Lactoferrin in food and supplements and health benefits: state of the art and future directions

Anne Blais; Francois  Blachier

doi:10.55976/fnds.32025133025-36

Home /

Archives /

Journal of Food, Nutrition and Diet Science, Volume 3 Issue 1, 2025 /

Review

Lactoferrin in food and supplements and health benefits: state of the art and future directions

Anne Blais ¹ , François Blachier ²

1. UMR PNCA, Nutrition Physiology and Alimentary Behavior, Université Paris-Saclay, AgroParisTech, INRAE, Palaiseau, France
2. Former Research director at the National Research Institute for Agriculture, Alimentation and Environment , Paris-Saclay University, France

Correspondence: francois.blachier@agroparistech.fr

DOI: https://doi.org/10.55976/fnds.32025133025-36

Received

02 December 2024
Revised

17 February 2025
Accepted

20 February 2025
Published

28 February 2025

Lactoferrin Dietary supplementation Antimicrobial effects Inflammation Bone health

Abstract

<p>Lactoferrin, a protein well known for its iron-binding capacity, is abundant in colostrum but is less concentrated in mature milk. Lactoferrin is relatively resistant to the action of proteases in the gastrointestinal tract, especially in neonates, and a small proportion of lactoferrin can be absorbed in intact form. In randomized, controlled clinical trials, lactoferrin reduces invasive fungal infections in neonates and the prevalence of diarrhea in children. Lactoferrin receptors have been identified in different cell phenotypes, including notably intestinal and liver cells, osteoblasts and immune cells. Lactoferrin, which is generally recognized as safe (GRAS), has been shown in experimental studies to have antibacterial, antifungal, antiviral and antiparasitic effects. Beneficial effects of lactoferrin in intestinal and liver inflammation have been reported in experimental situations. In addition, oral supplementation with lactoferrin appears to be beneficial in experimental situations of compromised bone health. The present review recapitulates the effects of lactoferrin on target tissues in experimental and clinical situations. The present results highlight future research directions aimed at testing the potential utilization of this alimentary compound in different contexts.</p>

<h5>Introduction</h5>
<p>Lactoferrin is a glycosylated globular protein that belongs to the transferrin family with iron-binding capacity <a href="#reference_list_0">[1-3]</a>. Lactoferrin is present at relatively high concentration in maternal colostrum (~ 6 mg/mL) and consumed immediately by newborns after birth <a href="#reference_list_3">[4]</a>. In mother’s mature milk, the concentration of lactoferrin is generally lower, averaging between 2 and 3 mg of lactoferrin per mL of milk <a href="#reference_list_4">[5]</a>. Infant milk formulas generally contain much lower amounts of lactoferrin (i.e. 0.1 mg/mL) when compared to mother’s mature milk <a href="#reference_list_5">[6]</a>.  As other proteins found in mammalian milk, lactoferrin is sensitive to denaturation caused by infant formula processing, such as heat treatment <a href="#reference_list_6">[7-8]</a>, which has led to the development of minimally processed infant formula <a href="#reference_list_8">[9-10]</a>.</p>
<p>Lactoferrin is one of the major whey proteins and is found in bovine milk at a concentration of  ~  0.1 mg/mL <a href="#reference_list_10">[11]</a>. Lactoferrin is also found in exocrine secretory products other than milk, but this latter aspect will not be discussed in this review. The biological effects of lactoferrin have been studied in humans following consumption of this protein present in diet and/or in supplements in different situations, and the reported consequences of such consumption have generally been considered beneficial. Lactoferrin originating from bovine milk is used as a food additive that is generally recognized as safe (GRAS) by the United States Food and Drug Administration <a href="#reference_list_11">[12]</a>. The biological activities of lactoferrin rely on mechanisms of action that can be different depending on the targets considered.</p>
<p>The aim of this review is to provide an up-to-date overview of the published data obtained from clinical and experimental studies aiming at evaluating the effects of lactoferrin in different physiological and pathophysiological situations.</p>
<h5>1. Lactoferrin can withstand digestion in the gastrointestinal tract and be partiallyabsorbed in intact form</h5>
<p>Lactoferrin is only partially digested by pepsin in the stomach. This partial digestion releases peptides with antibiotic capacity called collectively lactoferricin <a href="#reference_list_12">[13]</a>. The biochemical properties of lactoferricin peptides enable them to interact with lipid compounds, as well as with negatively charged surfaces both of Gram-negative and Gram-positive bacteria, fungi, viruses and parasites, thus exerting antibacterial, antifungal, antiviral and antiparasitic effects <a href="#reference_list_13">[14-15]</a>. Four decades ago, it was shown that lactoferrin is relatively resistant to the exocrine enzymatic protease activities of the pancreas <a href="#reference_list_15">[16]</a>. A small proportion of lactoferrin is absorbed in its intact form by the intestine <a href="#reference_list_16">[17-18]</a>, and lactoferrin can be detected in the bloodstream after alimentary consumption <a href="#reference_list_18">[19]</a>. Although the exact amplitude of lactoferrin degradation in the gastrointestinal tract remains unclear, it has been found that substantial amounts of lactoferrin can stay intact during gastric transit. Gastric pH and the presence of other proteins such as β-lactoglobulin modulate the extent of degradation in the gastrointestinal tract <a href="#reference_list_19">[20-22]</a>. In fact, the timing of lactoferrin administration can modify its digestion, as the degradation of lactoferrin in gastric juice is different when it is administered prior or after a meal <a href="#reference_list_22">[23]</a>. Furthermore, lactoferrin degradation in the gastrointestinal tract may be different according to the developmental stages. For instance, lactoferrin is not extensively digested in the gastrointestinal tract of newborns, resulting in the recovery of this protein in feces <a href="#reference_list_23">[24]</a>. However, the amplitude of lactoferrin absorption remains debated <a href="#reference_list_24">[25]</a>, and it is assumed that approximately 10% of the lactoferrin present in the intestinal luminal fluid is absorbed <a href="#reference_list_17">[18]</a>. However, this latter value, which is based on in vitro tests and in vivo assays in animal models, represents only a rough estimation of the actual intestinal absorption. Encapsulated lactoferrin appears to be more resistant to gastrointestinal proteases, thus representing an interesting and promising way of administration <a href="#reference_list_25">[26]</a>. In healthy individuals, lactoferrin in the circulation is found in a concentration range between 2 and 7 µg/mL <a href="#reference_list_26">[27]</a>.</p>
<p>The presence of lactoferrin in the intestinal fluid and in the blood is consistent with the effects of this protein in several tissues, particularly in intestine, liver and bones. Lactoferrin performs various functions by binding to a wide range of receptors on target cells, resulting in a variety of biological responses. The target cells equipped with receptors to lactoferrin include intestinal epithelial cells <a href="#reference_list_27">[28-29]</a>, liver cells <a href="#reference_list_29">[30-31]</a>, osteoblasts <a href="#reference_list_31">[32]</a>, endothelial cells <a href="#reference_list_32">[33]</a>, fibroblasts <a href="#reference_list_33">[34]</a>, lymphocytes <a href="#reference_list_34">[35]</a>, macrophages <a href="#reference_list_35">[36]</a> and platelets <a href="#reference_list_36">[37]</a>.</p>
<h5>2. Lactoferrin displays numerous effects on the intestinal ecosystem</h5>
<p>The small and large intestines are well known to be inhabited by a complex mixture of microbes, among which bacteria have been the subject of most studies. The concentration of bacteria in the large intestine is in the range of 10<sup>9</sup><sup> </sup>to 10<sup>12</sup> colony-forming unit (CFU) per g of content. The spectacular increase in the concentration of bacteria in the large intestine is mainly due to the fact that the intestinal content is transported much more slowly in the large intestine than in the small intestine, allowing intense metabolism of the available substrates supplied by the host <a href="#reference_list_37">[38]</a>. This microbial population includes not only bacteria, but also archaea, viruses and fungi. Lastly, the protozoans in the intestine, although not classically included as part of the microbiota itself, represent a heterogeneous group of eukaryotic organisms, some of which are considered as parasites <a href="#reference_list_38">[39]</a>.</p>
<p>In numerous studies, it has been shown that lactoferrin, like lactoferricin (see above) can exert antibacterial, antiviral, antifungal and antiparasitic effects and contribute to the specific regulation of the immune response <a href="#reference_list_39">[40-42]</a>. Lactoferrin can modulate cytokine production by intestinal immune cells <a href="#reference_list_42">[43-44]</a>.</p>
<p>The antimicrobial effect of lactoferrin is mainly attributed to its capacity to bind iron and thus allowing reduction of its availability to bacteria. However, other mechanisms of action have been shown to be presumably involved in the antimicrobial effect of lactoferrin, such as the presence of lactoferrin receptors in bacteria <a href="#reference_list_44">[45]</a>, the capacity of lactoferrin to bind to bacterial cell walls, and thus to disrupt the integrity of bacteria, contributes to the bacterial death, as well as the direct interaction with Gram-negative bacteria leading to cell membrane damages <a href="#reference_list_1">[2, 46]</a>. Interestingly, lactoferrin has been shown for instance to affect <em>Helicobacter pylori</em> infection <a href="#reference_list_46">[47]</a>. It is also interesting to note that bovine holo-lactoferrin can retard the growth of the pathogenic bacteria <em>Clostridium difficile </em>and reduce the production of toxins by these bacteria in a model of bacterial infection <a href="#reference_list_47">[48]</a>. However, the global effects of lactoferrin on the intestinal bacteria composition and metabolic activity remain largely unknown <a href="#reference_list_48">[49]</a>. As recently investigated by Li and collaborators, lactoferrin appears to act not only on enteropathogenic bacteria, but also as a prebiotic that induces changes in the intestinal ecosystem characteristics and in host intestinal physiology <a href="#reference_list_49">[50]</a>. For instance, an experimental study with suckling piglets has shown that lactoferrin supplementation modifies the composition of the microbiota in the colon, an effect that was associated with an increased concentration of the bacterial metabolite butyrate in the colonic fluid and with an increased expression of genes involved in the maintenance of the colonic barrier function <a href="#reference_list_50">[51]</a>.</p>
<p>Regarding the antiviral effect of lactoferrin, this protein has been demonstrated to inhibit the growth of both DNA and RNA viruses, in particular human immunodeficiency virus (HIV), human cytomegalovirus (HCMV), rotavirus, respiratory syncytial virus and herpesviruses <a href="#reference_list_51">[52-53]</a>. Dietary supplementation with lactoferrin may represent an adjunctive treatment to medication for the treatment of viral infection <a href="#reference_list_53">[54]</a>. The mechanisms by which lactoferrin exerts its antiviral effect remains unclear, but interestingly, this protein has been shown to bind to receptors such as ACE2, which are used by SARS-CoV-2, thus reducing the attachment of the viral pathogen to the host cells <a href="#reference_list_54">[55-56]</a>. The fungicidal activity of lactoferrin has been shown against various Candida species, including <em>Candida albicans </em><a href="#reference_list_56">[57-58]</a>. Furthermore, the antiparasitic effect of lactoferrin has been demonstrated in vitro against the malaria parasite <em>Plasmodium falciparum </em><a href="#reference_list_58">[59]</a> and in vivo and in vitro against the protozoan parasite <em>Toxoplasma gondii</em> <a href="#reference_list_59">[60]</a>. Lastly, microbicidal effects of lactoferrin-derived peptides have been demonstrated against the parasite <em>Entamoeba histolytica</em> <a href="#reference_list_60">[61]</a>.</p>
<p>Lactoferrin is bioactive at different stages of development. In newborns, lactoferrin modulates the intestinal permeability and exerts a trophic effect on the mucosa <a href="#reference_list_61">[62]</a>. These effects have been similarly observed in an in vitro study and in an in vivo animal study <a href="#reference_list_62">[63-64]</a>. Furthermore, lactoferrin efficiently increases the proliferation and differentiation of intestinal cells in an in vivo rodent model and in an in vitro study with intestinal epithelial cells <a href="#reference_list_64">[65]</a>. Moreover, it was shown that the ingestion of lactoferrin by the mother during gestation and lactation promotes the early development of the pups in a rodent model <a href="#reference_list_65">[66]</a>. This latter effect on pups coincided with an increased differentiation of small intestine epithelial cell and an increased colon barrier function. The increased epithelial cell differentiation and the increased expression of genes coding for the tight-junction proteins were associated with higher plasma amino acid concentrations. In two randomized controlled trials, lactoferrin supplementation was found to exert beneficial effects on children by reducing the prevalence and severity of diarrhea <a href="#reference_list_66">[67]</a> and to prevent invasive infection in neonates <a href="#reference_list_67">[68]</a>. In the first trial which was randomized, controlled and double-blinded, 555 children enrolled at 12-18 months were given bovine lactoferrin (0.5 g twice a day) or placebo for six months (half children in the lactoferrin group and half children in the placebo group). Lactoferrin supplementation was associated with a reduction in the longitudinal prevalence of diarrhea (p = 0.0046), a reduction in the median duration of diarrhea episodes (p =0.0046), a reduction in liquid stool load (p < 0.001), and a reduction in episodes of dehydration (p = 0.0045) <a href="#reference_list_66">[67]</a>. In the second randomized controlled trial involving 472 neonates, it was found that 6 weeks administration of bovine lactoferrin (0.1 g/day) to very low birth weight infants reduced invasive fungal infections compared to the placebo group (p = 0.002) <a href="#reference_list_67">[68]</a>.  </p>
<h5>3. Lactoferrin exerts anti-inflammatory effects in situation of intestinal inflammation</h5>
<p>Oral administration of lactoferrin in animal models of colitis alleviates the symptoms of intestinal inflammation by modulating the immune system and reducing the production of pro-inflammatory cytokines in colonic tissue <a href="#reference_list_68">[69-71]</a>. In addition, lactoferrin and its derived peptides reduce the signs of colitis in mice when administered orally <a href="#reference_list_71">[72]</a>. Indeed, in this latter experiment, lactoferrin was able to reduce the presence of occult blood in the feces and the number of tumor necrosis factor alpha (TNF-α)-producing cells in the distal colon. Furthermore, in the model of colitis induced by dextran sulfate sodium (DSS), bovine lactoferrin was found to reduce inflammation and impairment of colonic epithelial barrier function <a href="#reference_list_72">[73]</a>. Interestingly, oral administration of a <em>Lactococcus lactis</em> strain that secretes lactoferrin-derived peptides was found to alleviate the development of acute colitis in mice <a href="#reference_list_73">[74]</a>.</p>
