Milk extracellular vesicles attenuate pre-inflammatory bowel disease via Lactobacillus murinus-mediated TLR2 signaling modulation

Pre-inflammatory bowel disease (pre-IBD) represents a transitional state between irritable bowel syndrome and IBD, characterized by heightened susceptibility to mucosal inflammation driven by chronic high-fat diet intake and antibiotic exposure. However, effective intervention strategies remain poorly defined. Here, we identify milk-derived extracellular vesicles (mEVs) as a potent nanotherapeutic capable of attenuating pre-IBD pathology. Pre-IBD mice displayed marked gut microbiota dysbiosis and mucosal inflammation, both of which were substantially ameliorated by oral mEVs administration. Mechanistically, mEVs restored microbial homeostasis by enriching Lactobacillus murinus ( L. murinus ), which in turn reduced lysophosphatidylcholine (LPC) accumulation, two factors that exerted opposing and functionally instructive effects on intestinal inflammation. LPC activated the TLR2/MAPK axis to promote M1 polarization, whereas L. murinus engaged the TLR2/STAT3 pathway to drive M2 polarization. Collectively, these findings demonstrate that mEVs reprogram TLR2-dependent macrophage responses by modulating LPC and L. murinus , thereby mitigating mucosal inflammation and preventing the progression of pre-IBD.