SUMMARY Macrophages contribute to the induction and resolution of inflammation and play a central role in the chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3’sialyllactose (3’SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3’SL attenuates a selected set of inflammatory gene expression and promotes activity of LXR and SREBP. These acute anti-inflammatory effects of 3’SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CTCF, IRF2, BCL6, and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3’SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3’SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

The Human Milk Oligosaccharide 3’Sialyllactose Promotes Inflammation Resolution and Reduces Atherosclerosis Development in Mice