<p>Lactoferrin supplementation was also tested in a model of in vivo endotoxemia induced by administration of lipopolysaccharide (LPS) which is characterized by a systemic inflammatory response <a href="#reference_list_74">[75]</a>. LPSs are bacterial surface glycolipids produced by Gram-negative bacteria which can be transferred from the luminal intestinal fluid into the bloodstream. At the intestinal level, systemic administration of LPS increases intestinal permeability, epithelial cell apoptosis and shedding, while causing villus shortening and diarrhea <a href="#reference_list_75">[76-79]</a>. These effects of LPS are associated with reduced intestinal mucosa oxygen consumption and intestinal absorption of amino acids <a href="#reference_list_79">[80-81]</a>. Lactoferrin alleviates LPS-induced inflammation in different in vivo experimental models <a href="#reference_list_81">[82-85]</a>, and lactoferrin deficiency further aggravates LPS-induced inflammation <a href="#reference_list_85">[86]</a>. From a mechanistic point of view, lactoferrin and its derived peptides inhibit the secretion of pro-inflammatory cytokines through different actions, including sequestration of LPS <a href="#reference_list_86">[87-88]</a> and inhibition of the binding of nuclear transcription factor kappa B (NF-κB) to the TNF-α promoter following cellular uptake of lactoferrin <a href="#reference_list_88">[89]</a>. Lactoferrin can apparently bind directly to intact LPS <a href="#reference_list_89">[90]</a> and to bacterial LPS on the bacterial surface <a href="#reference_list_90">[91]</a>. Lactoferrin supplementation, when performed before LPS administration, has been recently shown to reduce the circulating concentration of the inflammatory cytokine TNF-α, improve intestinal permeability, and maintain the morphology of the intestinal mucosa <a href="#reference_list_89">[90]</a>.</p>
<p>Iron deficiency anemia is often associated with inflammatory bowel diseases <a href="#reference_list_91">[92]</a>. In a randomized clinical trial involving 80 children with anemia associated inflammatory bowel disease, it was found that lactoferrin (0.1 g/day) was more effective than ferrous sulfate (6mg/kg/day), when both supplements were administrated for 3 months, on blood hemoglobin (p < 0.001), serum iron (p < 0.001) and serum ferritin concentration (p = 0.006) <a href="#reference_list_92">[93]</a>.</p>
<p>Incidentally, the amount of lactoferrin in the feces is considered representative of activated neutrophil infiltration in the case of intestinal inflammation and thus represents a fecal marker for such inflammation <a href="#reference_list_93">[94]</a>. It has been shown that the amounts of lactoferrin released by neutrophils correlate with the severity of inflammation in the gastrointestinal tract <a href="#reference_list_94">[95]</a>. The respective prognostic value of lactoferrin and another fecal indicator, namely calprotectin, has been discussed <a href="#reference_list_95">[96]</a>. Although the lactoferrin release from neutrophils is endogenous but not from dietary origin in that case, the presence of lactoferrin in fecal material suggests that this protein is not extensively degraded by the intestinal microbiota.</p>
<h5>4. Lactoferrin exerts anti-inflammatory effects in situation of liver inflammation</h5>
<p>The fact that lactoferrin can bind to hepatocytes and in particular to plasma membranes, and that this protein can be taken up by liver cells <a href="#reference_list_96">[97-99]</a> has motivated studies on the effects of lactoferrin on the liver in different experimental situations in recent years. In mice receiving the contaminating mycotoxin deoxynivalenol, lactoferrin has anti-inflammatory and antioxidative effects on the liver by regulating nuclear factor-E2-related factor 2/mitogen-activated protein kinase (Nrf2/MAPK) signaling pathways <a href="#reference_list_99">[100]</a>. In a rodent model of non-alcoholic steatohepatitis, lactoferrin prevents hepatic fibrosis via the inhibition of NF-κB signaling <a href="#reference_list_100">[101]</a>. In another model of liver damage provoked by acute alcohol consumption, lactoferrin was shown to improve the redox-stress response and thus to reduce liver damage <a href="#reference_list_101">[102]</a>. The beneficial effects of lactoferrin on liver injury induced by ethanol consumption have been shown to be associated with nuclear translocation of Nrf2 in a rat model <a href="#reference_list_102">[103]</a>.</p>
<p>Beneficial effects of lactoferrin were also recorded in models of liver injury induced by adverse dietary conditions. Xiong and collaborators have shown that lactoferrin attenuates high-fat diet-induced hepatic steatosis by limiting hepatic lipogenesis in association with a reduction in inflammatory state <a href="#reference_list_103">[104]</a>. Finally, Liu and collaborators have obtained encouraging results regarding the use of lactoferrin-producing bacteria in case of liver injury <a href="#reference_list_104">[105]</a>. Indeed, lactoferrin produced by lactic acid bacteria was found to be beneficial in mice with non-alcoholic fatty liver disease, since it diminished the hepatic steatosis in such experimental situation.</p>
<h5>5. Lactoferrin exerts beneficial effects on bones</h5>
<p>Using ovariectomized mice as a model for the postmenopause, Blais and collaborators found that this protein was recovered in the peripheral blood after ingesting lactoferrin in the diet, thus being partially absorbed. Such supplementation allows to ameliorate bone mineral density and to increase the strength on the femurs <a href="#reference_list_105">[106]</a>. In this latter study, lactoferrin stimulated the growth and differentiation of osteoblastic cells while reducing the growth of preosteoclastic cells. These beneficial effects of lactoferrin on bone physiology were found to be associated with modulation of lymphocyte activation and cytokine release in the bone microenvironment. This suggests that lactoferrin exerts its beneficial effects on postmenopausal bone loss partly by modulating immune functions <a href="#reference_list_106">[107]</a>. Lactoferrin increases the proliferation of osteoblast-like cells as shown by thymidine incorporation into these cells, as well as their differentiation. Furthermore, lactoferrin reduces the apoptosis of osteoblast-like cell and at the same time reduces osteoclastogenesis <a href="#reference_list_107">[108]</a>. In vitro, lactoferrin enhanced osteogenesis of adipose-derived stem cells <a href="#reference_list_108">[109]</a>. Lactoferrin-derived peptides treated with pepsin have been shown to stimulate osteoblast proliferation <a href="#reference_list_109">[110]</a>, indicating that lactoferrin-derived peptides may be involved in the overall beneficial effects of lactoferrin on bone physiology. Finally, in the rat model, bone mineral density was higher in pups from mothers who received the lactoferrin supplements during gestation and lactation periods than in their counterparts in control group <a href="#reference_list_65">[66]</a>, which suggests that the dietary consumption of lactoferrin by mothers has beneficial effects on bone physiology in offspring.</p>
<p>In a recent study, using a new experimental model of ovariectomized mice with moderate dietary protein restriction, Blais and collaborators have shown that oral supplementation with lactoferrin significantly improves bone properties in this model characterized by severely impaired bone quality <a href="#reference_list_110">[111]</a>, while such supplementation was found effective in maintaining bone mass and microarchitecture in ovariectomized rats <a href="#reference_list_111">[112]</a>. The in vitro and in vivo experimental studies on the effects of lactoferrin on bone cells and bone properties suggest potential therapeutic effects of this protein and its derived peptides for some bone-related diseases including osteoporosis <a href="#reference_list_112">[113]</a>. Lactoferrin signaling in osteoblasts includes low density lipoprotein receptor-related protein-1 (LRP-1), transforming growth factor-β (TGF-β) and insulin-like growth factor-1 (IGF-1), which activate downstream pathways such as extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and NF-κB that are involved in osteoblast proliferation, differentiation and mineralization <a href="#reference_list_112">[113]</a>.</p>
<h5>6. Conclusion and future directions</h5>
<p>The available experimental arguments indicate that lactoferrin is bioactive in different situations on different prokaryotic and eukaryotic cells, including bacteria, fungi, parasites, intestinal and hepatic cells, and bone cells; and the effects obtained are generally considered as beneficial. Figure 1 summarizes the main beneficial effects of lactoferrin.</p>
<p><img src="https://file.luminescience.cn/67c1509518e741740722325" alt="" width="550" height="380" /></p>
<p><strong>Figure 1. </strong>Schematic representation of the main beneficial effects of lactoferrin</p>
<p>However, it is obvious that further research is needed to convert the promising results obtained from experimental works with animal and cell models into applications in real life. The proposed research directions are presented in Table 1.</p>
<p><img src="https://file.luminescience.cn/67c150f18be3c1740722417" alt="" width="800" height="335" /></p>
<p>First, as indicated in Table 1, we need to know more about the distribution of ingested lactoferrin between the intestinal luminal fluid and the bloodstream according to the dose of lactoferrin used. Such results will help us to understand the origin of lactoferrin, either from the intestinal contents or from the bloodstream, for the observed effects. In particular, it would be much helpful to determine the concentration of lactoferrin in the small and large intestine after dietary supplementation. If as some experimental studies suggest, lactoferrin is partially resistant to proteases in the gastrointestinal tract, it can be assumed that part of the lactoferrin is transferred from the small to the large intestine through the ileocecal junction. The resistance of lactoferrin to proteases of the intestinal microbiota also needs to be tested. In pre-clinical experimental studies with rodents and pigs, different doses of orally administrated bovine lactoferrin could be tested for the concentration of lactoferrin and its degradation products in blood and luminal fluid obtained from the different parts of the small and large intestine at different time points after oral ingestion.  Indeed, rodents and pigs are a useful model for studies on the effects of dietary supplementation on metabolic and physiological parameters <a href="#reference_list_113">[114]</a>. Randomized, controlled clinical studies with increasing doses of oral lactoferrin and assay of lactoferrin in feces and blood in healthy subjects will be obviously also useful to answer this question.</p>
<p>We also need to better know the effects of lactoferrin in oral supplements on microbiota composition and metabolic activity. Although the available results clearly indicate an antimicrobial effect of lactoferrin, we do not know the effects of increasing amounts of oral lactoferrin on fecal microbiota composition and metabolic activity. The efficacy of lactoferrin in the cases of infection with pathogenic bacteria, fungi, viruses and parasites could usefully be tested in animal models. Animal models of infection with these microbes could be tested for the efficacy of different doses of orally delivered lactoferrin on microbial infection kinetics. The encouraging results obtained after oral supplementation with lactoferrin in experimental intestinal inflammation and liver steatosis motivate the test of the utilization of lactoferrin as an additional treatment in clinical trials with volunteers prone to chronic inflammation of the intestinal mucosa and liver injury. Although it is obvious that lactoferrin per se cannot substitute for pharmacological treatment in patients with steatosis or chronic inflammatory bowel diseases, lactoferrin supplementation may prove effective as an adjunctive therapy in future randomized, controlled clinical trials.</p>
<p>The effects of oral supplementation with lactoferrin on bone properties in experimental studies urge for testing this protein in clinical situations of impaired (and risk of impaired) bone health. For instance, it would be of interest to test the effect of different doses of orally delivered bovine lactoferrin in volunteers prone to osteoporosis. The potential synergistic effects of lactoferrin with other dietary components such as total dietary proteins, calcium and vitamin D also remains to be tested in experimental and clinical trials. Interestingly, in the mouse model, lactoferrin supplementation enhances the expression of the vitamin D receptor in bone, an effect associated with increased bone mineral density <a href="#reference_list_114">[115]</a>. These results raise the view that lactoferrin and vitamin D may act in synergy to promote bone health.</p>
<p>Secondly, progress in the identification of lactoferrin-derived peptides and their biochemical (heat resistance, resistance to bacterial proteases) and physiological properties (absorption through the intestinal epithelium, dose-response curves on pathophysiological parameters) would help to select the most efficient peptides in given situations of inflammatory states, allowing then the tests of the efficacy of these compounds in experimental and clinical studies.</p>
<p>Finally, it should be noted that the absorption and bioavailability of lactoferrin may be different in different subpopulations such as the newborn, infant and the elderly, but little information is available on that topic <a href="#reference_list_115">[116]</a>. Furthermore, still limited evidence is available from clinical trials on the biological effects of lactoferrin since most of studies published are related to experimental preclinical studies. Lastly, possible side effects of lactoferrin supplementation need to be considered and investigated to fully evaluate the potential of lactoferrin in clinical applications in the different situations mentioned above.</p>
<h5>Conflict of interest</h5>
<p>The authors declare there is no conflict of interest.</p>
<h5>Authors' contribution</h5>
<p>Both authors participated equally in the writing of this review.</p>
<h5>Acknowledgments</h5>
<p>The authors wish to thank INRAE, Université Paris-Saclay and AgroParisTech for their continual support.</p>
<h5>Funding information</h5>
<p>No financial support was sollicitated for this review.</p>

