Image from Servier Medical Art: https://www.ncbi.nlm.nih.gov/pubmed/26981846

Lactoferrin is a naturally occurring protein that is found in milk and bodily fluids. It is a potent anti-microbial and modulator of the immune system. Several studies have shown that natural lactoferrin has many important roles. Read this post to learn more about the properties and health benefits of lactoferrin.

What is Lactoferrin?

Lactoferrin (also known as lactotransferrin or Lf) is a type of iron-binding glycoprotein that is mostly secreted from bodily fluids including milk, saliva, tears, vaginal fluids, semen, secretions from lungs and nose, bile, digestive juices, and urine [1].

It provides anti-bacterial activity to human infants and also has anticarcinogenic properties.

It is a component of the immune system responsible for defense at the mucosal level, due to its high antimicrobial activity.

It is crucial to the increase in immune functions for infants who are still nursing off of their mothers. It is also believed to be widely important to maintaining immune functions further in life past infancy.

Lactoferrin is also found in secondary neutrophil granules, blood, and amniotic fluid [2].

It functions as an antimicrobial protein and immune-modulator.

It also binds to DNA and other molecules in milk like IgA, casein, albumin, etc. [1].

It helps develop the gastrointestinal and immune system in newborns [3].

The iron-bound form of lactoferrin is called holo-lactoferrin, whereas the lactoferrin without iron is apo-lactoferrin.

Snapshot

Pros
  • Helps the immune system and prevents inflammation
  • Fights against cancer
  • Anti-bacterial, anti-fungal, anti-viral
  • Promote bone health
  • Prevents obesity
Cons
  • Common side effects: diarrhea, constipation, abdominal pain

As a Marker of Inflammation and Infections

Lactoferrin kills bacteria and protects from infections and inflammation. Therefore, natural lactoferrin levels in our bodies rise during times of infections and inflammation.

To combat bacterial infections, blood lactoferrin rapidly rises and iron levels drop during E. coli infection in the blood in mice [4].

Doctors test lactoferrin in the stool to detect inflammation in the intestines, especially to diagnose inflammatory bowel disease [5].

Fecal lactoferrin levels also naturally rise in the case of Clostridium difficile infections in humans [6].

Health Benefits of Lactoferrin

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Lactoferrin is the first line host defense against invading pathogens and also regulates the innate immune response.

1) Has Antioxidant Properties

Because iron can cause oxidative stress, lactoferrin can reduce oxidative stress by binding and removing iron, which prevents cell damage or cell death [7].

Lactoferrin supplementation can support the immune system as an antioxidant [8].

2) Modulates the Immune System

There are lactoferrin receptors on many immune cells, so lactoferrin directly affects how these cells function [9, 10, 11].

Lactoferrin can exert changes on white blood cells, through increasing natural killer cell, neutrophils, and macrophage activities [12, 13, 14]. This increases cytokine, and Nitric Oxide production as well as limit pathogen growth.

Lactoferrin also affects adaptive immune cells (T-cells and B-cells) [15].

In infants, lactoferrin is crucial to the development of their natural immune system function to prevent infection [16].

In mice treated with chemotherapy, treatment with lactoferrin post-chemotherapy accelerated the reconstitution of the immune system, reducing the chances for infection following chemotherapy treatment [17].

In mice suffering from colitis-associated colorectal dysplasia, treatment with lactoferrin reduced their overall deficiency and also reduced the symptoms and inflammation caused by the dysplasia [18].

3) Protects Against Inflammation

Although the direct mechanism has not been established yet, lactoferrin is still shown to be effective in preventing inflammation in humans [19].

Lactoferrin in the amniotic fluid is an important component to reducing fetal inflammation in pregnant women through reducing IL-6 levels and reducing infection causing the inflammation [20].

Lactoferrin has anti-inflammatory properties when interacting with the immune system against the Epstein-Barr virus, reducing inflammation by inhibiting the activation of TLR2 and TLR9 in the virus DNA [21].

In rats, a combination of glycine and lactoferrin prevents skin inflammation [22].

It prevents the stimulation of granulocyte-macrophage colony activity in mouse liver cells [23].

4) Helps with Allergies and Asthma

Lactoferrin helps reduce airway inflammation in a mouse asthma model [24].

Lactoferrin blocks histamine release from colon mast cells [25].

5) Helps with Bacterial Infections

Lactoferrin helps stop the activity of bacteria. Most bacteria need iron to function, and lactoferrin can stop bacteria from taking up iron in the human body [1].  

In addition to this, it can block bacteria’s carbohydrate metabolism, destabilize their cell walls, or interact with lysozymes in milk to stop bacteria [1].

In animals with bacterial LPS toxicity, injecting them with lactoferrin reduces many symptoms of toxicity, and reduce risks of death from LPS toxicity by five-fold [26, 27].

