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The human milk oligosaccharides 2'-fucosyllactose and 6'-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling.
- Source :
-
Pediatric research [Pediatr Res] 2021 Jan; Vol. 89 (1), pp. 91-101. Date of Electronic Publication: 2020 Mar 27. - Publication Year :
- 2021
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Abstract
- Background: Necrotizing enterocolitis (NEC) develops through exaggerated toll-like receptor 4 (TLR4) signaling in the intestinal epithelium. Breast milk is rich in non-digestible oligosaccharides and prevents NEC through unclear mechanisms. We now hypothesize that the human milk oligosaccharides 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL) can reduce NEC through inhibition of TLR4 signaling.<br />Methods: NEC was induced in newborn mice and premature piglets and infant formula was supplemented with 2'-FL, 6'-SL, or lactose. Intestinal tissue was obtained at surgical resection. HMO inhibition of TLR4 was assessed in IEC-6 enterocytes, mice, and human tissue explants and via in silico modeling.<br />Results: Supplementation of infant formula with either 2'-FL and/or 6'-SL, but not the parent sugar lactose, reduced NEC in mice and piglets via reduced apoptosis, inflammation, weight loss, and histological appearance. Mechanistically, both 2'-FL and 6'-SL, but not lactose, reduced TLR4-mediated nuclear factor kappa light-chain enhancer of activated B cells (NF-kB) inflammatory signaling in the mouse and human intestine. Strikingly, in silico modeling revealed 2'-FL and 6'-SL, but not lactose, to dock into the binding pocket of the TLR4-MD2 complex, explaining their ability to inhibit TLR4 signaling.<br />Conclusions: 2'-FL and 6'-SL, but not lactose, prevent NEC in mice and piglet models and attenuate NEC inflammation in the human ileum, in part through TLR4 inhibition.<br />Impact: Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants that occurs in the setting of bacterial colonization of the gut and administration of formula feeds and activation by the innate immune receptor toll-like receptor 4 (TLR4). Breast milk prevents NEC through unclear mechanisms. We now show that breast milk-enriched human milk oligosaccharides (HMOs) that are derived from lactose prevent NEC through inhibition of TLR4. The human milk oligosaccharides 2'-FL and 6'-SL, but not the backbone sugar lactose, prevent NEC in mice and piglets. 2'-FL and 6'-SL but not lactose inhibited TLR4 signaling in cultured enterocytes, in enteroids derived from mouse intestine, and in human intestinal explants obtained at the time of surgical resection for patients with NEC. In seeking the mechanisms involved, 2'-FL and 6'-SL but not lactose were found to directly bind to TLR4, explaining the inhibition and protection against NEC. These findings may impact clinical practice by suggesting that administration of HMOs could serve as a preventive strategy for premature infants at risk for NEC development.
- Subjects :
- Animals
Animals, Newborn
Apoptosis drug effects
Cell Line
Disease Models, Animal
Enterocolitis, Necrotizing immunology
Enterocolitis, Necrotizing metabolism
Enterocolitis, Necrotizing pathology
Humans
Ileum immunology
Ileum metabolism
Ileum pathology
Inflammation Mediators metabolism
Intestinal Mucosa immunology
Intestinal Mucosa metabolism
Intestinal Mucosa pathology
Lactose isolation & purification
Lactose pharmacology
Mice
Molecular Docking Simulation
Signal Transduction
Sus scrofa
Toll-Like Receptor 4 metabolism
Trisaccharides isolation & purification
Weight Loss drug effects
Enterocolitis, Necrotizing prevention & control
Ileum drug effects
Intestinal Mucosa drug effects
Lactose analogs & derivatives
Milk, Human chemistry
Toll-Like Receptor 4 antagonists & inhibitors
Trisaccharides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0447
- Volume :
- 89
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Pediatric research
- Publication Type :
- Academic Journal
- Accession number :
- 32221473
- Full Text :
- https://doi.org/10.1038/s41390-020-0852-3