References

[1]González-Chávez SA, Arévalo-Gallegos S, Rascón-Cruz Q. Lactoferrin: structure, function and applications. International Journal of Antimicrobial Agents. 2009; 33(4): 301.e1-8. doi: 10.1016/j.ijantimicag.2008.07.020.

[2]Ashraf MF, Zubair D, Bashir MN, Alagawany M, Ahmed S, Shah QA, Buzdar JA, Arain MA. Nutraceutical and health-promoting potential of lactoferrin, an iron-binding protein in human and animal: current knowledge. Biological Trace Element Reseach. 2024; 202(1): 56-72. doi: 10.1007/s12011-023-03658-4.

[3]Zhang Y, Lu C, Zhang J. Lactoferrin and its detection methods : a review. Nutrients. 2021; 13(8):2492. doi: 10.3390/nu13082492.

[4]Montagne P, Cuillière ML, Molé C, Béné MC, Faure G. Changes in lactoferrin and lysozyme levels in human milk during the first twelve weeks of lactation. Advances in Experimental Medicine and Biology. 2001; 501:241-247. doi: 10.1007/978-1-4615-1371-1_30.

[5]Czosnykowska-Łukacka M, Orczyk-Pawiłowicz M, Broers B, Królak-Olejnik B. Lactoferrin in human milk of prolonged lactation. Nutrients. 2019; 11(10): 2350. doi: 10.3390/nu11102350.

[6]Satué-Gracia MT, Frankel EN, Rangavajhyala N, German JB. Lactoferrin in infant formulas: effect on oxidation. Journal of Agriculture and Food Chemistry. 2000; 48(10):4984-4990. doi: 10.1021/jf0002490.

[7]Manzardo OA, Toll LJ, Müller K, Nickel E, Jonas D, Baumgartner J, Wenzel F, Klotz D. A novel heat treatment protocol for human milk. Frontiers in Pediatry. 2022;10:990871. doi: 10.3389/fped.2022.990871.

[8]Wang B, Timilsena YP, Blanch E, Adhikari B. Lactoferrin: Structure, function, denaturation and digestion. Critical Reviews in Food Science and Nutrition. 2019; 59(4):580-596. doi: 10.1080/10408398.2017.1381583.

[9]Yu X, Leconte N, Méjean S, Garric G, Even S, Henry G, Tessier FJ, Howsam M, Croguennec T, Gésan-Guiziou G, Dupont D, Jeantet R, Deglaire A. Semi-industrial production of a minimally processed infant formula powder using membrane filtration. Journal of Dairy Science. 2021; 104(5): 5265-5278. doi: 10.3168/jds.2020-19529.

[10]Calvez J, Blais A, Deglaire A, Gaudichon C, Blachier F, Davila AM. Minimal processed infant formula vs. conventional shows comparable protein quality and increased postprandial plasma amino acid kinetics in rats. British Journal of Nutrition. 2024; 131(7):1115-1124. doi: 10.1017/S0007114523002696.

[11]Sánchez L, Aranda P, Pérez MD, Calvo M. Concentration of lactoferrin and transferrin throughout lactation in cow's colostrum and milk. Biological Chemistry Hoppe Seyler. 1988; 369(9):1005-1008. doi: 10.1515/bchm3.1988.369.2.1005.

[12]Superti F. Lactoferrin from bovine milk: a protective companion for life. Nutrients. 2020; 12(9):2562. doi: 10.3390/nu12092562.

[13]Wu J, Zang M, Wang S, Qiao X, Zhao B, Bai J, Zhao Y, Shi Y. Lactoferricin, an antimicrobial motif derived from lactoferrin with food preservation potential. Critical Reviews in Food Science and Nutrition. 2024; 64(25): 9032-9044. doi: 10.1080/10408398.2023.2207650.

[14]Zarzosa-Moreno D, Avalos-Gómez C, Ramírez-Texcalco LS, Torres-López E, Ramírez-Mondragón R, Hernández-Ramírez JO, Serrano-Luna J, de la Garza M. Lactoferrin and its derived peptides: an alternative for combating virulence mechanisms developed by pathogens. Molecules. 2020; 25(24): 5763. doi: 10.3390/molecules25245763.

[15]Drago-Serrano ME, Campos-Rodriguez R, Carrero JC, de la Garza M. Lactoferrin and peptide-derivatives: antimicrobial agents with potential use in nonspecific immunity modulation. Current Pharmaceutical Design. 2018; 24(10):1067-1078. doi: 10.2174/1381612824666180327155929.

[16]Brines RD, Brock JH. The effect of trypsin and chymotrypsin on the in vitro antimicrobial and iron-binding properties of lactoferrin in human milk and bovine colostrum. Unusual resistance of human apolactoferrin to proteolytic digestion. Biochimica et Biophysica Acta. 1983; 759(3):229-235. doi: 10.1016/0304-4165(83)90317-3.

