Lactoferrin

What Was Reviewed?

This review article comprehensively examined the biological functions of lactoferrin (LF) and the various methods developed for its detection in biological and food samples. Lactoferrin is an iron-binding glycoprotein involved in multiple physiological roles, including antimicrobial, antiviral, anti-inflammatory, antioxidant, and immunomodulatory activities. The review also explored LF’s emerging role as a biomarker for several conditions, such as inflammatory bowel disease (IBD), Alzheimer’s disease (AD), and dry eye disease (DED), due to its presence in bodily secretions like tears, saliva, and feces. In parallel, the authors provided an in-depth analysis of current detection technologies, including immunoassays, instrumental techniques, and advanced biosensors such as electrochemical and surface plasmon resonance (SPR) sensors.

Who Was Reviewed?

The review focused on both animal models (primarily rats) and human participants across various referenced studies to establish lactoferrin's role as a biomarker and therapeutic target. It incorporated data from clinical and preclinical studies analyzing LF levels in subjects with IBD, AD, and DED, along with experimental detection methods evaluated in human biological fluids and food matrices (such as milk, whey, and infant formula).

What Were the Most Important Findings?

Lactoferrin demonstrates a clear dual functionality in the microbiome context: it restricts pathogen proliferation by sequestering iron and disrupting microbial membranes while simultaneously supporting beneficial microbes such as Lactobacillus and Bifidobacterium. As a biomarker, fecal LF is highly specific and moderately sensitive for diagnosing IBD, with stronger performance in ulcerative colitis than Crohn’s disease. Alzheimer’s patients show a marked decrease in salivary LF, which may help predict early neurodegenerative changes before traditional CSF markers. Tear LF levels are consistently lower in patients with DED, correlating with disease severity. Methodologically, ELISA remains the most widely used detection tool due to its high specificity and sensitivity, though fluorescence-based aptasensors and SPR devices are emerging as promising alternatives due to their real-time capabilities and low detection limits.

What Are the Implications of This Review?

This review underscores lactoferrin’s robust diagnostic potential across a spectrum of diseases with microbial or inflammatory underpinnings. Clinically, its utility as a non-invasive biomarker in feces, saliva, and tears presents a path forward for early screening and monitoring of diseases like IBD and AD—conditions where traditional diagnostics are either invasive or limited in sensitivity. For microbiome research, lactoferrin acts as a major microbial association (MMA) molecule that reflects both microbial health and host immunity. From a translational perspective, there is a clear need for the development of portable, cost-effective, and highly sensitive LF detection platforms, especially biosensor technologies, to bridge laboratory research and clinical utility. The review positions lactoferrin as both a sentinel and a shield in mucosal immunity, making it a valuable target for diagnostics, microbiome profiling, and therapeutic intervention.

What Was Reviewed?

The article presents a comprehensive synthesis of the latest research on lactoferrin (Lf), a multifunctional glycoprotein naturally found in mammalian milk and various bodily secretions. The review emphasizes lactoferrin’s structural biology, physicochemical properties, mechanisms of action, and its emerging clinical and industrial applications with emphasis on its antimicrobial, antiviral, anticancer, immunomodulatory, and antioxidant roles. The authors also explore lactoferrin’s impact on chronic diseases, neurodegenerative disorders, gastrointestinal health, and microbiota composition, highlighting its significance as a candidate for therapeutic interventions and functional food applications.

Who Was Reviewed?

This review draws upon a wide range of experimental models, including in vitro studies, animal models (especially mice and rats), and human clinical trials. Populations reviewed include neonates, patients with gastrointestinal and neurodegenerative disorders, cancer patients, individuals with cardiovascular or metabolic conditions, and those exposed to viral infections, including SARS-CoV-2. Additionally, the review presents data from livestock and aquaculture studies in which researchers applied lactoferrin as a dietary supplement, further supporting its immunological and microbiome-modulating roles.

Most Important Findings?

Lactoferrin exhibits broad antimicrobial, antiviral, and immunomodulatory activity, largely through its high-affinity iron-binding ability. It promotes beneficial gut bacteria such as Bifidobacterium and Lactobacillus while inhibiting pathogens, making it a key microbiome modulator. Clinically, this is evident in trials where lactoferrin improved vaginal microbiota and reduced neonatal infections. Its antiviral effects extend to HPV, HSV, HIV, and SARS-CoV-2 by blocking viral entry and replication. Lactoferrin also dampens inflammation through NF-κB and MAPK pathway inhibition and improves chronic conditions like colitis, hypertension, and insulin resistance.

Lactoferrin's role in chronic disease prevention is significant. It modulates insulin signaling via the AKT and ERK1/2 pathways, reduces blood pressure by inhibiting angiotensin-I-converting enzyme (ACE), and supports bone growth by promoting osteoblast activity and suppressing osteoclastogenesis. In the brain, lactoferrin crosses the blood-brain barrier and influences neuroregeneration, with differential levels observed in Alzheimer’s vs. Parkinson’s disease patients.

From a microbiome database perspective, researchers reinforce lactoferrin’s MMA status by demonstrating its consistent impact on beneficial microbial populations, its ability to suppress opportunistic pathogens, and its role in maintaining mucosal immunity and gut barrier integrity. Its dual function as both a prebiotic and a postbiotic effector further amplifies its influence in shaping microbial ecologies.

What Are the Greatest Implications of This Review?

This review affirms lactoferrin as a multifunctional molecule with far-reaching therapeutic potential across immunological, infectious, oncological, and metabolic domains. For clinicians, it offers a natural, well-tolerated adjunct for managing dysbiosis-related diseases, enhancing mucosal immunity, and reducing inflammation. Lactoferrin’s inclusion in functional foods, infant formulas, and pharmaceutical formulations is already underway, supported by its favorable safety profile. Future research should refine delivery systems to improve bioavailability and identify precise microbial signatures associated with therapeutic success. As an immune-modulating and microbiome-supporting molecule, lactoferrin deserves integration into microbiome-targeted clinical interventions, particularly in vulnerable populations such as neonates, elderly individuals, and immunocompromised patients.

Who Was Reviewed?

The paper explores the wide-ranging biological functions and therapeutic potential of lactoferrin (LF), a naturally occurring glycoprotein predominantly found in milk and various human secretions. The authors aim to elucidate the multifaceted roles lactoferrin plays in human physiology and pathology across the lifespan, from fetal development through old age. In addition, this review synthesizes findings from in vitro, animal, and clinical studies to establish LF as a key molecule in host defense, cellular protection, and disease modulation.

Who Was Reviewed?