Streptococcus pneumoniae colonizes in the nasopharynx of humans, which can spread to cells leading to infection.

Supplementation of lactoferrin and lysozyme increases the mucosal immune system response in the nasopharynx, preventing the spread of Streptococcus pneumoniae to sterile cells [28].

It is also used to boost the efficacy of the Bacillus Calmette-Guerin vaccine to fight against tuberculosis in mice [29].

In mice infected with Listeria monocytogenes, treatment with lactoferrin boosted the immune function of the mice and decreased the overall level of invading bacteria in the mouse’s system [30].

Human lactoferrin taken alongside iron supplementation was successful in fighting actinobacillus pleuropneumoniae infection by inhibiting the growth and spread of the bacteria [31].

6) Stops Viruses

In human cell cultures and patients, lactoferrin can also act as an antivirus by preventing viruses from entering human cells by blocking cellular receptors or directly binding to the viruses [32].

The bovine lactoferrin was more efficient than the human version in stopping the herpes virus in human cell culture. However, both types were able to stop the virus from entering the cells [32].

Lactoferrin was also effective in stopping the effects of HIV by blocking the entry process in vitro [32].

Human patients suffering from hepatitis C showed similar effects of lactoferrin preventing virus entry. It helped eradicate the hepatitis C virus from the patients’ bodies [32].

While Lactoferrin is also a viable treatment for hepatitis C, heavy doses are needed which may require doctor observation for adverse effects.

In human cells, lactoferrin also inhibited many other viruses such as hepatitis B, HPV, rotavirus, and influenza by using similar mechanisms [32].

Some antiviral mechanisms:

  • Increases the production of IL-12 (Th1) [7].
  • The anti-HSV activity of lactoferrin involves viral interaction with the cell surface glycosaminoglycan heparan sulfate, thereby blocking viral entry. Lactoferrin inhibited cell-to-cell spread of both HSV-1 and HSV-2 [32].

7) Antifungal

Both bovine (cow) and human lactoferrin stop the growth of fungi in human cell cultures. This suggests that this protein can be used in vivo to help prevent fungal growths in the human body [33].

8) Antiparasitic

In cows infected with a parasite, lactoferrin supplementation increases the immune system response to the parasite, helping to expel it from the body of the bovine [34].

9) Helps Increase Iron Absorption

Lactoferrin intake by adults helps increase iron absorption in the intestine.

It is also responsible for the delivery of iron to cells, important for basic cell function.

In pregnant women, straight iron vitamins could be an unsafe supplement for the fetus. Lactoferrin proved to be a viable substitute for increasing iron levels while reducing side effects.

10) Helps Fight Against Cancer

Bovine lactotransferrin decreases breast cancer cell viability and cell growth, and increased cell death in a cell study [35].

It also stopped cancer cell growth during the cell cycle and disrupt the cancer cells’ membranes [36].

In rats, it also had the ability to restore white and red blood cell count after chemotherapy [37].

Humans suffering from lung cancer undergoing chemotherapy had increased immune system response after taking lactoferrin post-treatment [38].

In rats, supplementation of bovine lactoferrin interacted with phase 1 enzymes to reduce the carcinogenic effects of lung, bladder, tongue, colon, and liver cancer (39).

11) May Reduce Insulin Resistance

There is a correlation between lactoferrin concentration in the blood and insulin sensitivity. In humans, lactotransferrin improved the insulin-signaling response and increased glucose absorption [40].

12) Helps Brain Development

In piglets, lactoferrin helps improve cognition and brain development. They learned how to complete learning tasks more efficiently [41].

13) Helps Clear Acne and Injured Skin

Human patients aged 18-30 were given milk with lactoferrin and their skin condition improved. They had less acne and skin inflammation compared to the placebo group [42].

In adolescents, lactoferrin can improve acne conditions without serious drying out of the skin, or other side effects.

Psoriasis patients also benefited from topical application. The redness and size of their skin lesions lessened [43].

In diabetic human patients, topical applications of recombinant lactoferrin improved the healing of neuropathic foot ulcers better than a healing cream with no side effects [44].

Lactoferrin applied topically to patients suffering from psoriatic plaque buildup had reduced redness and scaling, but increased their immune response to the skin [45].

14) Might Have Anti-Obesity Effects

Obese Japanese men and women were given enteric-coated lactoferrin tablets for eight weeks. This reduced their fat mass and body weight. Their BMI also got smaller, as well as their waist circumference [46].

Lactoferrin can help control fat accumulation in humans. There is also some evidence that iron deficiency might be related to obesity, but more studies need to be done [40].

15) Promotes Bone Health

In postmenopausal women, RNAse-enriched lactoferrin supplementation significantly improved their bone health. Bone formation increased and bone reabsorption decreased [47].

16) Prevents Iron Deficiency in Pregnant Women

Pregnant women can develop iron deficiency, which can cause premature delivery [48].