[17]Li W, Liu B, Lin Y, Xue P, Lu Y, Song S, Li Y, Szeto IM, Ren F, Guo H. The application of lactoferrin in infant formula: The past, present and future. Critical Reviews in Food Science and Nutrition. 2024; 64(17):5748-5767. doi: 10.1080/10408398.2022.2157792.

[18]Manzoni P. Clinical benefits of lactoferrin for infants and children. The Journal of Pediatrics. 2016; 173 Suppl:S43-S52. doi: 10.1016/j.jpeds.2016.02.075.

[19]Fischer R, Debbabi H, Blais A, Dubarry M, Rautureau M, Boyaka PN, Tome D. Uptake of ingested bovine lactoferrin and its accumulation in adult mouse tissues. International Journal of Immunopharmacology. 2007; 7(10):1387-1393. doi: 10.1016/j.intimp.2007.05.019.

[20]Furlund CB, Ulleberg EK, Devold TG, Flengsrud R, Jacobsen M, Sekse C, Holm H, Vegarud GE. Identification of lactoferrin peptides generated by digestion with human gastrointestinal enzymes. Journal of Dairy Science. 2013; 96(1): 75-88. doi: 10.3168/jds.2012-5946.

[21]Troost FJ, Steijns J, Saris WH, Brummer RJ. Gastric digestion of bovine lactoferrin in vivo in adults. The Journal of Nutrition. 2001; 131(8):2101-2104. doi: 10.1093/jn/131.8.2101.

[22]Xiong L, Boeren S, Vervoort J, Hettinga K. Effect of milk serum proteins on aggregation, bacteriostatic activity and digestion of lactoferrin after heat treatment. Food Chemistry. 2021; 337:127973. doi: 10.1016/j.foodchem.2020.127973.

[23]Rosa L, Lepanto MS, Cutone A, Siciliano RA, Paesano R, Costi R, Musci G, Valenti P. Influence of oral administration mode on the efficacy of commercial bovine Lactoferrin against iron and inflammatory homeostasis disorders. Biometals. 2020; 33(2-3):159-168. doi: 10.1007/s10534-020-00236-2.

[24]Spik G, Brunet B, Mazurier-Dehaine C, Fontaine G, Montreuil J. Characterization and properties of the human and bovine lactotransferrins extracted from the faeces of newborn infants. Acta Paediatr Scand. 1982; 71(6):979-85. doi: 10.1111/j.1651-2227.

[25]Teraguchi S, Wakabayashi H, Kuwata H, Yamauchi K, Tamura Y. Protection against infections by oral lactoferrin: evaluation in animal models. Biometals. 2004; 17(3):231-4. doi: 10.1023/b:biom.0000027697.83706.32.

[26]Yao X, Bunt C, Cornish J, Quek SY, Wen J. Preparation, optimization and characterization of bovine lactoferrin-loaded liposomes and solid lipid particles modified by hydrophilic polymers using factorial design. Chemical Biology & Drug Design. 2014; 83(5): 560-575. doi: 10.1111/cbdd.12269.

[27]Naot D, Grey A, Reid IR, Cornish J. Lactoferrin--a novel bone growth factor. Clinical Medicine Research. 2005; 3(2): 93-101. doi: 10.3121/cmr.3.2.93.

[28]Suzuki YA, Lopez V, Lönnerdal B. Mammalian lactoferrin receptors: structure and function. Cellular and Molecular Life Sciences. 2005; 62(22): 2560-2575. doi: 10.1007/s00018-005-5371-1.

[29]Takayama Y, Aoki R, Uchida R, Tajima A, Aoki-Yoshida A. Role of CXC chemokine receptor type 4 as a lactoferrin receptor. Biochemistry and Cell Biology. 2017; 95(1): 57-63. doi: 10.1139/bcb-2016-0039.

[30]Ziere GJ, Bijsterbosch MK, van Berkel TJ. Removal of 14 N-terminal amino acids of lactoferrin enhances its affinity for parenchymal liver cells and potentiates the inhibition of beta- very low density lipoprotein binding. Journal of Biological Chemistry. 1993; 268(36):27069-27075.

[31]Bennatt DJ, McAbee DD. Identification and isolation of a 45-kDa calcium-dependent lactoferrin receptor from rat hepatocytes. Biochemistry. 1997; 36(27):8359-8366. doi: 10.1021/bi963078u.

[32]Grey A, Banovic T, Zhu Q, Watson M, Callon K, Palmano K, Ross J, Naot D, Reid IR, Cornish J. The low-density lipoprotein receptor-related protein 1 is a mitogenic receptor for lactoferrin in osteoblastic cells. Molecular Endocrinology. 2004; 18(9):2268-2278. doi: 10.1210/me.2003-0456.

[33]Baveye S, Elass E, Fernig DG, Blanquart C, Mazurier J, Legrand D. Human lactoferrin interacts with soluble CD14 and inhibits expression of endothelial adhesion molecules, E-selectin and ICAM-1, induced by the CD14-lipopolysaccharide complex. Infection and Immunity. 2000; 68(12):6519-6525. doi: 10.1128/IAI.68.12.6519-6525.2000.

[34]Takayama Y, Takahashi H, Mizumachi K, Takezawa T. Low density lipoprotein receptor-related protein (LRP) is required for lactoferrin-enhanced collagen gel contractile activity of human fibroblasts. Journal of Biological Chemistry. 2003; 278(24):22112-22118. doi: 10.1074/jbc.M300894200.

[35]Mazurier J, Legrand D, Leveugle B, Rochard E, Montreuil J, Spik G. Study on the binding of lactotransferrin (lactoferrin) to human PHA-activated lymphocytes and non-activated platelets. Localisation and description of the receptor-binding site. Advances in Experimental Medicine and Biology. 1994; 357:111-119. doi: 10.1007/978-1-4615-2548-6_11.

[36]Curran CS, Demick KP, Mansfield JM. Lactoferrin activates macrophages via TLR4-dependent and -independent signaling pathways. Cellular Immunology. 2006; 242(1):23-30. doi: 10.1016/j.cellimm.2006.08.006.

[37]Leveugle B, Mazurier J, Legrand D, Mazurier C, Montreuil J, Spik G. Lactotransferrin binding to its platelet receptor inhibits platelet aggregation. European Journal of Biochemistry. 1993; 213(3):1205-1211. doi: 10.1111/j.1432-1033.1993.tb17871.x.

[38]Blachier F, Kong X. Metabolism of alimentary compounds by the intestinal microbiota and consequences for gut health. Journal of Food, Nutrition and Diet Science. 2023;1(1):3-19. doi: https://doi.org/10.55976/.

[39]Burgess SL, Gilchrist CA, Lynn TC, Petri WA Jr. Parasitic protozoa and interactions with the host intestinal microbiota. Infection and Immunity. 2017; 85(8):e00101-17. doi: 10.1128/IAI.00101-17.

[40]Actor JK, Hwang SA, Kruzel ML. Lactoferrin as a natural immune modulator. Current Pharmaceutical Design. 2009; 15(17):1956-1973. doi: 10.2174/138161209788453202.

[41]Kawasaki Y, Sato K, Shinmoto H, Dosako S. Role of basic residues of human lactoferrin in the interaction with B lymphocytes. Bioscience Biotechnology and Biochemistry. 2000; 64(2):314-318. doi: 10.1271/bbb.64.314.

[42]Legrand D, Elass E, Carpentier M, Mazurier J. Lactoferrin: a modulator of immune and inflammatory responses. Cellular and Molecular Life Sciences. 2005; 62(22):2549-2559. doi: 10.1007/s00018-005-5370-2.

[43]Takakura N, Wakabayashi H, Yamauchi K, Takase M. Influences of orally administered lactoferrin on IFN-gamma and IL-10 production by intestinal intraepithelial lymphocytes and mesenteric lymph-node cells. Biochemistry and Cell Biology. 2006; 84(3):363-368. doi: 10.1139/o06-056.

