2. Academic Validation
  3. Human Milk Oligosaccharides Activate Epidermal Growth Factor Receptor and Protect Against Hypoxia-Induced Injuries in the Mouse Intestinal Epithelium and Caco2 Cells

Human Milk Oligosaccharides Activate Epidermal Growth Factor Receptor and Protect Against Hypoxia-Induced Injuries in the Mouse Intestinal Epithelium and Caco2 Cells

  • J Nutr. 2020 Apr 1;150(4):756-762. doi: 10.1093/jn/nxz297.
Chenyuan Wang 1 2,  Ming Zhang 3,  Huiyuan Guo 1 2,  Jingyu Yan 4,  Lingli Chen 1 2,  Wendi Teng 1 2,  Fazheng Ren 1 2,  Yiran Li 1 2,  Xifan Wang 1 2,  Jie Luo 5,  Yixuan Li 1
Affiliations

Affiliations

  • 1 Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, China.
  • 2 Key Laboratory of Functional Dairy, China Agricultural University, Beijing, China.
  • 3 School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China.
  • 4 Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
  • 5 College of Food Science and Technology, Hunan Agricultural University, Changsha, China.
PMID: 31915826 DOI: 10.1093/jn/nxz297
Abstract

Background: Hypoxia-induced intestinal barrier injuries lead to necrotizing enterocolitis (NEC). Although NEC in preterm neonates is preventable by human milk oligosaccharides (HMOs), the underlying mechanism remains unknown.

Objective: To reveal the role and mechanism of HMOs in protecting against hypoxia-induced injuries in intestinal epithelium of neonatal mice and cultured Caco2 cells.

Methods: NEC was induced by hypoxia and cold stress. Seventy C57BL/C pups (7-d-old) were divided into 5 groups and fed maternal breast milk (BM), formula alone (FF), or the formula added with HMOs at 5 (LHMO), 10 (MHMO), or 20 mg/mL (HHMO) for 3 d. Ileal hypoxia inducible factor 1α (HIF1α) and cleaved Caspase 3 were determined, along with staining for Ki-67 protein to labeled proliferative cells. In vitro, adherent Caco2 cells (undifferentiated, passage 14) were treated with HMOs, galacto-oligosaccharides, fructo-oligosaccharides, or mixed oligosaccharides at 10 mg/mL for 1 d exposed to 1% O2. Cell proliferation and Apoptosis, along with phosphorylated epidermal growth factor receptor (P-EGFR) and 38KD MAPK (P-P38), were assayed in differentiated or undifferentiated Caco2 cells.

Results: Compared with the FF-fed mice, those fed MHMO and HHMO had 52% lower (P < 0.05) NEC scores, 60-80% greater (P < 0.05) KI67-positive cell numbers, and 56-71% decreases (P < 0.05) in ileal HIF1α and cleaved Caspase 3 (56-71%). Compared with those untreated, the HMO-treated Caco2 cells displayed 60% greater (P < 0.05) proliferative activity and 19% lower (P < 0.05) apoptotic cells after the hypoxia exposure. The HMO treatment led to 58% or 10-fold increases (P < 0.05) of P-EGFR and 48-89% decreases (P < 0.05) of P-P38 in either differentiated or undifferentiated Caco2 cells compared with the controls.

Conclusion: Supplementing HMOs at 10-20 mg/mL into the formula for neonatal mice or media for Caco2 cells conferred protection against the hypoxia-induced injuries. The protection in the Caco2 cells was associated with an activation of EGFR.

Keywords

EGFR; P38; human milk oligosaccharides; hypoxia; necrotizing enterocolitis.

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