The review brings together findings from a variety of models, including cell lines, animal models—especially rodents, calves, and human populations. Specifically, it focuses on neonates, infants, and patients with conditions such as infections, cancers, and neurodegenerative diseases. The authors emphasized the immunological development of preterm infants and the clinical outcomes of lactoferrin supplementation in these vulnerable groups. The review incorporates both epidemiological and experimental studies that explore lactoferrin’s effects on aging, microbiota modulation, inflammation, and systemic diseases.

What Were the Most Important Findings?

The review highlights lactoferrin as a multifunctional protein with powerful antioxidant, antimicrobial, anti-inflammatory, immunomodulatory, and anticancer properties. At the molecular level, lactoferrin binds iron ions with high affinity, limiting their availability to pathogenic microbes and thereby reducing oxidative stress. Moreover, lactoferrin directly influences the gut microbiome by promoting the growth of probiotic species (e.g., Bifidobacterium, Lactobacillus) and helping to restore microbial balance after antibiotic use. In addition, it modulates both innate and adaptive immunity, further underscoring its therapeutic potential.

It enhances mucosal immunity in infants, reduces necrotizing enterocolitis (NEC), and mitigates neonatal sepsis. It stimulates the production of cytokines (TNF-α, IL-6, IL-10), augments the activity of lymphocytes and monocytes, and even influences Vitamin D receptor expression, crucial for bone health and immunity.

On the cancer front, lactoferrin exhibits selective cytotoxicity toward tumor cells by inducing apoptosis, arresting cell cycles, and regulating gene expression in pathways related to cell survival and proliferation. Notably, nuclear LF acts as a transcription factor influencing pro-apoptotic and tumor-suppressor genes. LF’s ability to traverse the blood-brain barrier adds potential for treating brain tumors.

Pertinent to microbiome-focused databases, lactoferrin’s role as a prebiotic and a postbiotic effector is significant. Its ability to maintain eubiosis, promote beneficial microbes, and prevent dysbiosis-linked conditions like inflammatory bowel disease and sepsis places it among the major microbial association modulators (MMAs). It appears in both direct (microbial growth stimulation) and indirect (immune modulation, epithelial protection) pathways impacting host-microbe interactions.

What Are the Implications of This Review?

This review strongly supports the inclusion of lactoferrin as a therapeutic and preventive agent across various life stages and disease states. Its wide-ranging roles in microbial balance, immune homeostasis, and cellular protection establish it as a key molecule for translational microbiome medicine. Clinicians could consider lactoferrin supplementation, especially in pediatric, geriatric, and immunocompromised populations. Given its antimicrobial and immunoregulatory capacities, lactoferrin may reduce antibiotic reliance and aid in combating antimicrobial resistance. Moreover, its application in functional foods and pharmaceuticals broadens its clinical relevance.

What Was Reviewed?

The article offers a foundational synthesis of the biological properties, mechanisms, and therapeutic roles of lactoferrin (Lf), a multifunctional glycoprotein found in milk, secretions from exocrine glands, and neutrophil granules. As a member of the transferrin family, lactoferrin primarily binds iron but exerts a wide range of biological effects that extend beyond its iron-binding capabilities. This review discusses lactoferrin’s molecular structure, synthesis, metabolism, receptor interactions, and its influence on various physiological and pathological processes, including microbial infections, immune responses, inflammation, cancer progression, and bone metabolism.

Who Was Reviewed?

This review draws from in vitro experiments, animal studies, and human clinical and observational data, examining how lactoferrin behaves across various biological systems and species. Populations include neonates, pregnant women, and individuals exposed to pathogens or inflammatory conditions. Animal models such as rodents, cattle, rabbits, and horses also inform the physiological relevance of lactoferrin in veterinary and human health. The review compares lactoferrin concentrations and functions across species and contexts, emphasizing its potential in both human and veterinary medicine.

Most Important Findings?

Lactoferrin exerts potent antimicrobial effects by sequestering iron, thereby limiting bacterial growth, while simultaneously promoting beneficial microbiota such as Lactobacillus and Bifidobacterium. This dual action defines it as a major microbial association (MMA) molecule with both prebiotic and antimicrobial characteristics. It demonstrates direct bactericidal effects independent of iron binding, especially through its N-terminal domain and pepsin-derived fragments like lactoferricin. Lf also prevents biofilm formation (e.g., Pseudomonas aeruginosa) and blocks pathogen adhesion to host cells.

Beyond bacteria, lactoferrin inhibits viral entry by binding to glycosaminoglycans on host cells, disrupting infections from HSV, CMV, HIV, and others. It also demonstrates antiparasitic effects via iron competition and membrane disruption. Immunologically, Lf modulates inflammation by suppressing TNF-α, IL-1β, and IL-6 while upregulating IL-10, and interacts with immune cells such as neutrophils, macrophages, and NK cells. Its tumor-suppressive activity involves cell-cycle arrest, increased Fas-mediated apoptosis, and enhanced NK cell cytotoxicity.

The review reinforces lactoferrin’s microbial and immunomodulatory actions by highlighting its presence at mucosal sites, where it maintains barrier integrity and regulates microbial colonization. They have documented its effects across several species, particularly in humans and cattle, where lactoferrin concentrations correlate with stages of development, lactation, and immune status.

What Are the Implications of This Review?

This review highlights lactoferrin as a promising, naturally occurring therapeutic agent that interfaces meaningfully with the microbiome, immune system, and inflammatory processes. Its ability to regulate microbial populations while enhancing host defense mechanisms positions it as a vital molecule for managing infections, supporting mucosal immunity, and mitigating inflammatory diseases. Its broad spectrum of action, from antimicrobial and antiviral defense to cancer inhibition and bone support, makes lactoferrin highly relevant in both clinical and veterinary applications. For clinicians, lactoferrin represents an opportunity to integrate a microbiome-altering compound into therapeutic protocols for neonatal care, gastrointestinal disorders, chronic inflammation, and immune modulation.

What was reviewed?

This review comprehensively examined lactoferrin, a multifunctional iron-binding glycoprotein, highlighting its capacity as a natural immunomodulator that bridges innate and adaptive immunity. The paper assessed lactoferrin’s roles in infection, inflammation, oxidative stress, and immune system regulation, including its therapeutic potential in systemic inflammatory response syndrome (SIRS), sepsis, and bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA).

Who was reviewed?

The review synthesized findings from preclinical in vivo and in vitro studies, particularly in murine models, along with limited human data, to explore the immune mechanisms regulated by lactoferrin. It included evidence across diverse immune cell types, including macrophages, neutrophils, dendritic cells, and T and B lymphocytes.