[44]Sfeir RM, Dubarry M, Boyaka PN, Rautureau M, Tomé D. The mode of oral bovine lactoferrin administration influences mucosal and systemic immune responses in mice. Journal of Nutrition. 2004; 134(2):403-409. doi: 10.1093/jn/134.2.403.

[45]Ostan NKH, Moraes TF, Schryvers AB. Lactoferrin receptors in Gram-negative bacteria: an evolutionary perspective. Biochemistry and Cell Biology. 2021; 99(1):102-108. doi: 10.1139/bcb-2020-0079.

[46]Ellison RT 3rd, Giehl TJ, LaForce FM. Damage of the outer membrane of enteric gram-negative bacteria by lactoferrin and transferrin. Infection and Immunity. 1988; 56(11):2774-2781. doi: 10.1128/iai.56.11.2774-2781.1988.

[47]Imoto I, Yasuma T, D'Alessandro-Gabazza CN, Oka S, Misaki M, Horiki N, Gabazza EC. Antimicrobial effects of lactoferrin against Helicobacter pylori infection. Pathogens. 2023; 12(4):599. doi: 10.3390/pathogens12040599.

[48]Chilton CH, Crowther GS, Śpiewak K, Brindell M, Singh G, Wilcox MH, Monaghan TM. Potential of lactoferrin to prevent antibiotic-induced Clostridium difficile infection. Journal of Antimicrobial Chemotherapy. 2016; 71(4):975-985. doi: 10.1093/jac/dkv452.

[49]Conesa C, Bellés A, Grasa L, Sánchez L. The role of lactoferrin in intestinal health. Pharmaceutics. 2023;15(6):1569. doi: 10.3390/pharmaceutics15061569.

[50]Li B, Zhang B, Zhang F, Liu X, Zhang Y, Peng W, Teng D, Mao R, Yang N, Hao Y, Wang J. Interaction between Dietary Lactoferrin and Gut Microbiota in Host Health. Journal of Agricultural and Food Chemistry. 2024; 72(14):7596-7606. doi: 10.1021/acs.jafc.3c09050.

[51]Hu P, Zhao F, Wang J, Zhu W. Early-life lactoferrin intervention modulates the colonic microbiota, colonic microbial metabolites and intestinal function in suckling piglets. Applied Microbiology and Biotechnology. 2020; 104(14):6185-6197. doi: 10.1007/s00253-020-10675-z.

[52]Florisa R, Recio I, Berkhout B, Visser S. Antibacterial and antiviral effects of milk proteins and derivatives thereof. Current Pharmceutical Design. 2003; 9(16): 1257-1275. doi: 10.2174/1381612033454810.

[53]van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK. Antiviral activities of lactoferrin. Antiviral Research. 2001; 52(3): 225-239. doi: 10.1016/s0166-3542(01)00195-4.

[54]Azam MS, Islam MN, Wahiduzzaman M, Alam M, Dhrubo AAK. Antiviral foods in the battle against viral infections: Understanding the molecular mechanism. Food Science & Nutrition. 2023;11(8): 4444-4459. doi: 10.1002/fsn3.3454.

[55]Miotto M, Di Rienzo L, Bò L, Boffi A, Ruocco G, Milanetti E. Molecular mechanisms behind anti SARS-CoV-2 action of lactoferrin. Frontiers in Molecular Biosciences. 2021; 8:607443. doi: 10.3389/fmolb.2021.607443.

[56]Salaris C, Scarpa M, Elli M, Bertolini A, Guglielmetti S, Pregliasco F, Blandizzi C, Brun P, Castagliuolo I. Protective Effects of Lactoferrin against SARS-CoV-2 Infection In Vitro. Nutrients. 2021; 13(2):328. doi: 10.3390/nu13020328.

[57]Velliyagounder K, Rozario SD, Fine DH. The effects of human lactoferrin in experimentally induced systemic candidiasis. Journal of Medical Microbiology. 2019; 68(12):1802-1812. doi: 10.1099/jmm.0.001098.

[58]Krupińska AM, Bogucki Z. Lactoferrin as a potential therapeutic for the treatment of Candida-associated denture stomatitis. Journal of Oral Biosciences. 2024; 66(2):308-313. doi: 10.1016/j.job.2024.05.007.

[59]Fritsch G, Sawatzki G, Treumer J, Jung A, Spira DT. Plasmodium falciparum: inhibition in vitro with lactoferrin, desferriferrithiocin, and desferricrocin. Experimental Parasitology. 1987; 63(1):1-9. doi: 10.1016/0014-4894(87)90072-5.

[60]Orsi N. The antimicrobial activity of lactoferrin: current status and perspectives. Biometals. 2004; 17(3):189-196. doi: 10.1023/b:biom.0000027691.86757.e2.

[61]López-Soto F, León-Sicairos N, Nazmi K, Bolscher JG, de la Garza M. Microbicidal effect of the lactoferrin peptides lactoferricin17-30, lactoferrampin265-284, and lactoferrin chimera on the parasite Entamoeba histolytica. Biometals. 2010; 23(3):563-568. doi: 10.1007/s10534-010-9295-3.

[62]Goldman AS. Modulation of the gastrointestinal tract of infants by human milk. Interfaces and interactions. An evolutionary perspective. Journal of Nutrition. 2000; 130(2S Suppl):426S-431S. doi: 10.1093/jn/130.2.426S.

[63]Buccigrossi V, de Marco G, Bruzzese E, Ombrato L, Bracale I, Polito G, Guarino A. Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatric Research. 2007; 61(4): 410-414. doi: 10.1203/pdr.0b013e3180332c8d.

[64]Reznikov EA, Comstock SS, Yi C, Contractor N, Donovan SM. Dietary bovine lactoferrin increases intestinal cell proliferation in neonatal piglets. Journal of Nutrition. 2014; 144(9):1401-1408. doi: 10.3945/jn.114.196568.

[65]Blais A, Fan C, Voisin T, Aattouri N, Dubarry M, Blachier F, Tomé D. Effects of lactoferrin on intestinal epithelial cell growth and differentiation: an in vivo and in vitro study. Biometals. 2014; 27(5):857-874. doi: 10.1007/s10534-014-9779-7.

[66]Blais A, Lan A, Boluktas A, Grauso-Culetto M, Chaumontet C, Blachier F, Davila AM. Lactoferrin supplementation during gestation and lactation is efficient for boosting rat pup development. Nutrients. 2022; 14(14):2814. doi: 10.3390/nu14142814.

[67]Ochoa TJ, Chea-Woo E, Baiocchi N, Pecho I, Campos M, Prada A, Valdiviezo G, Lluque A, Lai D, Cleary TG. Randomized double-blind controlled trial of bovine lactoferrin for prevention of diarrhea in children. The Journal of Pediatrics. 2013; 162(2):349-356. doi: 10.1016/j.jpeds.2012.07.043.

[68]Manzoni P, Stolfi I, Messner H, Cattani S, Laforgia N, Romeo MG, Bollani L, Rinaldi M, Gallo E, Quercia M, Maule M, Mostert M, Decembrino L, Magaldi R, Mosca F, Vagnarelli F, Memo L, Betta PM, Stronati M, Farina D; Italian task force for the study and prevention of neonatal fungal infections–the Italian society of neonatology. Bovine lactoferrin prevents invasive fungal infections in very low birth weight infants: a randomized controlled trial. Pediatrics. 2012; 129(1):116-123. doi: 10.1542/peds.2011-0279.

[69]Togawa J, Nagase H, Tanaka K, Inamori M, Umezawa T, Nakajima A, Naito M, Sato S, Saito T, Sekihara H. Lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. American Journal of Physiology. 2002; 283(1): G187-G195. doi: 10.1152/ajpgi.00331.2001.

[70]Togawa J, Nagase H, Tanaka K, Inamori M, Nakajima A, Ueno N, Saito T, Sekihara H. Oral administration of lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. Journal of Gastroenterology and Hepatology. 2002; 17(12):1291-1298. doi: 10.1046/j.1440-1746.2002.02868.x.

