See “Bovine Lactoferrin Can Be Taken Up by the Human Intestinal Lactoferrin Receptor and Exert Bioactivities” by Lönnerdal et al on page 606.
Lactoferrin (LF) is an iron-binding glycoprotein and is the second most abundant protein in human milk (1,2). In human milk, concentrations are high in colostrum and then decline; however, the decline in concentration is slower in the milk of mothers delivering premature infants (3). LF is found on mucosal surfaces and less so in mature human milk, tears, saliva, seminal fluid, and secondary granules of neutrophils. The expression and secretion of LF on mucosal surfaces and its release at inflammatory sites have established its role as an agent of innate immunity and could be an attractive synergistic agent with antifungals (4) and probiotics (5). Bovine LF (bLF) inhibits the growth of a wide variety of bacteria, fungi, viruses, and parasites. Furthermore, a high homology between the human and bovine forms of LF suggests that supplementation of infant formulas with LF may provide similar protection against sepsis as observed with the use of human milk.
In this issue of the Journal, Lönnerdal et al (6) investigated the feasibility of adding commercially available bovine LF (CbLF) to infant formula. Using Caco-2 cells, they compared the ability of bLF purified in their laboratory, CbLF, and human LF (hLF) to resist digestion, bind to the receptor, and exert bioactivity. The hLF was isolated from pooled frozen human milk, bLF from fresh cow's milk, and cbLF was obtained from a commercial source.
All 3 LF samples were capable of binding iron, with hLF having the lower degree of iron saturation compared with bLF and CbLF, and all 3 products were capable of binding additional iron to form holo-LF. Notably, the commercial infant formulas had higher levels of lipopolysaccharides compared with the LF preparations, raising the issue of whether the LF added would be used to bind with lipopolysaccharides. There were differences in the promotion of cell proliferation and differentiation between samples that were saturated versus those that were not. Native forms of hLF and bLF increased expression of TGF-β1 and the holo-forms simulated interleukin-18 secretion. Studies also demonstrated that bLF and CbLF can resist digestion in the presence of infant formula.
One important observation is that all 3 forms of LF had low degrees of iron saturation and raised concern about their behavior if excess iron was present as it would be in infant formula. All 3 forms, however, were capable of binding iron and transforming to the holo-form, making it feasible to add LF in formulas that have higher concentrations of iron compared with human milk.
The present study, although in vitro, has several implications. Because addition of LF to human milk–fed infants has been demonstrated to reduce infections in neonates, the present study demonstrates the feasibility of adding LF to infant formulas, thus possibly affording similar protection from infections. Differences in infection and necrotizing enterocolitis between human milk and formula-fed infants are well established. Addition of LF to infant formulas and performing appropriate randomized controlled trials would be the next appropriate steps. There are ongoing trials using LF supplementation, but the last Cochrane review on oral LF concluded that “there is no evidence to recommend or refute the use of LF for the treatment of neonatal sepsis or necrotizing enterocolitis as an adjunct to antibiotic therapy (7).” The safety and efficacy of the different preparations and appropriate doses need to be established.
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3. Hirai Y, Kawakata N, Satoh K, et al. Concentrations of lactoferrin and iron at different stages of lactation. J Nutr Sci Vitaminol (Tokyo)
4. Lupetti A, Paulusma-Annema A, Welling MM, et al. Synergistic activity of the N-terminal peptide of human lactoferrin and fluconazole against candida species. Antimicrob Agents Chemother
5. Manzoni P, Rinaldi M, Cattani S, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates. JAMA
6. Lönnerdal B, Jiang R, Du X. Bovine lactoferrin can be taken up by the human intestinal lactoferrin receptor and exert bioactivities. J Pediatr Gastroenterol Nutr
7. Pammi M, Abrams SA. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev