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Gut. 2016 Jan;65(1):33-46. doi: 10.1136/gutjnl-2014-307544. Epub 2014 Nov 27.

The human milk oligosaccharide 2'-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation.

Author information

1
Laboratory of Gastroenterology and Nutrition, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA Program in Glycobiology, Department of Biology, Boston College, Chestnut Hill, Massachusetts, USA.
2
Laboratory of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3
Program in Glycobiology, Department of Biology, Boston College, Chestnut Hill, Massachusetts, USA.

Abstract

BACKGROUND:

A major cause of enteric infection, Gram-negative pathogenic bacteria activate mucosal inflammation through lipopolysaccharide (LPS) binding to intestinal toll-like receptor 4 (TLR4). Breast feeding lowers risk of disease, and human milk modulates inflammation.

OBJECTIVE:

This study tested whether human milk oligosaccharides (HMOSs) influence pathogenic Escherichia coli-induced interleukin (IL)-8 release by intestinal epithelial cells (IECs), identified specific proinflammatory signalling molecules modulated by HMOSs, specified the active HMOS and determined its mechanism of action.

METHODS:

Models of inflammation were IECs invaded by type 1 pili enterotoxigenic E. coli (ETEC) in vitro: T84 modelled mature, and H4 modelled immature IECs. LPS-induced signalling molecules co-varying with IL-8 release in the presence or absence of HMOSs were identified. Knockdown and overexpression verified signalling mediators. The oligosaccharide responsible for altered signalling was identified.

RESULTS:

HMOSs attenuated LPS-dependent induction of IL-8 caused by ETEC, uropathogenic E. coli, and adherent-invasive E. coli (AIEC) infection, and suppressed CD14 transcription and translation. CD14 knockdown recapitulated HMOS-induced attenuation. Overexpression of CD14 increased the inflammatory response to ETEC and sensitivity to inhibition by HMOSs. 2'-fucosyllactose (2'-FL), at milk concentrations, displayed equivalent ability as total HMOSs to suppress CD14 expression, and protected AIEC-infected mice.

CONCLUSIONS:

HMOSs and 2'-FL directly inhibit LPS-mediated inflammation during ETEC invasion of T84 and H4 IECs through attenuation of CD14 induction. CD14 expression mediates LPS-TLR4 stimulation of portions of the 'macrophage migration inhibitory factors' inflammatory pathway via suppressors of cytokine signalling 2/signal transducer and activator of transcription 3/NF-κB. HMOS direct inhibition of inflammation supports its functioning as an innate immune system whereby the mother protects her vulnerable neonate through her milk. 2'-FL, a principal HMOS, quenches inflammatory signalling.

KEYWORDS:

BACTERIAL PATHOGENESIS; BREAST MILK; INFLAMMATION; MUCOSAL IMMUNOLOGY; OLIGOSACCHARIDES

PMID:
25431457
DOI:
10.1136/gutjnl-2014-307544
[Indexed for MEDLINE]

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