Porcine Milk-Derived Small Extracellular Vesicles Promote Intestinal Immunoglobulin Production through pIgR

Area of Science:

• Immunology
• Molecular Biology
• Gastroenterology

Background:

• Secretory immunoglobulin A (SIgA) is crucial for gut immunity and mucosal homeostasis.
• Milk-derived small extracellular vesicles (sEVs) and their RNA cargo show potential in regulating intestinal health.
• The specific mechanisms by which milk sEVs influence recipient intestinal immunity remain largely unexplored.

Purpose of the Study:

• To investigate the impact of porcine milk small extracellular vesicles (PM-sEVs) on intestinal immunity in recipients.
• To elucidate the molecular mechanisms by which PM-sEVs modulate intestinal immune factors, specifically SIgA and pIgR.
• To identify key RNA molecules within PM-sEVs responsible for these immunomodulatory effects.

Main Methods:

• In vivo experiments in mice and piglets to assess the effects of PM-sEVs on SIgA and pIgR levels.
• In vitro studies using a porcine small intestine epithelial cell line (IPEC-J2) to examine pIgR expression regulation.
• Bioinformatics analysis, dual-luciferase reporter assays, and RNA overexpression/knockdown to identify functional circRNAs and microRNAs.

Main Results:

• Oral administration of PM-sEVs significantly increased intestinal SIgA levels and pIgR expression in both mice and piglets.
• PM-sEVs were found to increase pIgR expression in IPEC-J2 cells via the suppression of miR-221-5p by circ-XPO4.
• In piglets, PM-sEVs increased circ-XPO4 and decreased miR-221-5p in the small intestine, confirming the in vivo function of circRNAs as miRNA sponges.

Conclusions:

• Porcine milk small extracellular vesicles (PM-sEVs) stimulate intestinal SIgA production and enhance gut immunity.
• Circ-XPO4 within PM-sEVs plays a critical role by acting as a sponge for miR-221-5p, thereby upregulating pIgR expression.
• This study provides novel insights into the mechanism of milk sEV-mediated immune regulation in the gut, highlighting the role of exosomal circRNAs.