If you’re not already familiar with lactoferrin, then it’s time to get to know this naturally occurring protein. Classed as a glycoprotein, it is primarily secreted by neutrophils (the most abundant type of white blood cell) and through exocrine glands and so is found in fluids such as saliva, tears, semen, bile, digestive juices, urine, blood plasma and amniotic fluid.1
While human lactoferrin (also known as lactotransferrin or Lf) is perhaps best known as one of the transferrin proteins involved in transferring iron to cells and controlling levels of free iron in the blood, it is also a potent immune modulator, with significant anti-bacterial, anti-viral and antioxidant properties.
This protein can be found in the milk of humans and other mammals. Colostrum, the first milk produced post-birth contains high levels of lactoferrin – about seven times the amount found in more mature breast milk as it is required to support immune and gastrointestinal development in infants.
Lactoferrin levels in the body can be used as a marker of inflammation. In fact, lactoferrin levels in stool may be used as part of the diagnostic work-up for conditions such as inflammatory bowel disease (IBD) and some bacterial infections of the digestive tract.
How does lactoferrin work in the body?
Bovine and human derived lactoferrin share a high degree of structural similarity. Evidence has shown that bovine derived lactoferrin can be taken up by the lactoferrin receptors in the human intestinal tract and have bioactivity.2
When lactoferrin reaches the stomach, a proportion passes to the intestine intact and some is digested by pepsin to release a number of peptides including a potent peptide antibiotic called ‘lactoferricin’ (Lfcin), which has greater antimicrobial properties than the lactoferrin protein. This process occurs with both human and bovine lactoferrin as they have the same amino acid peptide terminal.4 Other lactoferrin peptides, each with their own unique properties, formed following pepsin digestion, are Lf (anti-bacterial) and Lfampin (anti-bacterial, anti-fungal and anti-parasitic).
Once lactoferrin and its peptides reach the intestine, they may be taken up by the gut immune system or travel through the lymphatic system and into circulation.5,6
What does the research say?
While iron absorption is a well-established function of lactoferrin in the body, numerous research studies have uncovered a plethora of applications for this protein; from immune and gastrointestinal support, to antioxidant, bone and skin support. Lactoferrin’s properties are also being researched for use alongside chemotherapy treatment for cancer.
- Iron absorption and uptake
As a member of the transferrin family of iron-binding proteins, lactoferrin aids the intestinal absorption, uptake and delivery of iron to cells. During pregnancy, lactoferrin supplementation has been proposed as a means of increasing iron levels in women where iron supplements are poorly tolerated, without increasing the risk of potential side effects of high dose iron supplementation, such as miscarriage.7 An added advantage to this approach is that vaginal infections may also be inhibited by the lactoferrin.8
- Antioxidant properties
Production of free radicals or oxidative stress has been associated with unbound iron in the system. As lactoferrin binds to and removes free iron, it prevents cell damage from iron induced oxidative stress.9
- Immune modulation
Lactoferrin can directly influence the function of human immune cells due to the presence of several lactoferrin receptors along the intestinal tract.10–12 It can increase the activity of innate immune cells such as natural killer cells, neutrophils and macrophages,13–15 while also having effects on adaptive immune cells such as T-cells and B-cells16
As a natural component of breastmilk, the effects of lactoferrin on the neonatal microbiome have been widely researched, with findings suggesting a central role in gut and immune development.17 In fact, evidence suggests that mothers of premature infants may sustain higher lactoferrin concentrations in their colostrum compared to mothers of term infants.18 Buccigrossi et al demonstrated lactoferrin’s role as a key modulator of intestinal epithelium development.19 This promotion of cells lining the intestine suggests a role for lactoferrin in creating a less permeable gut wall by helping the intestinal tight junctions to become tighter. Both bovine and human lactoferrin exhibited the same effects on the nascent gut. This has been confirmed by other studies which suggest that bovine lactoferrin exerts several of the same effects as human lactoferrin when added to infant formula.2 As well as supporting the infant immune system, lactoferrin regulates bone growth in the early stages of foetal development,20 while also promoting cartilaginous tissue growth through stimulation of immature osteocytes and osteoblasts21
- Anti-inflammatory agent
Lactoferrin is an effective anti-inflammatory agent in humans.22 Its ability to sequester iron and thus inhibit free radical formation plays a major role in mitigating damage due to excesses in the inflammatory response. During pregnancy, lactoferrin reduces levels of the inflammatory mediator IL-6, thus minimising amniotic and foetal inflammation. Furthermore, inflammation can be reduced as a consequence of lactoferrin’s interaction with the immune system. For example, in cells infected with the Epstein-Barr virus (EBV), lactoferrin suppressed the EBV-induced inflammatory response by interfering with the activation of TLR2 and TLR9 (proteins which play a key role in the innate immune response). 23
Lactoferrin has many mechanisms through which it elicits anti-bacterial effects in the body. As most bacteria require iron to thrive, lactoferrin can impede their function by stopping these bacteria from taking up iron in the body.24 In fact, bacterial infections were successfully inhibited when a combination of lactoferrin and iron was administered.25 In addition, lactoferrin can reduce symptoms of bacterial lipopolysaccharide (LPS) toxicity, while also reducing the risk of cell death as a consequence of infection.26 Finally, it has been found that lactoferrin can inhibit bacterial carbohydrate metabolism, thus restricting their energy source and leading to the destabilisation of their cell walls,24 demonstrating another potential mechanism behind its anti-bacterial function.