What were the most important findings?

Lactoferrin significantly modulates immune function through both direct and indirect pathways. It acts as an antimicrobial by binding iron, limiting pathogen proliferation, and neutralizing lipopolysaccharides (LPS). In the microbiome context, this review emphasizes that lactoferrin plays a regulatory role by reducing oxidative stress through iron sequestration and decreasing reactive oxygen species (ROS), which often rise during inflammatory and infectious states.

Lactoferrin dampens excessive immune responses during sepsis and endotoxemia by suppressing mitochondrial ROS and pro-inflammatory cytokines such as IL-6 and TNF-α. It also protects mucosal integrity by reducing bacterial translocation, especially in gut-associated lymphoid tissue. Notably, in both Gram-negative (E. coli) and Gram-positive (MRSA) infection models, lactoferrin improved survival and reduced inflammatory biomarkers. Regarding adaptive immunity, lactoferrin promotes Th1 responses, enhances antigen presentation via dendritic cells and macrophages, and drives T-cell maturation and B-cell isotype switching—thereby reinforcing host microbial surveillance and immunological memory.

Microbiome relevance lies in lactoferrin’s ability to preserve mucosal immunity, reduce gut inflammation, and prevent dysbiosis-linked bacterial dissemination, especially under systemic infectious stress. These actions suggest lactoferrin supports a microbiome-resilient host immune state.

What are the implications of this review?

This review highlights lactoferrin’s potential as a natural immunomodulatory intervention. Its ability to simultaneously enhance protective immunity while dampening harmful inflammation makes it a promising candidate for clinical use in sepsis, autoimmune diseases, infections, and potentially microbiome-targeted therapies. Its role in bridging innate and adaptive immunity also supports its use as a vaccine adjuvant, especially for pathogens requiring strong Th1-type responses. For microbiome-focused clinicians, lactoferrin’s action on mucosal immunity and bacterial translocation pathways suggests a powerful tool for managing dysbiosis-linked systemic inflammation.

What Was Reviewed?

This paper is a comprehensive review of the immunomodulatory effects of lactoferrin (Lf), a multifunctional iron-binding glycoprotein found abundantly in mammalian colostrum and other secretions. The review synthesizes evidence from in vitro and in vivo studies to explore Lf’s diverse roles in immune modulation, antimicrobial defense, and its therapeutic potential. It places special emphasis on Lf’s interactions with various immune cells and outlines how these interactions affect innate and adaptive immune responses. Additionally, the review discusses lactoferrin’s emerging applications in infant formulas, antimicrobial therapies, chronic inflammation, and potentially in oncology and metabolic disorders.

Who Was Reviewed?

The review aggregates findings across multiple model systems, including human and animal in vitro cell lines and in vivo studies conducted in mice, piglets, and preterm infants. It references clinical data involving human supplementation trials, particularly in neonates and immunocompromised individuals, along with recombinant and bovine lactoferrin applications across species.

What Were the Most Important Findings?

Lactoferrin modulates immunity by influencing both innate and adaptive arms. It suppresses pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), promotes anti-inflammatory mediators (IL-10), and interacts with key immune receptors like CD14 and TLR4 to temper inflammatory responses. Notably, Lf blocks LPS-CD14 interaction, preventing downstream NF-κB activation, and enhances antigen presentation by upregulating dendritic cell function and stimulating Th1 responses. It also boosts B-cell maturation and IgA/IgG secretion, acting as an immune bridge molecule. On a microbiome level, Lf inhibits pathogenic colonization and biofilm formation while supporting the proliferation of beneficial gut bacteria by promoting mucosal immunity and epithelial barrier integrity, especially crucial in neonates with immature guts. Lf’s impact on early microbial colonization and interaction with Lf receptors in intestinal brush border cells underscores its role in shaping the neonatal immune-microbiome axis.

What Are the Implications of This Review?

The review establishes lactoferrin as a potent immunomodulatory agent with both therapeutic and prophylactic relevance. Its ability to bridge innate and adaptive immunity, regulate cytokine networks, and reduce inflammation presents major opportunities in managing inflammatory diseases, sepsis, neonatal necrotizing enterocolitis, and microbial infections. From a microbiome perspective, Lf represents a natural intervention that supports epithelial integrity, regulates microbial-host interactions, and facilitates immune tolerance during early colonization. Clinically, this positions Lf as a valuable adjunct in infant formula, immunocompromised care, and potentially as an anti-inflammatory nutraceutical or therapeutic biologic in chronic disease.

What was reviewed?

This review comprehensively examined the structure, mechanisms, and functional role of lactoferrin (LF) in gut health, with a strong emphasis on its prebiotic effects, immune modulation, gut barrier integrity, and anti-pathogenic activity. The authors synthesized findings from in vitro, in vivo, and clinical studies to present LF as a multifaceted intervention for modulating the intestinal microbiota, suppressing inflammation, and supporting host immunity.

Who was reviewed?

The review included data from a broad range of models: human clinical trials, animal studies (mice, rats, piglets, zebrafish), and cell cultures (Caco-2, IPEC-J2, HT-29, macrophage lines). It also encompassed microbial interaction studies with Gram-positive and Gram-negative bacteria, viruses, and protozoa to assess the antimicrobial and immunological effects of LF.

Most Important Findings

Lactoferrin exhibits potent immunomodulatory effects and serves as a dual-function agent, simultaneously suppressing enteric pathogens and promoting beneficial microbial taxa such as Bifidobacterium and Lactobacillus species while suppressing Enterobacteriaceae, E. coli O157:H7, and Salmonella. It may serve as a potent microbiota-shaping agent in dysbiotic conditions.

LF reduces intestinal inflammation by modulating pro-inflammatory cytokines and enhancing anti-inflammatory mediators like IL-10. LF also reinforces gut barrier integrity by upregulating tight junction proteins (Claudin-1, Occludin, ZO-1) and restoring epithelial morphology in models of colitis and inflammatory damage. Notably, in both its apo- (iron-depleted) and holo- (iron-saturated) forms, LF inhibits adhesion and proliferation of pathogens such as E. coli, Salmonella, Shigella, and Staphylococcus aureus, often through iron sequestration or membrane disruption.

LF and its peptide derivatives—lactoferricin and lactoferrampin, enhance gut immunity and exhibit higher antimicrobial activity than the intact protein. LF has also been shown to modulate Toll-like receptor (TLR) signaling and gut microbiota composition disrupted by antibiotics. Clinical studies revealed its efficacy in reducing diarrhea, improving iron absorption without gastrointestinal side effects, and lowering the risk of sepsis in neonates.

