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 6

Six-week s.c. treatment with 3′SL leads to reduced atherosclerotic development without negative side effects associated with body weight, plasma lipid parameters, and blood glucose.

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Six-week s.c. treatment with 3′SL leads to reduced atherosclerotic devel...
(A) Pharmacokinetics of 3′SL after s.c. injections (n = 3 per group/time point). (B) Treatment regimen. Male Ldlr–/– were put on a Western-type diet (WTD) for 8 weeks. After 2 weeks, mice were treated twice daily with s.c. injections of 400 μg 3′SL in PBS per mouse for 6 weeks. PBS injections served as a control. (C) Biweekly plasma cholesterol levels in 3′SL-treated and control Ldlr–/– mice (n = 14–15). (D and E) Representative H&E staining (D) and quantification of atherosclerotic lesion size (E) in the aortic sinus. Scale bar: 100 μm (n = 7–8). (F) Atherosclerotic lesion staging analysis (n = 7–8). (G and H) Atherosclerotic lesions stained with CD68 for macrophages (G) and quantification (H) of the positive stained area (n = 4–6). (I and J) Smooth muscle actin (SMA) staining (I) and quantification (J) of the positive stained area (n = 5–6). (K and L) Picrosirius red staining for collagen (K) and quantification (L) of the positive stained area (n = 5). (M) Cytokine concentrations in the plasma after 6 weeks of treatment (n = 6). (N) Relative expression of inflammatory marker mRNA levels in human umbilical vein endothelial cells (HUVECs) treated with PBS or LPS (10 ng/mL) ± 3′SL (100 μg/mL) (n = 3). (O) Cytokine secretion of CCL2 and IL-8 after 24-hour stimulation with LPS in the presence or absence of 3′SL at the indicated concentrations (n = 3). Two-way ANOVA with Fisher’s LSD test and, in H, J, and L, we used an unpaired 2-tailed Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001. Data represent mean ± SEM.