The human milk oligosaccharide 3′sialyllactose reduces low-grade inflammation and atherosclerosis development in mice
Ariane R. Pessentheiner, … , Lars Bode, Philip L.S.M. Gordts
Ariane R. Pessentheiner, … , Lars Bode, Philip L.S.M. Gordts
Published September 26, 2024
Citation Information: JCI Insight. 2024;9(21):e181329. https://doi.org/10.1172/jci.insight.181329.
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Research Article Cell biology Inflammation

The human milk oligosaccharide 3′sialyllactose reduces low-grade inflammation and atherosclerosis development in mice

Abstract

Macrophages contribute to the induction and resolution of inflammation and play a central role in 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 mRNA levels of a selected set of inflammatory genes and promotes the activity of liver X receptor (LXR) and sterol regulatory element binding protein-1 (SREBP1). These acute antiinflammatory effects of 3′SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), IFN regulatory factor 2 (IRF2), B cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both s.c. 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.

Authors

Ariane R. Pessentheiner, Nathanael J. Spann, Chloe A. Autran, Tae Gyu Oh, Kaare V. Grunddal, Joanna K.C. Coker, Chelsea D. Painter, Bastian Ramms, Austin W.T. Chiang, Chen-Yi Wang, Jason Hsiao, Yiwen Wang, Anthony Quach, Laela M. Booshehri, Alexandra Hammond, Chiara Tognaccini, Joanna Latasiewicz, Lisa Willemsen, Karsten Zengler, Menno P.J. de Winther, Hal M. Hoffman, Martin Philpott, Adam P. Cribbs, Udo Oppermann, Nathan E. Lewis, Joseph L. Witztum, Ruth Yu, Annette R. Atkins, Michael Downes, Ron M. Evans, Christopher K. Glass, Lars Bode, Philip L.S.M. Gordts

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Figure 3

3′SL downregulates inflammatory pathways and upregulates cholesterol biosynthesis in LPS-stimulated BMDMs.

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3′SL downregulates inflammatory pathways and upregulates cholesterol bio...
(A and B) Venn diagrams of differentially expressed mRNAs of genes detected by RNA-Seq (cut-off P < 0.05 and fold change [FC] > 1.5) of 3′SL downregulated (A) and upregulated (B) mRNA levels of genes in LPS-activated BMDMs compared with quiescent, PBS-treated BMDMs. Corresponding pathway analyses of LPS versus LPS + 3′SL–treated BMDMs are below the diagrams (n = 3). (C) Heatmaps representing Z-normalized row mRNA levels of each gene for RNA-Seq from independent biological duplicates showing the 50 most upregulated (right) or downregulated (left) genes in BMDMs at 6 hours after LPS ± 3′SL stimulation. (D and E) UCSC genome browser images illustrating normalized tag counts for Ptgs2 and Cxcl3 with normalized tag count averages (n = 3). (F and G) UCSC genome browser images illustrating relative mRNA levels for cholesterol biosynthesis genes Fdps and Sle with normalized tag count averages (n = 3). (H) Scheme of KEGG-pathway cholesterol biosynthesis. Red marked genes are upregulated by 3′SL coincubation with LPS. Red numbers above gene names indicate fold-change. (I) Enriched pathways identified by Ingenuity Pathway Analysis (IPA) software. All significantly, differentially expressed mRNAs of genes in the LPS versus LPS + 3′SL RNA-Seq datasets were used for the analysis with IPA (cut-off > 1.5-fold) with Z score ≥ ±2. (J) Scatter plot depicting the relationship between fold change of 3′SL and LPS–repressed and 3′SL-induced mRNAs of genes, overlaid with LXR- and SREBP-associated accessible loci from a previously generated ATAC-Seq dataset (33). Unpaired 2-tailed Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001. Data represent mean ± SEM.