What Are the Implications of This Review?

Lactoferrin’s ability to modulate both host immunity and microbial communities establishes it as a promising natural therapeutic or adjunct intervention for gut-related conditions, including colitis, infections, and colorectal cancer. Its compatibility with probiotic therapies and its low side-effect profile make it a compelling candidate for both preventative and therapeutic applications. LF’s prebiotic classification is increasingly supported by mechanistic insights, including direct microbial interactions and epithelial barrier restoration. This positions lactoferrin as a valuable clinical tool in microbiome-targeted interventions, particularly in patients with inflammatory bowel disorders, antibiotic-induced dysbiosis, and vulnerable populations such as infants and immunocompromised individuals.

What Was Reviewed?

This paper is a detailed review of lactoferrin’s multifaceted role as a natural immune modulator, highlighting both its innate and adaptive immunological functions. It synthesizes findings from molecular, cellular, and systemic levels, addressing lactoferrin's antimicrobial properties, cytokine modulation capabilities, and receptor interactions that drive immune balance. The review emphasizes lactoferrin’s structural features that allow it to bind to microbial components (like LPS), host receptors, and immune signaling molecules, thereby influencing immune responses at mucosal surfaces and beyond.

Who Was Reviewed?

The review draws from a broad body of in vivo and in vitro studies, including data from human and animal models. It reviews evidence involving polymorphonuclear neutrophils (PMNs), antigen-presenting cells (APCs), lymphocytes, and epithelial/endothelial cells. This paper also evaluates lactoferrin’s impact in both physiological and inflammatory contexts, including infection, allergy, and neurodegenerative conditions, with particular emphasis on its oral supplementation as a dietary immune intervention.

What Were the Most Important Findings?

Lactoferrin serves as a potent immune modulator by interacting with both pathogen-associated molecular patterns (PAMPs) and host receptors. It regulates cytokine balance—reducing pro-inflammatory mediators like TNF-α, IL-1, and IL-6, while enhancing IL-4 and IL-10. Lactoferrin binds and neutralizes LPS and unmethylated CpG DNA, thereby dampening toll-like receptor (TLR)-mediated inflammation. Notably, its N-terminal domain (especially lactoferricin and lactoferrampin peptides) mediates many of these effects through high-affinity interactions with cellular and microbial targets.

Lactoferrin also modulates immune cell activity by engaging various surface receptors, such as intelectin-1 and surface nucleolin. These interactions influence immune cell migration, cytokine release, and antigen presentation. Furthermore, lactoferrin’s ability to form complexes with immunoregulatory proteins like osteopontin and ceruloplasmin expands its functional repertoire. It acts as an alarmin, recruiting dendritic cells and monocytes and linking innate to adaptive immunity, while shaping the Th1/Th2 balance—a critical aspect for microbiome-host equilibrium.

What Are the Implications of This Review?

This review affirms lactoferrin as a versatile regulator of immune responses, positioning it as a central molecule for both microbial control and immune tolerance. Its capacity to simultaneously suppress excessive inflammation and support immune activation makes it a highly valuable agent for microbiome-integrated therapies. From a clinical standpoint, lactoferrin holds therapeutic potential for managing conditions involving chronic inflammation, infection, and immune dysregulation, including IBD, neonatal sepsis, and neuroinflammation. Its oral bioactivity also supports its application in functional foods and infant formulas designed to fortify immune resilience via gut-immune interactions.

What Was Reviewed?

The paper is a comprehensive review that consolidates current scientific understanding of lactoferrin (Lf) as a multifunctional protein with potent antioxidant and immune-regulating capabilities. The review explores lactoferrin's capacity to modulate oxidative stress, regulate iron metabolism, and exert neuroprotective effects. Additionally, it highlights Lf’s therapeutic potential in chronic diseases such as cardiovascular disease, neurodegeneration (particularly Parkinson’s and Alzheimer’s), obesity, hepatitis, respiratory conditions, dry eye disease, anemia, and inflammation-driven conditions. The authors synthesize both in vitro and in vivo findings that underline the systemic effects of Lf across multiple organ systems, with a focus on its antioxidant, anti-inflammatory, and antimicrobial mechanisms.

Who Was Reviewed?

This review draws on a wide body of experimental and clinical studies involving animal models (e.g., Wistar rats, murine models of cystic fibrosis, and neonatal rat models of brain injury), human subjects (e.g., obese pediatric patients, pregnant women, athletes, individuals with anemia, and patients with neurodegenerative and liver diseases), and in vitro studies on human cell cultures. The subjects span age, species, and physiological status, enabling a multifaceted perspective on lactoferrin's biological activities and clinical applicability.

What Were the Most Important Findings?

The review underscores that lactoferrin functions as a potent natural antioxidant, capable of neutralizing reactive oxygen species (ROS) and mitigating lipid peroxidation. It stimulates endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), often via Nrf2-dependent pathways. Lactoferrin's iron-chelating activity plays a central role in minimizing iron-induced oxidative damage, particularly in neurodegenerative diseases. It regulates ferroptosis by altering the expression of iron transport and storage proteins, which is contextually beneficial—for instance, reducing ferroptosis in liver injury while promoting it in cancer therapy.

From a microbiome perspective, lactoferrin’s iron sequestration impairs biofilm formation in E. coli and other pathogens, suggesting prebiotic and antimicrobial benefits in the gastrointestinal tract. Furthermore, it interacts with receptors such as TLR4, CD14, CXCR4, and LRP1, mediating immune signaling and potentially influencing the composition and activity of microbial communities. The review also touches on how lactoferrin supports mucosal immunity and modulates cytokine expression, contributing to a stable and functional microbiome-host interface.

What Are the Implications of This Review?

Clinically, this review identifies lactoferrin as a promising therapeutic agent for preventing and managing chronic conditions characterized by oxidative stress, iron dysregulation, and immune imbalance. Its ability to modulate ROS, chelate iron, and activate host defense mechanisms without promoting microbial resistance or systemic toxicity offers a valuable alternative to conventional interventions. Its potential neuroprotective effects, particularly in Alzheimer's and Parkinson's diseases—may open pathways for non-invasive therapeutic strategies targeting the blood-brain barrier. Moreover, lactoferrin’s systemic influence on inflammation and microbial dynamics highlights its emerging role in microbiome-informed clinical practice. For clinicians, the evidence supports considering lactoferrin as a supplemental strategy in managing oxidative stress-related pathologies and enhancing gut-immune-brain axis resilience.

What was reviewed?

