Lactoferrin and the bowel

There’s a lot of activity in Lactoferrin research recently, this protein is very promising as prophylaxis against infections and perhaps also against necrotising enterocolitis.

First of all a study giving bovine lactoferrin to newborn piglets which showed a stimulatory effect on crypt cells in the developing intestine. Reznikov EA, Comstock SS, Yi C, Contractor N, Donovan SM: Dietary bovine lactoferrin increases intestinal cell proliferation in neonatal piglets. J Nutr 2014, 144(9):1401-1408. Exactly which cell type isn’t clear to me, but Paneth cells in the crypt have been suggested to be important in the pathophysiology of NEC. (McElroy SJ, Underwood MA, Sherman MP: Paneth Cells and Necrotizing Enterocolitis: A Novel Hypothesis for Disease Pathogenesis. Neonatology 2013, 103(1):10-20).

Another study from the same group, in the same model (in fact I think it is the same piglets) Comstock SS, Reznikov EA, Contractor N, Donovan SM: Dietary Bovine Lactoferrin Alters Mucosal and Systemic Immune Cell Responses in Neonatal Piglets. The Journal of Nutrition 2014, 144(4):525-532. Both spleen cells and mesenteric lymph node cells showed signs of enhanced immune responses with dietary bovine lactoferrin.

Colostrum, and mature breast milk contain significant amounts of lactoferrin. (in fact the piglets in the previous study were deprived of sow colostrum in order to do the study). Breast milk is almost always colonized with bacteria, very often bifidobacteria are present, and often lactobacilli also. In this study, which included both full term (34) and preterm (14) mother infant (human) pairs, the lactoferrin concentrations were similar to previous data, with around 7 mg/mL in colostrum dropping to 2.3 in mature milk, similar in term and preterm subjects. Mastromarino P, Capobianco D, Campagna G, Laforgia N, Drimaco P, Dileone A, Baldassarre ME: Correlation between lactoferrin and beneficial microbiota in breast milk and infant’s feces. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014, 27(5):1077-1086. They also showed bacterial DNA of lactobacilli in all of the breast milk, and bifidobacteria in all but one of the breast milk samples, with a higher concentration of lactobacilli in the preterm milk, and similar bifidobacteria concentrations. They also analyzed stool samples, and were able to find lactoferrin in the stools, and found lactobacilli and bifidobacteria in almost all the stools also.

The next study examined the effects of heat-treatment and ultraviolet light on the lactoferrin concentration of colostrum (also on what they call hospital milk, which is milk supplied by sick cows which cannot be sold, and may be contaminated with many bacteria). The heat treatment was to 63 degrees for 60 minutes, which is similar to many human milk bank standards I believe. Lactoferrin was measured by an ELISA, and I don’t know whether lactoferricin, or other active or potentially active parts of the molecule would react with the assay. Teixeira AGV, Bicalho MLS, Machado VS, Oikonomou G, Kacar C, Foditsch C, Young R, Knauer WA, Nydam DV, Bicalho RC: Heat and ultraviolet light treatment of colostrum and hospital milk: Effects on colostrum and hospital milk characteristics and calf health and growth parameters. The Veterinary Journal 2013, 197(2):175-181. The study shows a number of things : cows’ milk colostrum has much less lactoferrin than human (which was already known), about 0.3 mg/mL falling to around 0.2 in mature milk. Both heat treatment and ultraviolet treatment reduced the lactoferrin concentrations, and also the IgG concentrations. It’s interesting sometimes to read research form other fields in some detail, this study was performed in a farm which has 2800 cows, and they randomized over 280 animals into the 3 groups. They calculate the sample size based on daily weight gain, which is therefore the primary outcome variable, but they don’t use the term, and report that outcome in very little detail, right at the end of the results.

Also interestingly, low birth weight calves are at higher risk of infection than normal birth weight, being LCBW (low calf birth weight) less than 37 kg is associated with much more diarrhoea, and they also had lower serum IgG concentrations.

Part of the efficacy of lactoferrin may be that it sequesters iron, so that it is no longer available for organisms that rely on iron to replicate, such as E Coli (although there are several other mechanisms also). If you then add more iron to the feed, does this overcome the benefits? A number of in vitro studies have had variable results, the latest took colostrum from mothers delivering at term, and tested bacterial growth effects of the milk with and without the addition of a human milk fortifier, used for preterm infants, that contains iron. They found no effect of the iron on Pseudomonas or Staph Aureus, but E Coli grew a little more actively when the fortifier with iron was used. Apparently other studies have had different effects, such as showing a direct bacteriostatic effect of breast milk, and showing more adverse effects of the iron. Campos LF, Repka JCD, Falcão MC: Effects of human milk fortifier with iron on the bacteriostatic properties of breast milk. Jornal de Pediatria 2013, 89(4):394-399.

Of course iron is also important as a catalyst for the production of reactive oxygen species, so another potential benefit of lactoferrin may be to reduce free iron, and therefore to reduce potential oxidative injury of the gut. This is suggested by the results of another study: Jegasothy H, Weerakkody R, Selby-Pham S, Bennett LE: In vitro heme and non-heme iron capture from hemoglobin, myoglobin and ferritin by bovine lactoferrin and implications for suppression of reactive oxygen species in vivo. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014, 27(6):1371-1382.

Finally a review article which discusses the potential benefit of lactoferrin supplementation. Michael Sherman, who has studied lactoferrin, including recombinant human lactoferrin relates the importance of ensuring that preterm babies get colostrum. Which I certainly agree with. The authors also state however that there is no lactoferrin preparation proved by the FDA for use in preterm infants, which is of course true, but they state in the abstract ‘regulatory burdens required to bring lactoferrin to the bedside may limit its availability’. When the list of trials completed and in progress at the end of the article are examined, I hope that is not true. If the data are confirmatory, we should have plenty of good data to be able to obtain approval. Sherman M, Miller M, Sherman J, Niklas V: Lactoferrin and necrotizing enterocolitis. Current Opinion in Pediatrics 2014, 26(2):146-150.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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