Summary
Lactoferrin, found in human and mammalian milk, is a multifunctional glycoprotein with multiple functions, such as immune regulation, anti-inflammatory, antibacterial, antiviral, and antioxidant. These functions are largely attributed to its high affinity for iron. It belongs to the transferrin family of proteins and is the main iron-binding protein in human milk. In addition, it has no toxicity and is compatible with the intake of other nutrients, including dietary supplements.
This review summarizes the most relevant aspects of the mechanisms of action, biological function and metabolism of lactoferrin. It describes the different dietary sources of lactoferrin (including dietary supplements) and provides recommendations on lactoferrin intake for health and optimizing physical performance in physically active individuals, including endurance, strength, and power athletes.
The available evidence suggests that oral lactoferrin supplementation may have a beneficial impact on health and physical performance, particularly in physically active individuals performing resistance training. Lactoferrin is a safe and well-tolerated supplement. It prevents gastric discomfort associated with oral iron supplementation. An effective dose to support health and physical performance capacity in healthy individuals ranges from 100 to 200 mg daily, taken in one or two daily doses of 100 mg each, for a period of 1 to 3 months.
Introduction
Lactoferrin (formerly known as lactotransferrin) is a glycoprotein with a molecular weight of about 80 kDa, which shows a high affinity for iron.1 It belongs to the transferrin family of proteins and is the main iron-binding protein in human milk. 2 Lactoferrin is produced and released by mucous epithelial cells and neutrophils in several mammalian species, including humans, cattle, cows, goats, horses, dogs, various rodents, and fish. 2
In addition to bovine milk and colostrum, where lactoferrin is in a concentration of 7 g/L, being the second most abundant protein after caseins, lactoferrin is found in tears, saliva, vaginal fluids, semen, nasal and bronchial secretions, bile, gastrointestinal fluids and urine. In addition, a considerable amount is found in the secondary granules of neutrophils (15 g/10⁶ neutrophils) and in other fluids such as blood plasma and amniotic fluid.2
Many studies have shown that lactoferrin is well tolerated in humans. 2 In fact, oral lactoferrin intake has been approved by the FDA (USA) and the European Food Safety Authority as a dietary supplement in food products. 3 However, as orally ingested lactoferrin is susceptible to peptic digestion in the stomach, it cannot easily access the digestive tract. To overcome this problem and improve the nutritional and, where applicable, therapeutic effect of lactoferrin, the use of microparticles or liposomes has been shown to enhance its action by increasing stability against gastric degradation and facilitating interaction with the intestinal membrane and with specific lactoferrin receptors. 4 As such, oral lactoferrin supplementation has aroused interest due to its multifaceted physiological and protective functions, including regulation of iron absorption in the gut; modulation of immune function, antioxidant, anti-inflammatory, antimicrobial, and anti-cancer effects. 2 These properties suggest that oral lactoferrin supplementation would positively impact health by optimizing physical performance and recovery in physically active people. 3
Key Mechanisms of Lactoferrin in the Human Body
Each lactoferrin molecule can bind two ferric ions (Fe³⁺), one in each of its two lobes, with an extremely high affinity. In fact, lactoferrin retains bound iron even at acidic pH (as low as 3–4), allowing it to regulate free iron levels by sequestering free iron in biological fluids and inflamed tissues.5 These properties give lactoferrin potent bacteriostatic and antioxidant functions: it deprives microbes of the iron they need to thrive and protects tissues from iron-catalyzed oxidative damage. 5 In fact, many of the biological activities of lactoferrin (antimicrobial, anti-inflammatory, etc.) are closely related to its ability to bind strongly and control iron availability. Thus, lactoferrin reduces hepcidin (a hormone that restricts the release of iron), being able to prevent iron deficiency anemia. 6 In addition, lactoferrin extracted from cattle and administered orally significantly increased its probiotic activity in both adults and infants, including those born prematurely. 2 Lactoferrin also exhibits potent antiviral activity against cytomegalovirus (CMV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV). The antiparasitic activity of oral lactoferrin appears to involve interference with iron acquisition in some parasites, e.g., Pneumocystis carinii, or acting as a specific iron donor in others, such as Tritrichomonas foetus. 2
Lactoferrin contributes to the absorption and distribution of iron in various compartments of the human body, including the small intestine. Specific lactoferrin receptors mediate the uptake of iron in enterocytes, which is absorbed without causing the pro-oxidant stress associated with free iron in the intestine. 7 In fact, the addition of bovine lactoferrin to the diet may improve iron absorption and iron status in infants and pregnant women. 8