This paper presents a comprehensive narrative review of lactoferrin (LF) as a modulator of iron homeostasis and its implications in cancer, focusing on its iron-chelating, antioxidant, and immunomodulatory properties. The authors reviewed peer-reviewed literature published from 2000 to the present, prioritizing research from the last five years. The review included studies from in vitro models, human trials, and clinical interventions, particularly those exploring LF’s role in regulating iron metabolism in cancer, mitigating iron-driven oxidative stress, and influencing the gut microbiome.

Who was reviewed?

The review encompassed a diverse array of sources, including studies on cancer patients, healthy adults, pregnant women, infants, athletes, and individuals with iron-deficiency anemia (IDA). These included intervention trials using bovine or human lactoferrin, in vitro cell line studies (such as colorectal cancer cells, neuroblastoma cells, and fibroblasts), and animal models, all analyzing LF’s effectiveness in modulating oxidative stress, supporting iron homeostasis, and altering inflammatory and microbial pathways.

What were the most important findings?

Lactoferrin emerged as a potent multifunctional glycoprotein with the ability to influence systemic and cellular iron regulation—a key factor in cancer progression. By chelating free iron, LF limits its availability to cancer cells, reducing the generation of reactive oxygen species (ROS), inhibiting tumor proliferation, and even inducing ferroptosis in iron-overloaded cancer cells. LF enhances ferroportin expression, downregulates ferritin, and interacts with transferrin receptor 1, thereby modulating major iron-related proteins. LF activates antioxidant pathways, such as the Nrf2 pathway, and suppresses inflammation via inhibition of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β.

Crucially for microbiome research, the review highlights that LF supports beneficial gut microbial populations, notably Bifidobacterium and Lactobacillus, while suppressing pathogens, largely through iron sequestration and direct antimicrobial activity. Iron dysregulation in cancer patients, often driven by treatment or disease-induced inflammation, disrupts microbial balance, promoting dysbiosis. LF appears to counteract this by restoring microbial equilibrium and reducing gut inflammation.

Clinical data confirm LF’s therapeutic utility in iron-deficiency anemia and cancer-related anemia, often outperforming traditional iron salts like ferrous sulfate with fewer gastrointestinal side effects. Supplementation not only improves hematological indices but also significantly reduces IL-6 and hepcidin levels, restoring iron export pathways. Multiple human trials, especially in pregnant women and hemodialysis patients, validated LF’s superior efficacy and tolerability.

What are the implications of this review?

This review underscores lactoferrin’s potential as a novel therapeutic adjunct in oncology, particularly for patients suffering from iron metabolism disturbances and inflammation-driven tumorigenesis. Its ability to simultaneously chelate iron, suppress oxidative stress, modulate immune responses, and restore microbiome balance positions LF as a multifaceted intervention in cancer prevention and management. Importantly for clinicians, LF offers a microbiome-friendly strategy that avoids the complications of conventional iron therapies, especially in populations at risk for dysbiosis and systemic inflammation. Its compatibility with dietary and nano-formulations further enhances its translational value.

What Was Reviewed?

The paper is a comprehensive review article that explores lactoferrin (Lf), an iron-binding glycoprotein, and its multifaceted role in human energy metabolism. The authors investigated the molecular and physiological actions of Lf in the modulation of glucose and lipid pathways, its impact on iron and trace metal homeostasis, and its implications for addressing metabolic syndrome, obesity, and related conditions. This review draws from both in vitro and in vivo studies, including human and animal models and integrates findings across disciplines such as immunology, metabolism, and microbiology.

Who Was Reviewed?

The review analyzed a wide range of subjects and experimental models, including human clinical data, animal studies (e.g., rats and mice under high-fat diet or glucose challenge), and cellular models (e.g., HepG2 hepatocytes, adipocytes, intestinal epithelial cells). Special attention was given to individuals with metabolic disorders such as insulin resistance, dyslipidemia, and type 2 diabetes. Pediatric and adult populations, as well as different Lf sources (bovine and camel), were also discussed for their therapeutic relevance.

What Were the Most Important Findings?

Lactoferrin plays a bidirectional role in energy metabolism—either boosting or resetting it depending on the physiological context. It regulates glucose metabolism by enhancing insulin signaling via the IRS-1/PI3K/Akt pathway, upregulating GLUT-4 translocation, and stimulating GLP-1 secretion. In diabetic and stressed animal models, lactoferrin reduced fasting glucose and insulin levels, improved glucose tolerance, and suppressed inflammatory cytokines like IL-6, TNF-α, and IL-1β. These benefits were also observed in pediatric patients with type 2 diabetes who received camel-derived Lf.

On lipid metabolism, lactoferrin modulated adipogenesis by downregulating key pathways such as PPARγ, SREBP-1, and ACC, and decreased serum LDL-C and hepatic lipid accumulation while enhancing HDL-C levels. It exerted these effects partly through activation of AMPK and LRP1-related signaling. Notably, lactoferrin interacted with gut microbiota and bile acids to influence lipid and cholesterol absorption and excretion, suggesting a microbiome-mediated mechanism. Studies showed that Mn- or Zn-bound Lf enhanced Lactobacillus growth, linking it to microbiome modulation.

What Are the Implications of This Review?

This review establishes lactoferrin as a safe, non-toxic, and clinically promising nutraceutical for managing metabolic dysfunctions such as insulin resistance, type 2 diabetes, dyslipidemia, and obesity. Its capacity to influence both host cell signaling and gut microbiota highlights its role as a multitargeted intervention. The dual behavior of Lf—either activating or repressing metabolic pathways depending on the condition—suggests its adaptive potential in both preventive and therapeutic settings. Furthermore, the recognition of Lf’s impact on iron and trace metal balance underscores its broader relevance in inflammatory and infectious disease contexts. Future clinical implementation will require attention to formulation (e.g., apo- vs. holo-Lf), dosage, and patient-specific factors.

What was reviewed?

This review explores the dual immunomodulatory role of lactoferrin (Lf) in regulating inflammation caused by microbial infections. It comprehensively examines in vitro and in vivo findings on both human and bovine lactoferrin across various organ systems, primarily the gastrointestinal and respiratory tracts, highlighting how Lf modulates innate and adaptive immune responses. The review also discusses the biochemical properties of Lf, its structural variants (apo- and holo-forms), synthetic derivatives like lactoferricins, and nanoparticle formulations, emphasizing their therapeutic implications.

Who was reviewed?

The review includes research findings across numerous models: mice, rats, rabbits, piglets, and human clinical samples. It integrates studies on different Lf sources (human, bovine, porcine, camelid, etc.) and their effects in microbial infections by bacteria, viruses, fungi, and protozoa. It also reviews immune cell responses and epithelial cell culture models.

