Extracellular Vesicle‐Encapsulated Small RNAs From Clostridium Butyricum Modulate Host Intestinal Lipid Metabolism

ABSTRACT The gut microbiota plays a critical role in regulating intestinal lipid metabolism, yet the mechanisms governing microbiota–host interactions during lipid uptake remain unclear. Here, we examined the relationship between fat digestibility and gut microbial composition, and found that piglets with higher apparent crude fat digestibility exhibited enhanced lipid absorption and oxidation, accompanied by reduced abundance of Clostridium butyricum in the ileal mucosa. Furthermore, oral administration of C. butyricum suppressed intestinal lipid absorption and oxidation by inhibiting PPARα signaling. Mechanistically, extracellular vesicles (EVs) derived from C. butyricum can enter intestinal epithelial cells and mediate the anti‐lipid absorption effects by delivering miRNA‐like RNAs (milRNAs), particularly milRNA‐3020179, which primarily targeted host genes including PPARα and Rxra . Supplementation with C. butyricum or its EVs prevented lipid accumulation and attenuated the development of metabolic abnormalities in high‐fat diet‐fed mice, whereas deletion of milRNA‐3020179 in C. butyricum abolished its effects on lipid deposition in intestinal organoids. Collectively, these findings identify C. butyricum ‐derived EV milRNAs as candidate microbial regulators of host lipid metabolism through modulation of PPARα signaling, providing insights into microbiota‐driven control of intestinal lipid homeostasis.