects, exacerbating the allergic response. BMEs alleviate FA by delivering miR-320a, which targets the STAT3/RORγt axis and corrects Th17/Treg imbalance. These findings reveal a novel cross-species regulatory mechanism of BMEs and support their potential as a natural intervention strategy for FA.