Table 1.

Lactoferrin-related Research Leading to Its Use to Prevent Necrotizing Enterocolitis

YEAR	DISCOVERY AND MEANING	CITATION
1972	Lactoferrin (LF) with low amounts of bound Fe3+ iron, called apo-lactoferrin, and restricts the growth of Escherichia coli. The study proposed LF in breast milk controls the growth of gut-related bacterial pathogens.	8
1987	Human LF increased thymidine incorporation into rat crypt cells and suggests a role for LF in intestinal growth after birth.	9
1991	LF and lysozyme, anti-bacterial proteins in milk, have an additive effect and kill enteric pathogens.	10
1991	A ‘nicked’ 78 kDa LF that was largely intact was identified in the urine of preterm infants; the modified protein retained iron-binding activity, receptor- binding properties, and the proposed immune cell regulatory functions. The ‘nicked’ protein may represent removal of peptide antibiotics.13	11
1995	In infant mice, human LF is a maturation factor for B cells enhancing their phenotype and function; this might mediate more secretory IgA into gut lumen.	12
1995	Human LF was expressed in Aspergillus awamori and a fully functional protein could be produced in large quantities using good manufacturing practices.	6
1998	In the stomach, pepsin releases a ‘defensin-like’ peptide from LF that is called lactoferricin, and it disrupts cell membranes of Gram-negative enteric bacteria.	13
2001	Feeding human recombinant LF to neonatal rats before an intestinal infection with Escherichia coli significantly reduces translocation, bacteremia and death.	14
2004	Feeding recombinant human LF (rhLF) + Lactobacillus GG (LLG) had more of an effect than feeding LGG alone in reducing gut-related translocation after an enteral infection with E. coli; rhLF enhanced intestinal colonization with LGG. This research was the basis for the first clinical trial of LF in preterm infants.	15
2005	Feeding LF and vitamin A to calves enhances epithelial cell maturation, villus growth, and size and nature of Peyer’s patches (PP). An accelerated development of PP may result in increased production of secretory IgA.	16
2009	In very preterm infants, oral prophylaxis with bovine LF (bLF) + Lactobacillus GG (LGG) significantly reduced late-onset sepsis and necrotizing enterocolitis compared to bLF only and placebo. Bovine LF + LGG versus bLF alone had no difference when NEC stage ≥2 and death were the outcomes (P = .06).	5