Pregnant women were given lactoferrin orally and it stabilized their iron levels. There were no adverse effects and the women also did not miscarry [49].  

The protein stopped shortening of the cervical length and increased fetal fibronectin, both which prolonged pregnancy [48].

Additionally, lactotransferrin stopped vaginal infections in pregnant women [50].

17) Stops Dying Intestinal Damage in Premature Babies

Many preterm babies suffer from necrotizing enterocolitis when the bacteria can cause inflammation in gut-related tissues and might destroy the intestinal walls and causing the intestinal cells to die [51].

In infants, human and bovine lactotransferrin can kill bacteria in the intestines and help stop necrotizing enterocolitis. It can also block or prevent the invasion of pathogens in the gut and help destroy pathogens [51, 52].

18) May Help Cystic Fibrosis

In human cells from cystic fibrosis patients, lactotransferrin can help prevent inflammation, breaks bacterial biofilm, and protect the cells from damage [53].

19) Supports Fetal/Infant Development

Developing infants require lactoferrin to develop and adapt to the intestinal system. It is responsible for differentiating small intestinal epithelial cells, affecting small intestinal mass, length, and enzyme expression [54].

In human fetuses, lactoferrin serves as a bone growth regulator in the early phases of human bone development [55].

Lactoferrin promotes cartilaginous tissue growth at various stages of fetal development by stimulating immature osteocytes and osteoblasts [56].

In human fetuses, lactoferrin promotes iron absorption and development of the brush border, allowing for healthy growth and gut development before birth [57].

High levels of lactoferrin in the fetus prevent infection and ruptures of fetal membranes while increasing the ease of labor when it comes time for the fetus to be born [58].

Lactoferrin is in high concentrations in the developing salivary glands of human fetuses in order to increase their natural defense mechanisms [59].

In mice, lactoferrin is responsible for hormonal regulation and growth of developing uterine tissue and for the differentiation of the cells in neonatal mice [60].

20) Supports Good Gut Bacteria

Lactoferrin has been shown to decrease the growth of E. coli and Salmonella while promoting the growth of the beneficial Bifidobacteria [61].

Side Effects of Lactoferrin

There are not many side effects; high doses might cause some abdominal pain, diarrhea, or constipation [62]. However, this side effect is mainly present when patients take more than 1,100 mg a day.

In some human subjects, injections of 5 mg of Lf(1-11) may increase liver enzymes. Other side effects like diarrhea, dizziness, flatulence, and headache were observed but were not significantly different from the placebo group [63]. A larger study will be needed to observe the safety of Lf(1-11) injection in humans.

If iron levels are normal or above normal patients should avoid taking it to prevent excess iron in the blood.

Bioavailability

Pharmacokinetics

Lactoferrin is a very stable protein since it is typically present in the fluids that function as a protective barrier for the body. In addition, when ingested, it has to survive the digestive tract in order to reach the immune system.

Lactoferrin in Raw vs Pasteurized Milk

Lactoferrin is heat stable and may survive pasteurization, but not high-pressure treatment [64].

5 studies have shown that there is no significant reduction in lactoferrin levels in pasteurized milk comparing to raw milk, except for one study using UV-C pasteurization found that lactoferrin is significantly decreased after pasteurization [65].

In milk and colostrum, lactoferrin is at the concentration of 7g/L [66].

Digestion, Absorption, and Transportation

The structure of lactoferrin makes it more stable and resistant to digestion, even through harsh conditions like in the stomach.

About 60 – 80% of ingested lactoferrin from cow’s milk survives stomach digestion in humans depending on whether it is bound to iron [67].

Some lactoferrin is digested by stomach enzymes like pepsin. This digestion results in smaller proteins or peptides which have stronger antimicrobial activities than the protein itself. These peptides are more toxic to more types of bacteria. Pepsin-digested peptides of lactoferrin include [2]:

  • Lf(1-11) is the first 11 amino acids of lactoferrin. It is very positively charged, which allows it to interact with the bacterial cell membrane.
  • Lfcin is both positively charged and fat-soluble. It has antimicrobial and anti-cancer activities as it binds to lipopolysaccharides (LPS) or gram-negative bacteria and teichoic acid of gram-positive bacteria.
  • Lfampin is active against bacteria, yeasts, and parasites.

Injection of human-sourced) Lf(1-11) into humans does not result in their immune system developing antibodies against Lf(1-11) [63].

Lactoferrin and its peptides are absorbed either just through intestinal cells or through the Intelectin 1 receptor. It gets incorporated into the lymphatic system before entering systemic circulation. It can also be transported into the gut immune system [68].

Once lactoferrin enters systemic circulation, it is cleared rapidly by the liver [69].

https://www.ncbi.nlm.nih.gov/pubmed/26981846, image from Servier Medical Art

https://www.ncbi.nlm.nih.gov/pubmed/26981846, image from Servier Medical Art

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