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

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.

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Publication Details

Journal
JCI Insight
Published
2024-09-26
DOI
https://doi.org/10.1172/jci.insight.181329
Citations
13
Primary Topic
Infant Nutrition and Health
Type
article
Field-Weighted Citation Impact
4.02

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article

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

Tae Gyu Oh, Jason Hsiao, Hal M. Hoffman, Chelsea D. Painter et al.
13 citations
JCI Insight
Infant Nutrition and Health
4.02
article

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

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

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.

JCI InsightVol. 9(21)
Salk Institute for Biological Studies (US), University of Graz (AT), Novo Nordisk Foundation (DK), Nuffield Orthopaedic Centre (GB), National Institute for Health and Care Research (GB), University of California San Diego (US), Rady Children's Hospital-San Diego (US), NIHR Oxford Musculoskeletal Biomedical Research Centre (GB), MicroBio Engineering (United States) (US), Amsterdam Neuroscience (NL), Oxford Centre for Computational Neuroscience (GB), La Jolla Bioengineering Institute (US), Cellular Research (United States) (US), Amsterdam University Medical Centers (NL), Mothers’ Milk Bank (US), University of Amsterdam (NL)
March of Dimes Foundation, American Heart Association, Fondation Leducq, Austrian Science Fund, National Institutes of Health, University of California, San Diego, Medical Research Council
Zero hunger
Openalex Percentile: Top 6%
Infant Nutrition and Health
4.02
DOIOpen Access PDFOpenAlex
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