Effects of bovine lactoferrin on the immature porcine intestine

Abstract

Bioactive milk proteins may be important in protecting preterm infants from developing inflammation and necrotising enterocolitis (NEC). A preterm pig model was used to investigate the protective effects of enteral bovine lactoferrin (bLF) against NEC development and inflammation. Caesarean-delivered preterm pigs were fed parenteral and minimal enteral nutrition for the first 2 d followed by 2 d of total enteral nutrition before euthanasia. Pigs were stratified into two groups and fed with either a control formula (CON, n 15) or a 10 g/l of bLF-enriched formula (LF, n 13). NEC incidence, gut functions and inflammatory cytokines were analysed. NEC incidence and nutrient absorption were similar between the two groups. In pigs that developed NEC, disease outcome was more severe in the colon accompanied by increased intestinal permeability in LF pigs. In contrary, the LF pigs had a lowered IL-1b level in the proximal small intestine. Dosedependent effects of bLF on cell proliferation, intracellular signalling and cytokine secretion were tested in porcine intestinal epithelial cells (PsIc1) in vitro. Low doses (0·1 -1 g/l) increased cell proliferation via extracellular signal-regulated kinase (ERK), limited IL-8 secretion and prevented NF-kB and hypoxia-inducible factor-1a (HIF-1a) activation, suggesting anti-inflammatory effects. In contrast, at a higher dose (10 g/l), bLF exerted adverse effects by reducing cell proliferation, stimulating IL-8 release, inhibiting ERK activation and up-regulating NF-kB and HIF-1a activation. Overall, at a dose of 10 g/l, bLF exacerbated disease severity in pigs that developed NEC, while the in vitro studies indicated the positive effects of bLF at low doses (0·1-1 g/l). Supplementation of infant formulas with bLF should therefore be optimised carefully.

Lactoferrin Reduces Necrotizing Enterocolitis Severity by Upregulating Intestinal Epithelial Proliferation

“…14 Bovine lactoferrin of 0.1-1g/L administrated to NEC piglet can stabilize hypoxia-induced factor-1a (HIF-1α) and inhibit inflammation pathways including NF-κB, TNF receptorassociated factor 6 and p38 pathways. 4 Lactoferrin administration at a high concentration (10 g/L) upregulated NF-κB pathway and activated HIF-1α, resulting in colonic lesions and reduced intestinal villus height/crypt depth ratio in the immature small intestine of piglets. 4 At 6 g/L, we detected reduced nuclear NF-κB in lactoferrin-treated NEC mice compared with NEC alone.…”

“…Low dose (0.1-1g/L) lactoferrin can activate cell proliferation and downregulate inflammation, while a higher dose (10g/L) can be detrimental by inhibiting cell proliferation and upregulating inflammation. 4 In the present study, we used a dosage of recombinant lactoferrin (0.3 g/kg/day) at a concentration of 6 g/L, to approximate the concentration in human colostrum. We found that lactoferrin administration improved the severity of intestinal injury of experimental NEC, downregulated inflammation markers (IL-6, TNF-α, nuclear NF-kB), and significantly upregulated the expression of intestinal stem cell and proliferation markers (Lgr5, Ki67, and nuclear βcatenin).…”

“…3 Lactoferrin is also present in bovine milk at a concentration of 0.2 to 1.5 g/L with over 70% amino acid homology compared to human lactoferrin. 4,5 Therefore, both bovine lactoferrin and recombinant human lactoferrin can be used in the human infant diet and can supplement for the beneficial functions of human lactoferrin.…”

Bovine lactoferrin free of lipopolysaccharide can induce a proinflammatory response of macrophages

“…as newborn babies supplementation [24] or as a feed supplement for newborn piglets [25, 26]. Although there are several producing systems in which LF can be produced as recombinant [27, 28], bovine colostrum still remains as an important source of bioactive constituents incl.…”

Lactoferrin and prematurity: a promising milk protein?

“…In a neonatal rat model of NEC, bovine Lf significantly reduced NEC incidence; the protective effect was associated with increased density of mucin-producing goblet cells in the terminal ileum and changed ileal morphology (Wittke 2013). In a piglet model of NEC Lf had positive effects: increased cell proliferation via extracellular signal-regulated kinase, limited IL-8 secretion and prevented NF-kB and hypoxia-inducible factor-1a activation, suggesting strong anti-inflammatory effects (Nguyen et al 2014). …”