Lactoferrin enters the bloodstream and is able to reach bile and cerebrospinal fluid. It can cross the blood-brain barrier through transport mediated by specific receptors, delivering iron to the brain in a regulated manner. 9 Lactoferrin helps maintain the systemic balance of iron, acting as an iron transporter that complements the function of transferrin (the main iron transporter in plasma). Lactoferrin can take up iron at one site and, through specific receptors, deposit it at another, thus helping to distribute iron to where it is needed while keeping it away from pathogens or catalytic reactions. Thus, lactoferrin provides an additional layer of control over iron homeostasis on mucosal surfaces and within certain tissues. 10
Lactoferrin is a key mediator of nutritional immunity, with potent nutraceutical, immunomodulatory, and anti-inflammatory effects. 2 Since almost all pathogens require iron to replicate, lactoferrin's high affinity for iron constitutes a powerful antimicrobial mechanism for sequestering free iron in secretions and inflamed tissues, effectively depriving bacteria and fungi of this essential element. 11 It should be noted that in athletes, lactoferrin supplementation has been shown to reduce pro-inflammatory cytokines such as interleukin-6 (IL-6), indicating a decrease in systemic inflammation that is associated with better recovery between workouts.12 In addition, lactoferrin can also act as a prebiotic and support gut integrity. Peptides released from lactoferrin digestion promote the growth of beneficial gut bacteria (e.g., Bifidobacteria and Lactobacilli). A healthy gut microbiota and an intact gut barrier are vital for nutrient absorption, reducing exercise-induced gastrointestinal discomfort, indirectly benefiting performance by ensuring effective nutrient absorption in athletes. 13
The available evidence suggests that lactoferrin is an immunomodulatory agent that balances effective antimicrobial activity with the control of inflammation. By depriving microbes of iron, it limits oxidative damage and optimizes cytokine responses. Lactoferrin serves as a critical link between iron metabolism and immune function in humans. 11 In addition, lactoferrin may optimize performance (especially in endurance athletes) and recovery by attenuating exercise-related iron deficiency, inflammation, oxidative stress, and infections. 12
Dietary Sources of Lactoferrin
Bovine milk and colostrum products are the main natural dietary sources of lactoferrin. In colostrum (the first milk after birth), lactoferrin concentrations are very high (several grams per litre) and remain around 1–2 g/L in breast milk.14 Lactoferrin is a component of the whey protein fraction in all mammalian milk, but its lactoferrin content is lower compared to human milk. 14For example, cow's milk provides about 0,1–0,3 g/L of lactoferrin in standard mature milk, although bovine colostrum may have higher levels (~2–5 g/L) before declining after the first few days of lactation.15 Fermented dairy products (yogurt, cheese) may still contain some lactoferrin, but high-temperature heat treatments used in dairy processing (e.g., high-temperature pasteurization or milk powder production) can denature some of the lactoferrin.
Lactoferrin supplementation
The vast majority of lactoferrin supplements are obtained from bovine milk. Lactoferrin can be extracted by filtration and ion exchange chromatography techniques from skimmed cow's milk or whey derived from the manufacture of cheeses on a large scale. 16 The captured lactoferrin is eluted (e.g. using saline solutions), then the protein is purified, concentrated and dried into a high-purity powder (>95% pure protein) derived from bovine lactoferrin.16 In addition to extraction from bovine milk, colostrum products (powder or capsules) represent another commercial source of lactoferrin. 17 Purified lactoferrin for pharmaceutical/nutraceutical use is predominantly obtained from conventional cow's milk due to the large volumes available and established processing methods. Another form of lactoferrin is recombinant, which is obtained from the lactoferrin gene inserted into an expression system such as microbes, cell cultures or transgenic animals. Lactoferrin is thus synthesized in a controlled environment. This allows the production of human lactoferrin, produced particularly for therapeutic purposes, without the need for extractions from breast milk. Studies have confirmed that recombinant lactoferrin from transgenic cow's milk exhibits biological activities comparable to those of natural human lactoferrin. 18
It is worth mentioning that bovine lactoferrin is safe (as mentioned above, EFSA approved it as a new food ingredient in Europe in 2012), while recombinant lactoferrin (especially if produced using novel methods such as transgenic plants or animals) is subject to rigorous safety assessments before approval.
