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Updated: Jan 21, 2026
A Novel Human Epithelial Enteroid Model of Necrotizing Enterocolitis
Published on: April 10, 2019
Lactoferrin Reduces Necrotizing Enterocolitis Severity by Upregulating Intestinal Epithelial Proliferation
Jia Liu1,2, Haitao Zhu1,2, Bo Li2
1Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.
Insights
Lactoferrin reduces necrotizing enterocolitis (NEC) severity in premature infants by decreasing inflammation and increasing intestinal cell proliferation. This protective effect is mediated by the Wnt pathway, highlighting lactoferrin
Area of Science:
- Neonatal Medicine
- Gastroenterology
- Immunology
Background:
- Necrotizing enterocolitis (NEC) is a severe intestinal disease in premature infants with high mortality.
- Current therapies for NEC are insufficient, necessitating novel treatment strategies.
- Lactoferrin, a protein in human milk, possesses immunomodulatory properties with potential protective effects against NEC.
Purpose of the Study:
- To investigate the mechanism by which lactoferrin impacts inflammation and proliferation in experimental NEC.
- To determine if lactoferrin downregulates inflammation and upregulates intestinal epithelial proliferation during NEC.
Main Methods:
- NEC was induced in mice via hypoxia, formula feeding, and lipopolysaccharide.
- Lactoferrin was administered daily to NEC and control mice.
- Intestinal tissue was analyzed for disease severity, inflammation markers (IL-6, TNF-α), stem cell expression (Lgr5), and proliferation markers (Ki67, β-catenin).
Main Results:
- Lactoferrin treatment significantly reduced NEC disease severity and inflammation markers.
- Lactoferrin increased intestinal stem cell expression (Lgr5) and proliferation (Ki67, β-catenin) in NEC mice.
- Lactoferrin administration did not negatively impact inflammation or proliferation in healthy control mice, indicating safety.
Conclusions:
- Lactoferrin administration effectively reduces intestinal injury in experimental NEC.
- Lactoferrin exerts its beneficial effects by downregulating inflammation and upregulating cell proliferation via the Wnt pathway.
- This study elucidates lactoferrin's mechanism of action in NEC and its potential role in enteral feeding strategies.
Introduction:
Necrotizing enterocolitis (NEC) is a devastating intestinal illness in premature infants characterized by severe intestinal inflammation. Despite medical interventions, NEC mortality remains alarmingly high, which necessitates improved therapies. Lactoferrin is among the most abundant proteins in human milk and has important immunomodulatory functions. While previous studies have indicated protective effects of lactoferrin against neonatal sepsis and NEC, the underlying mechanism remains unclear. We hypothesize that lactoferrin downregulates inflammation and upregulates proliferation in intestinal epithelium during NEC injury.
Materials And Methods:
NEC was induced by hypoxia, gavage feeding of hyperosmolar formula and lipopolysaccharide between postnatal day P5 and P9 (n = 8). Breastfed mice were used as control (n = 7). Lactoferrin (0.3 g/kg/day) was administered once daily by gavage from P6 to P8 in both NEC (NEC + Lac; n = 9) and control mice (Cont + Lac; n = 5). Distal ileum was harvested on P9 and analyzed for disease severity, inflammation, and proliferation. Groups were compared using one-way ANOVA and t-test appropriately; p < 0.05 was considered significant.
Results:
Compared to NEC group, lactoferrin-treated NEC mice had reduced disease severity, reduced inflammation markers IL-6 and TNF-α expression and increased intestinal stem cell marker Lgr5 + expression. Lactoferrin-treated NEC mice exhibited increased nuclear β-catenin, indicating upregulated Wnt pathway, and increased Ki67 positivity, suggesting enhanced proliferation. Furthermore, lactoferrin administration to control mice did not affect intestinal inflammation as well as Lgr5 + stem cell expression and epithelial proliferation. This supports the safety of lactoferrin administration and indicates that the beneficial effects of lactoferrin are present when intestinal injury such as NEC is present.
Conclusion:
Lactoferrin administration reduces the intestinal injury in experimental NEC by downregulating inflammation and upregulating cell proliferation. This beneficial effect of lactoferrin in stimulating cell proliferation is mediated by the Wnt pathway. This experimental study provides insights on the mechanism of action of lactoferrin in NEC and the role of lactoferrin in enteral feeding.
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