What were the most important findings?

Lactoferrin plays a biphasic regulatory role in inflammation, acting either as an anti-inflammatory or pro-inflammatory agent depending on the context. Apo-lactoferrin (iron-free) often exhibits stronger anti-inflammatory and LPS-neutralizing effects, while holo-lactoferrin (iron-saturated) contributes more to pro-inflammatory activation. For example, in gut inflammation caused by enteropathogenic bacteria like E. coli, S. flexneri, and Salmonella, lactoferrin significantly downregulated cytokines like IL-6, IL-8, and TNF-α while promoting protective IgA responses and supporting barrier integrity.

Notably, lactoferrin enhanced beneficial microbiota like Bifidobacterium, supporting homeostasis. In Crohn's disease models, it regulated ferroportin expression, implicating its role in controlling intracellular iron to limit bacterial growth. Additionally, lactoferrin derivatives such as lactoferricins and synthetic peptides demonstrated enhanced antimicrobial and immunomodulatory effects, especially in antibiotic-resistant strains and biofilm-associated infections.

In respiratory tract infections, Lf modulated Th1 immune responses and reduced lung pathology when used alongside BCG vaccine in tuberculosis models. It also exhibited a protective effect in cystic fibrosis, reducing IL-1β and increasing IL-11. However, its efficacy varied in viral infections like RSV and influenza, indicating dependency on dosage, route, and timing.

From a microbiome perspective, lactoferrin influences the composition of gut microbiota, regulates iron-dependent microbial competition, and balances mucosal immunity, all of which are critical in shaping microbial signatures during infection and inflammation.

What are the implications of this review?

Lactoferrin emerges as a potent natural immune modulator with dual functionality, capable of either amplifying or suppressing inflammation. This makes it a promising adjunct therapy in infectious diseases, particularly where antibiotic resistance or immune-mediated tissue damage is a concern. Its ability to synergize with antibiotics and probiotics, regulate iron availability, and maintain mucosal homeostasis presents a strategic therapeutic avenue in managing gut dysbiosis, sepsis, and chronic inflammatory conditions such as Crohn’s disease and cystic fibrosis. Clinicians should consider Lf as a bioactive agent with implications for targeted microbiome modulation and immune recalibration in mucosal infections.

What Was Reviewed?

This paper reviewed the potential of lactoferrin (Lf) as a novel analgesic agent with anti-nociceptive and anti-inflammatory effects, particularly in preclinical models. The authors explored lactoferrin's mechanisms of action across various types of pain, including nociceptive, neuropathic, and nociplastic pain, and examined how Lf might modulate neuroimmune and neurochemical pathways to reduce pain perception. The paper focused on bovine lactoferrin (bLf) and human lactoferrin (hLf), assessing their safety, pharmacological actions, and signaling pathways that contribute to their analgesic effects.

Who Was Reviewed?

The review analyzed preclinical studies that used animal models, primarily rats, to evaluate lactoferrin’s effects on nociception and inflammation. These models included the formalin test, hot plate test, acetic acid-induced writhing, adjuvant-induced arthritis, and various neuropathic pain models such as chronic constriction injury (CCI), mental nerve transection (MNT), and oxaliplatin-induced neurotoxicity. Mechanistic studies involving spinal cord, peripheral nerve, and cerebrospinal fluid analyses were also reviewed to understand lactoferrin’s impact on key signaling pathways like TRAF6–NFκB and NO–cGMP–ATP-sensitive K+ channels.

What Were the Most Important Findings?

Lactoferrin consistently reduced nociceptive and neuropathic pain behaviors across multiple animal models when administered orally, intraperitoneally, or intrathecally. These effects were mediated through several key pathways. First, Lf downregulated the DAMP–TRAF6–NFκB signaling cascade, thereby suppressing pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and reducing spinal inflammation. Secondly, Lf activated the nitric oxide (NO)–cGMP–ATP-sensitive K+ channel pathway, leading to neuronal hyperpolarization and decreased nociceptive signaling. Notably, the anti-nociceptive effect was reversed by nitric oxide synthase (NOS) inhibitors, confirming the pathway’s role. Thirdly, Lf modulated the opioid system, particularly µ-opioid receptors, amplifying morphine’s effects and reducing opioid tolerance. These mechanisms indicate Lf’s multi-targeted modulation of neuroimmune and sensory pathways involved in pain processing. While the paper did not explore direct changes to microbiome composition, the signaling pathways regulated by Lf are shared with microbial pattern recognition, suggesting potential for microbiome-relevant therapeutic targeting.

What Are the Implications of This Review?

This review positions lactoferrin as a promising adjunct or alternative to traditional analgesics like opioids and NSAIDs. Given its safety profile, natural origin, and ability to modulate both inflammatory and neurochemical pathways without the adverse effects typical of standard drugs, Lf holds therapeutic potential across multiple pain conditions, including those refractory to conventional treatment. Importantly, its ability to influence pathways common to microbial pattern recognition makes it a candidate for microbiome-integrated pain management strategies. The review underscores the need for human clinical trials and mechanistic microbiome studies to validate and extend these findings.

What was studied?

This experimental study investigated the antifungal efficacy of lactoferrin (LF) against a wide range of clinically relevant yeasts and molds, and its potential to act synergistically with common antifungal drugs. The authors evaluated the minimum inhibitory concentrations (MICs) of lactoferrin from three different sources and analyzed how iron saturation, digestion state, and source purity influenced LF activity and synergy with antifungals, particularly amphotericin B (AMB).

Who was studied?

The study focused on 22 yeast species and 24 mold species, using both clinical isolates and reference strains. Key organisms included Candida albicans, Cryptococcus neoformans, C. glabrata, and Saccharomyces cerevisiae. In vivo efficacy was tested using a Galleria mellonella infection model inoculated with Candida and Cryptococcus species.

What were the most important findings?

Lactoferrin displayed broad antifungal activity against yeasts. The iron-depleted (apo) form was more active than the iron-rich (holo) form, affirming that iron chelation plays a major role in LF’s antifungal function. However, synergy with amphotericin B was independent of iron saturation and instead depended on peptide fragments within LF, highlighting that proteolytic digestion enhances its efficacy.

Most critically, LF synergized strongly with AMB against 19 of 22 yeast species, producing 4-fold reductions in AMB concentrations needed to inhibit growth. This combination therapy significantly reduced fungal burden and improved survival in the Galleria mellonella model, confirming in vivo relevance. Scanning electron microscopy (SEM) imaging showed that LF disrupted fungal morphology and, when combined with AMB, induced pore formation, hyphal thinning, and capsule collapse in Candida and Cryptococcus. The LF-AMB combination also impaired key virulence traits like biofilm formation and hyphal elongation in Candida, and capsule and cell size modulation in Cryptococcus, all of which are critical to pathogenesis and immune evasion.