Lactoferrin’s anti-viral effects can be attributed to its ability to block viruses from entering human cells either by binding with the virus itself or by closing off their cellular receptors.27 Lactoferrin has been found to be effective at stopping the spread of several viruses, including HIV, hepatitis B and C, HPV and influenza.27 In fact, in the case of herpes virus, bovine lactoferrin was found to be even more effective than human lactoferrin at inhibiting its spread.27
Lactoferrin has been repeatedly used in-vivo to prevent fungal growth in the human body.28 Early studies using Candida and Aspergillus fumigatus species attributed the effect to lactoferrin’s ability to sequester iron.29,30 Additional studies suggest that lactoferrin may induce mitochondrial dysfunction and apoptosis (cell death) of fungal cells.31
A bovine animal model showed that lactoferrin was effective at increasing the immune system’s response to a parasitic infection, thus helping to expel it from the body.32 A recent study found that lactoferrin effectively killed Cryptosporidium parvum sporozoites, which are essential to the infection process of this parasite, commonly found in the intestines of young children.33
- Promotion of gastrointestinal health
Lactoferrin has been shown to promote the growth of Bifidobacteria in the gut, while inhibiting the growth of E.coli and Salmonella.34 Lactoferrin also exerts protective effects against inflammation and infection induced intestinal barrier dysfunction in human cells.35 This makes sense considering the central role of lactoferrin in breast milk for developing and adapting the intestinal system in infants.36
- Bone support
We know that lactoferrin regulates bone growth in the early stages of foetal development,20 while also stimulating immature osteocytes and osteoblasts.21 Interestingly, studies show that this bone supportive effect is not limited to foetal development. Lactoferrin can stimulate osteoblast differentiation, which is an important process in the formation of bone.37 It also improved bone mass in rodent models,38 whereas bone formation was increased with a subsequent decrease in bone resorption in a post-menopausal model following administration.39
Lactoferrin can block histamine release from mast cells in the human colon.40 In a rodent model of asthma, inflammation induced by pollen exposure was decreased following administration of lactoferrin.41 More recently, it was shown that individuals suffering from ocular or eye surface allergies had lower levels of lactoferrin in their tears.42
- Blood sugar balance
Levels of circulating lactoferrin in the blood have been positively correlated with insulin resistance regardless of adiposity (fat cell) status.43 Higher levels of lactoferrin improved the insulin-signalling response and increased glucose absorption.44
- Skin health
While dairy intake has been contraindicated in many skin conditions including acne,45 a human trial which included lactoferrin enriched fermented milk supplementation found reductions in inflammation and the appearance of acne on the skin compared to placebo.46
- Cognitive function
Measurement of salivary lactoferrin levels has been validated as a non-invasive tool for early diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD).47 Levels of salivary lactoferrin were decreased in MCI and AD patients versus the control group. Supplementation of lactoferrin was found to improve cognitive and brain development in piglets.48 A 2019 pilot study in AD patients has also demonstrated a positive association between lactoferrin supplementation and the interruption of cognitive decline via modulation of the p-Akt/PTEN pathway.49 This pathway affects some key players involved in the progression of AD, including markers of inflammation and oxidative stress.
- Lactoferrin is a protein secreted in the body and found in saliva, tears, semen, bile, digestive juices, urine, blood plasma and amniotic fluid (the fluid which surrounds and protects the developing foetus). This protein is also present in the milk of humans and other mammals. Colostrum, the first milk produced post-birth contains high levels of lactoferrin
- Bovine and human-derived lactoferrin share a high structural similarity
- Lactoferrin is very stable during digestive transit. It is broken down into potent antibiotic peptides in the stomach and it can support the gut immune system or travel through the lymphatic system and into circulation
- One of the primary roles of lactoferrin is to uptake and absorb unbound iron in the body. As unbound iron has been associated with the development of free radicals, lactoferrin helps with protection from oxidative stress
- Lactoferrin supports both the innate and adaptive immune response. In infants, lactoferrin in breastmilk plays a central role in priming immune and gastrointestinal function
- Lactoferrin levels increase in response to inflammation and thus levels in stool can be used as a marker of inflammation. It exhibits potent anti-inflammatory effects in humans, most notably through its role in binding iron as well as its anti-bacterial, anti-viral, anti-parasitic properties and ability to block histamine release from mast cells in the colon
- Lactoferrin regulates bone growth during foetal development. It has also been found to increase bone formation while reducing bone resorption in human and animal models
- Research has also shown higher levels of lactoferrin are correlated with improvements in the insulin-signalling response and increased glucose absorption, lactoferrin enriched fermented milk reduced inflammation on the skin and the appearance of acne
If you have any questions regarding the topics that have been raised, or any other health matters, please do contact me (Amanda) by phone or email at any time.
Amanda Williams and the Cytoplan Editorial Team
References available upon request.