[71]Li L, Ren F, Yun Z, An Y, Wang C, Yan X. Determination of the effects of lactoferrin in a preclinical mouse model of experimental colitis. Molecular Medicine Reports. 2013; 8(4):1125-9. doi: 10.3892/mmr.2013.1632.

[72]Håversen LA, Baltzer L, Dolphin G, Hanson LA, Mattsby-Baltzer I. Anti-inflammatory activities of human lactoferrin in acute dextran sulphate-induced colitis in mice. Scandinavian Journal of Immunology. 2003; 57(1):2-10. doi: 10.1046/j.1365-3083.2003.01162.x.

[73]Wang S, Zhou J, Xiao D, Shu G, Gu L. Bovine Lactoferrin Protects Dextran Sulfate Sodium Salt Mice Against Inflammation and Impairment of Colonic Epithelial Barrier by Regulating Gut Microbial Structure and Metabolites. Frontiers in Nutrition. 2021; 8:660598. doi: 10.3389/fnut.2021.660598.

[74]Song L, Xie W, Liu Z, Guo D, Zhao D, Qiao X, Wang L, Zhou H, Cui W, Jiang Y, Li Y, Xu Y, Tang L. Oral delivery of a Lactococcus lactis strain secreting bovine lactoferricin-lactoferrampin alleviates the development of acute colitis in mice. Applied Microbiology and Biotechnology. 2019; 103(15): 6169-6186. doi: 10.1007/s00253-019-09898-6.

[75]Pool R, Gomez H, Kellum JA. Mechanisms of Organ Dysfunction in Sepsis. Critical Care in Clinics. 2018; 34(1):63-80. doi: 10.1016/j.ccc.2017.08.003.

[76]Williams JM, Duckworth CA, Watson AJ, Frey MR, Miguel JC, Burkitt MD, Sutton R, Hughes KR, Hall LJ, Caamaño JH, Campbell BJ, Pritchard DM. A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Disease Models and Mechanisms. 2013; 6(6):1388-1399. doi: 10.1242/dmm.013284.

[77]Stephens M, von der Weid PY. Lipopolysaccharides modulate intestinal epithelial permeability and inflammation in a species-specific manner. Gut Microbes. 2020; 11(3):421-432. doi: 10.1080/19490976.2019.1629235.

[78]Chambon-Savanovitch C, Farges MC, Raul F, Blachier F, Davot P, Cynober L, Vasson MP. Can a glutamate-enriched diet counteract glutamine depletion in endotoxemic rats? Journal of Nutritional Biochemistry. 1999; 10(6):331-337. doi: 10.1016/s0955-2863(99)00005-4.

[79]Hietbrink F, Besselink MG, Renooij W, de Smet MB, Draisma A, van der Hoeven H, Pickkers P. Systemic inflammation increases intestinal permeability during experimental human endotoxemia. Shock. 2009; 32(4):374-378. doi: 10.1097/SHK.0b013e3181a2bcd6.

[80]King CJ, Tytgat S, Delude RL, Fink MP. Ileal mucosal oxygen consumption is decreased in endotoxemic rats but is restored toward normal by treatment with aminoguanidine. Critical Care Medicine. 1999; 27(11):2518-2524. doi: 10.1097/00003246-199911000-00032.

[81]Boutry C, Matsumoto H, Bos C, Moinard C, Cynober L, Yin Y, Tomé D, Blachier F. Decreased glutamate, glutamine and citrulline concentrations in plasma and muscle in endotoxemia cannot be reversed by glutamate or glutamine supplementation: a primary intestinal defect? Amino Acids. 2012; 43(4):1485-1498. doi: 10.1007/s00726-012-1221-2.

[82]Kruzel ML, Harari Y, Chen CY, Castro GA. Lactoferrin protects gut mucosal integrity during endotoxemia induced by lipopolysaccharide in mice. Inflammation. 2000; 24(1):33-44. doi: 10.1023/a:1006935908960.

[83]Kruzel ML, Harari Y, Mailman D, Actor JK, Zimecki M. Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice. Clinical and Experimental Immunology. 2002; 130(1):25-31. doi: 10.1046/j.1365-2249.2002.01956.x.

[84]Li C, Liu X, Huang Z, Zhai Y, Li H, Wu J. Lactoferrin alleviates lipopolysaccharide-induced infantile intestinal immune barrier damage by regulating an ELAVL1-related signaling pathway. International Journal of Molecular Sciences. 2022; 23(22):13719. doi: 10.3390/ijms232213719.

[85]Doursout MF, Horton H, Hoang L, Liang Y, Hwang SA, Boyd S, Actor JK, Kruzel ML. Lactoferrin moderates LPS-induced hypotensive response and gut injury in rats. International Journal of Immunopharmacology. 2013; 15(2):227-231. doi: 10.1016/j.intimp.2012.12.009.

[86]Liu C, Peng Q, Wei L, Li Z, Zhang X, Wu Y, Wang J, Zheng X, Wen Y, Zheng R, Yan Q, Ye Q, Ma J. Deficiency of lactoferrin aggravates lipopolysaccharide-induced acute inflammation via recruitment macrophage in mice. Biometals. 2023; 36(3):549-562. doi: 10.1007/s10534-022-00398-1.

[87]Appelmelk BJ, An YQ, Geerts M, Thijs BG, de Boer HA, MacLaren DM, de Graaff J, Nuijens JH. Lactoferrin is a lipid A-binding protein. Infection and Immunity. 1994; 62(6):2628-2632. doi: 10.1128/iai.62.6.2628-2632.1994.

[88]Puddu P, Latorre D, Valenti P, Gessani S. Immunoregulatory role of lactoferrin-lipopolysaccharide interactions. Biometals. 2010; 23(3):387-397. doi: 10.1007/s10534-010-9307-3.

[89]Håversen L, Ohlsson BG, Hahn-Zoric M, Hanson LA, Mattsby-Baltzer I. Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-kappa B. Cellular Immunology. 2002; 220(2):83-95. doi: 10.1016/s0008-8749(03)00006-6.

[90]Blais A, Takakura N, Grauso M, Puel-Artero C, Blachier F, Lan A. Dietary bovine lactoferrin reduces the deleterious effects of lipopolysaccharide injection on mice intestine. Nutrients. 2024; 16(23), 4040. doi: 10.3390/nu16234040.

[91]Drago-Serrano ME, de la Garza-Amaya M, Luna JS, Campos-Rodríguez R. Lactoferrin-lipopolysaccharide (LPS) binding as key to antibacterial and antiendotoxic effects. International Immunopharmacology. 2012; 12(1):1-9. doi: 10.1016/j.intimp.2011.11.002.

[92]Mahadea D, Adamczewska E, Ratajczak AE, Rychter AM, Zawada A, Eder P, Dobrowolska A, Krela-Kaźmierczak I. Iron Deficiency Anemia in Inflammatory Bowel Diseases-A Narrative Review. Nutrients. 2021;13(11):4008. doi: 10.3390/nu13114008.

[93]El Amrousy D, El-Afify D, Elsawy A, Elsheikh M, Donia A, Nassar M. Lactoferrin for iron-deficiency anemia in children with inflammatory bowel disease: a clinical trial. Pediatric Research. 2022; 92(3):762-766. doi: 10.1038/s41390-022-02136-2.

[94]Zhou XL, Xu W, Tang XX, Luo LS, Tu JF, Zhang CJ, Xu X, Wu QD, Pan WS. Fecal lactoferrin in discriminating inflammatory bowel disease from irritable bowel syndrome: a diagnostic meta-analysis. BMC Gastroenterology. 2014; 14:121. doi: 10.1186/1471-230X-14-121.

[95]Abraham BP. Fecal lactoferrin testing. Gastroenterology and Hepatology. 2018;14(12):713-716.

[96]Caccaro R, Angriman I, D'Incà R. Relevance of fecal calprotectin and lactoferrin in the post-operative management of inflammatory bowel diseases. World Journal of Gastrointestinal Surgery. 2016; 8(3):193-201. doi: 10.4240/wjgs.v8.i3.193.

