The human milk oligosaccharide 3′sialyllactose reduces low-grade inflammation and atherosclerosis development in mice
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
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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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 7

Six-week oral 3′SL treatment reduced atherosclerotic development and associated inflammation.

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Six-week oral 3′SL treatment reduced atherosclerotic development and ass...
(A) Pharmacokinetics of 3′SL after oral 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 oral gavage of 90 mg 3′SL in water per mouse for 6 weeks. Water gavage served as a control. (C) Food intake of Ldlr–/– mice on a WTD measured 3 weeks into the treatment. (D) Biweekly plasma cholesterol levels in 3′SL-treated and control Ldlr–/– mice (n = 14–15). (E) FPLC cholesterol lipoprotein profiles after 6 weeks of treatment (2 pooled samples per group of 7–8). (F and G) Representative Oil Red O staining (F) and en face quantification of atherosclerotic lesion size (G) in the aorta (n = 14–15). (H and I) Representative H&E staining (H) and quantification of atherosclerotic lesion size (I) in the aortic sinus. Scale bar: 100 μm (n = 14–15). (J) Atherosclerotic lesion staging analysis (n = 8–9). (K) Cytokine concentrations in the plasma after 6 weeks treatment (n = 6). (L) Relative plasma IL-6 levels after 2 and 6 weeks of treatment (n = 6). (M) Plasma TNF levels after 2 and 6 weeks of treatment (n = 7–8). (N) Plasma SAA levels after 2 and 6 weeks of treatment (n = 6). Two-way ANOVA with Fisher’s LSD test and, in G, unpaired 2-tailed Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Data represent mean ± SEM.