Lactoferrin supplementation and physical performance: recommended protocols, safety and tolerance.
Due to its iron-binding capacity and its role as an immunomodulator, lactoferrin has been proposed as an effective nutritional supplement for physically active people, especially to optimize performance in endurance sports. 3,19 Since lactoferrin does not act like caffeine, acute intake of one or a few doses of lactoferrin has no immediate effect on health markers or physical performance. Its mechanisms (iron modulation and immunological effects) usually require time to influence immune status and performance. 20 In contrast, chronic supplementation for 8 to 12 weeks has shown benefits on iron stores (higher hemoglobin and ferritin levels), reduced inflammation [e.g., lower levels of interleukin 6 (IL-6) and hepcidin activity], and increased antioxidant capacity.20 These changes can prevent declines in performance associated with iron deficiency and excessive physical stress. 21
In healthy people training to improve aerobic endurance, a dose of ~100 mg (taken once daily, e.g. at breakfast or after training) lactoferrin intake has been shown to prevent serum iron depletion. Also, the intake of 200 mg (taken in two daily doses of 100 mg, one in the morning and one after training) is effective for those who have low ferritin or hemoglobin levels. Two to three months of supplementation may improve iron levels and may help maintain or increase VO₂ max in endurance athletes,22 either when lactoferrin is consumed alone or combined with low doses of iron (lactoferrin may amplify the positive effects of oral iron intake).21
In strength and power athletes, similar doses (e.g., 200 mg/day) are applied to support recovery and reduce inflammation induced by the accumulation of intense workouts.22 Higher doses (up to 400 mg/day, divided into two doses of 200 mg each) have been tested in special populations (patients) without safety concerns, although unless they are looking for additional benefits for the immune system or antioxidant, doses above 200 mg up to 400 mg/day are not usually necessary for most athletes who show acceptable levels of iron and hemoglobin. 20
A practical strategy for ingesting lactoferrin as a dietary supplement would be to start with ~100 mg/day and increase to 200 mg/day if a greater effect is desired. There is probably a "ceiling effect"; however, ultra-high doses (e.g., 1 gram/day) are not recommended outside of a specific medical setting. In fact, most commercial supplements provide between 100–300 mg per capsule.
In summary, lactoferrin is a safe and well-tolerated supplement. It avoids gastric discomfort associated with oral intake of traditional iron tablets and has no stimulant or hormonal effects. It can be consumed at high levels with no known health risks. Therefore, thanks to its high tolerability, lactoferrin does not usually require cycles or breaks for safety reasons. Some athletes periodize the use of lactoferrin, increasing the dose during intense training or phases of training at altitude (when iron needs and the risk of infections increase), and possibly stopping it during the off-season if the diet provides enough iron. Since lactoferrin is derived from food and is safe, its prolonged daily use is acceptable if benefits are perceived.
Conclusions
Oral lactoferrin supplementation can have a noticeable impact on health and physical performance. It has a superior safety profile than traditional iron supplements, with virtually no gastric discomfort. An effective dose for healthy people varies between 100 and 200 mg per day, in one daily dose or divided into two doses of 100 mg/day, for 1 to 3 months. Lactoferrin acts as a multifunctional support nutrient, supporting the immune system and antioxidant capacity, which in turn optimizes recovery, positively impacting physical training capacity positively impacting the improvement of performance in the long term.
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Author
Dr. Fernando Naclerio
Professor of Strength Training and Sports Nutrition
Centre for Exercise Activity and Rehabilitation
Institute for Lifecourse Development
School of Human Sciences
University of Greenwich
Contact email: f.j.naclerio@gre.ac.uk
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