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The human milk oligosaccharide 2′-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation
  1. YingYing He1,2,
  2. ShuBai Liu3,
  3. David E Kling2,
  4. Serena Leone2,
  5. Nathan T Lawlor2,
  6. Yi Huang2,
  7. Samuel B Feinberg2,
  8. David R Hill2,
  9. David S Newburg1,2
  1. 1Laboratory of Gastroenterology and Nutrition, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
  2. 2Program in Glycobiology, Department of Biology, Boston College, Chestnut Hill, Massachusetts, USA
  3. 3Laboratory of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Professor David S Newburg, Department of Biology, Higgins Hall, Boston College, 140 Commonwealth Ave, Chestnut Hill, MA 02467, USA; david.newburg{at}bc.edu

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.

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

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