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

Summary 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.