While LF alone exerted antifungal activity via iron sequestration and membrane damage, its synergy with AMB appears to rely on facilitating AMB’s cell entry and amplifying intracellular stress. These results underscore its multifaceted role as both an iron chelator and membrane-disrupting peptide complex.

What are the implications of this study?

This study provides compelling evidence that lactoferrin, particularly when derived from digested, iron-depleted sources, could serve as a low-toxicity, broad-spectrum antifungal adjunct. Its synergy with amphotericin B could enable lower dosing, reduce side effects, and enhance treatment efficacy against drug-resistant or biofilm-associated fungal infections. For microbiome-centered therapies, LF offers dual promise: direct suppression of fungal overgrowth and support for microbial balance via targeted pathogen reduction without broad-spectrum collateral damage. Moreover, its ability to impair fungal virulence traits suggests a novel pathway to disarm pathogenic fungi without solely relying on fungicidal pressure, potentially slowing the emergence of resistance.

What was reviewed?

This review examined the antifungal properties of lactoferrin (Lf) and its derived peptides, especially lactoferricin, lactoferrampin, and Lf(1–11), highlighting their mechanisms of action and potential for synergistic use with antifungal drugs. The paper consolidated findings from multiple in vitro and some in vivo studies to explain how these molecules exert direct antifungal activity, modulate immune responses, and interact with current antifungal agents like azoles.

Who was reviewed?

The review synthesized studies involving a broad spectrum of fungal pathogens, particularly various Candida species, Cryptococcus, Aspergillus, and several plant-pathogenic molds. It also discussed work done on mammalian Lf peptides derived from human and bovine sources, tested on both wild-type and resistant fungal strains. Mechanistic and structural insights were drawn from both laboratory experiments and structural analyses of peptide variants.

What were the most important findings?

Lactoferrin and its derived peptides exhibit significant antifungal activity through membrane destabilization, iron chelation, and, in some cases, induction of fungal apoptosis-like processes. While initial assumptions attributed Lf’s antifungal effect to iron sequestration, more recent evidence points to direct membrane interaction and intracellular disruption as the primary mechanisms. These peptides quickly penetrate fungal cells, alter membrane potential, cause ROS accumulation, and trigger apoptosis pathways in C. albicans and S. cerevisiae.

Lf-derived peptides, especially bLfcin and Lfampin, show broad-spectrum activity at lower MICs than the full protein, and structural modifications enhance this potency. Synergy was most notable with azole-class drugs, where co-treatment reduced MICs for fluconazole and itraconazole-resistant Candida strains. For microbiome study, these findings are crucial: Lf and its peptides act selectively, impairing fungal overgrowth without broad-spectrum microbial destruction, preserving beneficial taxa, and possibly reinforcing mucosal barrier integrity through indirect immune modulation.

What are the implications of this review?

This review highlights lactoferrin’s therapeutic versatility, not only as a standalone antifungal agent but also as a synergistic enhancer of existing antifungal drugs. Its derived peptides, due to higher potency and customizable structures, represent promising leads for targeted antifungal drug design. For microbiome-informed clinical strategies, Lf peptides offer a selective approach to managing fungal overgrowth, reducing the risk of resistance development, and preserving microbial homeostasis. Their ability to weaken virulence traits (e.g., biofilm formation, hyphal growth) while enhancing host immune responses aligns well with personalized, microbiome-centered care pathways.

What was reviewed?

This paper conducted a bibliometric and knowledge map analysis of the global research trends concerning the antibacterial properties of lactoferrin (LF). The authors systematically reviewed 1,923 articles and reviews published from 2000 to early 2022, drawing from the Web of Science Core Collection. The analysis identified publication trends, collaboration networks, research hotspots, and evolving themes, including LF’s role in host immunity and antibacterial mechanisms.

Who was reviewed?

The review covered contributions from 8,292 authors affiliated with 2,151 institutions across 86 countries. Notable contributors included the University of California system, Vrije Universiteit Amsterdam, and Morinaga Milk Industry Co., with key authors like Bolscher JGM and Yamauchi K. The research base spanned disciplines such as microbiology, food science, molecular biology, and immunology, involving both in vitro and in vivo studies focused on LF’s antibacterial functions.

What were the most important findings?

Lactoferrin was confirmed to exhibit broad-spectrum antibacterial activity through multiple mechanisms, including iron sequestration, membrane destabilization, biofilm disruption, and inhibition of microbial adhesion. The analysis showed significant interest in LF’s role against Gram-positive and Gram-negative bacteria, with Escherichia coli, Streptococcus spp., and Staphylococcus aureus frequently studied. LF also inhibited biofilm formation and supported the proliferation of beneficial gut microbes like Bifidobacterium species in vivo. The bibliometric trends showed that LF-derived peptides and nanotechnology applications are emerging as high-impact subfields. Notably, keyword analysis identified a research shift from mechanistic studies to applied research, especially in response to the COVID-19 pandemic, which triggered interest in LF’s immunomodulatory and adjunctive antiviral roles.

Microbiome relevance is reflected in LF’s non-disruptive antibacterial action. Unlike broad-spectrum antibiotics, LF selectively inhibits pathogens while preserving or promoting beneficial microbial communities. This is particularly critical in mucosal environments like the gut, where LF’s support of epithelial integrity and immune balance contributes to microbiome homeostasis.

What are the implications of this review?

This bibliometric review confirms lactoferrin’s sustained relevance as a multifunctional antimicrobial protein, with expanding potential in drug development, nanomedicine, and dietary interventions. For clinicians, LF represents a promising adjunct to antibiotic stewardship strategies, offering antimicrobial action without promoting resistance or dysbiosis. The shift toward translational applications positions LF as a natural compound that bridges innate immunity and microbiome-preserving therapy. Ongoing research must address standardization, bioavailability, and regulatory concerns, but the groundwork for LF’s broader clinical adoption is firmly established.

What was studied?

This in vitro experimental study evaluated the antibacterial activity of lactoferrin against both Gram-negative and Gram-positive clinical bacterial isolates. The goal was to compare lactoferrin’s effectiveness on different bacterial species and assess whether there was a differential effect between Gram-positive and Gram-negative organisms.

Who was studied?