[97]Sitaram MP, McAbee DD. Isolated rat hepatocytes differentially bind and internalize bovine lactoferrin N- and C-lobes. The Biochemical Journal. 1997; 323 ( Pt 3)(Pt 3):815-822. doi: 10.1042/bj3230815.

[98]Debanne MT, Regoeczi E, Sweeney GD, Krestynski F. Interaction of human lactoferrin with the rat liver. American Journal Physiology. 1985; 248(4 Pt 1):G463-G469. doi: 10.1152/ajpgi.1985.248.4.G463.

[99]Ziere GJ, van Dijk MC, Bijsterbosch MK, van Berkel TJ. Lactoferrin uptake by the rat liver. Characterization of the recognition site and effect of selective modification of arginine residues. Journal of Biological Chemistry. 1992; 267(16):11229-11235.

[100]Hu P, Liu Y, Li S, Zhao Y, Gu H, Zong Q, Ahmed AA, Bao W, Liu HY, Cai D. Lactoferrin relieves deoxynivalenol-induced oxidative stress and inflammatory response by modulating the Nrf2/MAPK pathways in the liver. Journal of Agricultural and Food Chemistry. 2023; 71(21):8182-8191. doi: 10.1021/acs.jafc.3c01035.

[101]Aoyama Y, Naiki-Ito A, Xiaochen K, Komura M, Kato H, Nagayasu Y, Inaguma S, Tsuda H, Tomita M, Matsuo Y, Takiguchi S, Takahashi S. Lactoferrin prevents hepatic injury and fibrosis via the inhibition of NF-κB signaling in a rat non-alcoholic steatohepatitis model. Nutrients. 2021;14(1):42. doi: 10.3390/nu14010042.

[102]Li D, Hu Z, He Q, Guo Y, Chong Y, Xu J, Qin L. Lactoferrin alleviates acute alcoholic liver injury by improving redox-stress response capacity in female C57BL/6J mice. Journal of Agricultural and Food Chemistry. 2021; 69(49):14856-14867. doi: 10.1021/acs.jafc.1c06813.

[103]Li D, Ding L, Yan Y, Xing Y, Xu J, Qin L. Lactoferrin alleviates ethanol-induced injury via promoting Nrf2 nuclear translocation in BRL-3A rat liver cells. International Journal of Molecular Sciences. 2023; 24(23):16848. doi: 10.3390/ijms242316848.

[104]Xiong L, Ren F, Lv J, Zhang H, Guo H . Lactoferrin attenuates high-fat diet-induced hepatic steatosis and lipid metabolic dysfunctions by suppressing hepatic lipogenesis and down-regulating inflammation in C57BL/6J mice. Food and Function. 2018; 9(8):4328-4339. doi: 10.1039/c8fo00317c.

[105]Liu ZS, Li PL, Ku YW, Chen PW. Oral administration of recombinant lactoferrin-expressing probiotics ameliorates diet-induced lipid accumulation and inflammation in non-alcoholic fatty liver disease in mice. Microorganisms. 2022; 10(11):2215. doi: 10.3390/microorganisms10112215.

[106]Blais A, Malet A, Mikogami T, Martin-Rouas C, Tomé D. Oral bovine lactoferrin improves bone status of ovariectomized mice. American Journal of Physiology. 2009; 296(6):E1281-E1288. doi: 10.1152/ajpendo.90938.2008.

[107]Malet A, Bournaud E, Lan A, Mikogami T, Tomé D, Blais A. Bovine lactoferrin improves bone status of ovariectomized mice via immune function modulation. Bone. 2011; 48(5):1028-35. doi: 10.1016/j.bone.2011.02.002.

[108]Cornish J, Callon KE, Naot D, Palmano KP, Banovic T, Bava U, Watson M, Lin JM, Tong PC, Chen Q, Chan VA, Reid HE, Fazzalari N, Baker HM, Baker EN, Haggarty NW, Grey AB, Reid IR. Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo. Endocrinology. 2004; 145(9):4366-4374. doi: 10.1210/en.2003-1307.

[109]Chang Y, Ping A, Chang C, Betz VM, Cai L, Ren B. Lactoferrin mediates enhanced osteogenesis of adipose-derived stem cells: innovative molecular and cellular therapy for bone repair. International Journal of Molecular Sciences. 2023; 24(2):1749. doi: 10.3390/ijms24021749.

[110]Wen P, Zhang W, Wang P, Zhang Y, Zhang W, Zhao Y, Guo H. Osteogenic effects of the peptide fraction derived from pepsin-hydrolyzed bovine lactoferrin. Journal of Dairy Science. 2021; 104(4):3853-3862. doi: 10.3168/jds.2020-19138.

[111]Blais A, Rochefort GY, Blachier F. Bovine lactoferrin is efficient for improving bone characteristics: a study based on a new preclinical model of marked bone fragility. Journal of Food, Nutrition and Diet Science. 2023; 1(1):32-42. doi: fnds.12023120032-42.

[112]Guo HY, Jiang L, Ibrahim SA, Zhang L, Zhang H, Zhang M, Ren FZ. Orally administered lactoferrin preserves bone mass and microarchitecture in ovariectomized rats. Journal of Nutrition. 2009; 139(5):958-964. doi: 10.3945/jn.108.100586.

[113]Tian M, Han YB, Yang GY, Li JL, Shi CS, Tian D. The role of lactoferrin in bone remodeling: evaluation of its potential in targeted delivery and treatment of metabolic bone diseases and orthopedic conditions. Frontiers in Endocrinology. 2023; 14:1218148. doi: 10.3389/fendo.2023.1218148. eCollection 2023.

[114]Chalvon-Demersay T, Blachier F, Tomé D, Blais A. Animal models for the study of the relationships between diet and obesity : a focus on dietary protein and estrogen deficiency. Frontiers in Nutrition. 2017; 4:5. doi: 10.3389/fnut.2017.00005.

[115]Li Y, Huang J, Wang J, Ma M, Lu Y, Wang R, Guo H. Lactoferrin Is a Potential Activator of the Vitamin D Receptor in Its Regulation of Osteogenic Activities in C57BL/6J Mice and MC3T3-E1 Cells. The Journal of Nutrition. 2021; 151(8):2105-2113. doi: 10.1093/jn/nxab105.

[116]Li W, Liu B, Lin Y, Xue P, Lu Y, Song S, Li Y, Szeto IM, Ren F, Guo H. The application of lactoferrin in infant formula: The past, present and future. Critical Reviews in Food Science and Nutrition. 2024; 64(17): 5748-5767. doi: 10.1080/10408398.2022.2157792.

Download PDF

Download XML

How to Cite

Blais, A., & Blachier, . F. . (2025). Lactoferrin in food and supplements and health benefits: state of the art and future directions. Journal of Food, Nutrition and Diet Science, 3(1), 25–36. https://doi.org/10.55976/fnds.32025133025-36

Download Citation

Issue

Journal of Food, Nutrition and Diet Science, Volume 3 Issue 1, 2025

Section

Review

License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Copyright licenses detail the rights for publication, distribution, and use of research. Open Access articles published by Luminescience do not require transfer of copyright, as the copyright remains with the author. In opting for open access, the author(s) should agree to publish the article under the CC BY license (Creative Commons Attribution 4.0 International License). The CC BY license allows for maximum dissemination and re-use of open access materials and is preferred by many research funding bodies. Under this license, users are free to share (copy, distribute and transmit) and remix (adapt) the contribution, including for commercial purposes, providing they attribute the contribution in the manner specified by the author or licensor.

Home /

Archives /

Journal of Food, Nutrition and Diet Science, Volume 3 Issue 1, 2025 /

Review

Lactoferrin in food and supplements and health benefits: state of the art and future directions

Abstract

How to Cite

Issue

Section

License

Follow Luminescience

Further Information

Home / Archives / Journal of Food, Nutrition and Diet Science, Volume 3 Issue 1, 2025 / Review

Lactoferrin in food and supplements and health benefits: state of the art and future directions

Abstract

How to Cite

Issue

Section

License

Follow Luminescience

Further Information

Home /

Archives /

Journal of Food, Nutrition and Diet Science, Volume 3 Issue 1, 2025 /

Review