The researchers tested four bacterial strains—two Gram-positive (Staphylococcus epidermidis and Bacillus cereus) and two Gram-negative (Campylobacter jejuni and Salmonella spp.)—all of which were clinical isolates from wound, blood, urine, stool, and sputum samples collected at Namazi Hospital in Shiraz, Iran.

What were the most important findings?

Lactoferrin demonstrated notable antibacterial activity against all tested strains, with higher efficacy against Gram-positive bacteria. Specifically, colony reduction rates were highest for S. epidermidis and B. cereus, compared to Salmonella and C. jejuni. The authors confirmed that the antibacterial effect was statistically significant across all species.

Mechanistically, lactoferrin exerts its antimicrobial activity primarily through iron sequestration, depriving bacteria of an essential growth factor. In addition, apolactoferrin damages bacterial membranes, especially in Gram-negative species, by binding lipid A in LPS and disrupting membrane integrity. This dual action supports lactoferrin’s bacteriostatic and bactericidal capabilities. From a microbiome perspective, the selective suppression of pathogens without affecting commensals supports lactoferrin’s role as a microbiome-compatible antimicrobial agent, particularly in mucosal environments where microbial balance is critical for immune and epithelial homeostasis.

What are the implications of this study?

This study supports lactoferrin as a natural antimicrobial agent with broad efficacy, especially against Gram-positive pathogens. The non-toxic, iron-modulating mechanism offers an advantage over conventional antibiotics, particularly in the context of rising antimicrobial resistance. Clinically, lactoferrin could serve as a preventive or adjunctive therapy in infections where microbial disruption must be minimized, such as in gastrointestinal or urogenital settings where microbiome preservation is essential. The study further underscores the need to explore lactoferrin’s integration into microbiome-sensitive antimicrobial protocols and as a candidate in nutraceutical formulations.

What was reviewed?

This review explored the broad-spectrum antiviral effects of lactoferrin (Lf), emphasizing its mechanistic actions across various viral families. The paper examined how both human and bovine lactoferrin, as well as derivative peptides like lactoferricin, inhibit the infection cycles of enveloped and non-enveloped viruses. It focused on Lf’s ability to block viral attachment, entry, and intracellular replication, and reviewed in vitro and in vivo findings spanning herpesviruses, HIV, hepatitis viruses, and respiratory pathogens.

Who was reviewed?

The authors synthesized studies involving a wide range of viruses, including Herpes Simplex Virus (HSV), HIV, Hepatitis B and C, Human Papillomavirus (HPV), Influenza A, Adenovirus, Cytomegalovirus (CMV), Rotavirus, Poliovirus, and Japanese Encephalitis Virus, among others. The review encompassed cellular studies using epithelial, fibroblast, and immune-derived cell lines, as well as several in vivo animal models (e.g., mice, rats, and transgenic species).

What were the most important findings?

Lactoferrin exerts antiviral activity primarily in the early stages of viral infection by binding either to host cell surface glycosaminoglycans (like heparan sulfate) or directly to viral envelope proteins, thereby blocking viral adhesion and entry. This mechanism is consistent across HSV, HIV, CMV, and several respiratory and enteric viruses. Additionally, Lf prevents virus-induced apoptosis and modulates inflammatory responses in infected tissues. The antiviral activity appears independent of iron saturation but is enhanced in some cases by zinc or manganese saturation.

From a microbiome context, these actions preserve epithelial barrier integrity and limit downstream inflammation, which is critical in preventing secondary dysbiosis. By preventing viral entry, especially in the mucosal interface, Lf supports immune homeostasis without inducing widespread microbial suppression. In viruses like HSV and HIV, lactoferrin also reduces syncytium formation and virus-mediated immune evasion, indirectly benefiting mucosal microbial stability.

What are the implications of this review?

Lactoferrin is positioned as a valuable adjunct in antiviral therapy, with utility in both prevention and early treatment. Its broad mechanism of action, including blocking host-virus interactions, reducing apoptosis, and regulating inflammation, offers therapeutic promise across multiple viral infections. This mucosal protection is particularly relevant for the microbiome, as viral damage to epithelial surfaces often precedes microbial imbalance. While human trials are still limited, the convergence of in vitro and in vivo findings supports lactoferrin’s future integration into antiviral, microbiome-stabilizing therapies, particularly in settings like viral gastroenteritis, respiratory infections, and sexually transmitted viral diseases.

What was reviewed?

This comprehensive review examined the multifaceted antimicrobial and immunomodulatory roles of lactoferrin (Lf) and its derived peptides. It synthesized mechanistic and preclinical findings that demonstrate how Lf and its peptides inhibit the virulence traits of a broad array of bacterial, fungal, viral, and parasitic pathogens. Particular focus was given to how Lf interferes with microbial adhesion, invasion, toxin production, biofilm formation, immune evasion strategies, and key mechanisms in host colonization and disease progression.

Who was reviewed?

The paper reviewed mechanistic studies, in vitro experiments, and in vivo models involving diverse pathogens, including Escherichia coli, Pseudomonas aeruginosa, Streptococcus pneumoniae, Giardia lamblia, Entamoeba histolytica, Cryptosporidium parvum, and multiple other bacterial and parasitic species. Both human and bovine sources of Lf, in apo- and holo-forms, were discussed, along with enzymatically derived and synthetic peptide variants.

What were the most important findings?

Lactoferrin and its peptides disrupt virulence by targeting microbial membranes, destabilizing surface structures, inhibiting iron uptake, and modulating gene expression linked to biofilm and toxin production. Apo-Lf acts as both a microbiostatic and microbicidal agent, chelating iron and causing membrane destabilization, while Lfcins exhibit potent direct antimicrobial activity independent of iron binding. Lf and its peptides suppress adhesion of pathogens to epithelial cells, block colonization, and interfere with secretion of critical virulence factors like pyocyanin, elastase, leukotoxin, and Shiga toxin.

In the microbiome context, this selective action helps control overgrowth of pathogens without disrupting commensal populations. Lf and Lfcins inhibit biofilm formation in resistant species like P. aeruginosa, K. pneumoniae, and S. pneumoniae, while promoting epithelial integrity and mitigating inflammation. Importantly, Lf and peptides show synergistic activity with antibiotics, restoring sensitivity in multidrug-resistant bacteria, which supports their integration into microbiome-preserving antimicrobial strategies.

What are the implications of this review?

This review positions lactoferrin and its peptides as promising natural alternatives or adjuncts to traditional antimicrobials, particularly for addressing virulence rather than simply killing pathogens. By targeting biofilms, adhesins, toxins, and iron acquisition systems—without broad-spectrum bactericidal activity—Lf interventions reduce pathogen fitness while maintaining microbial community balance. For clinicians, these agents could support the treatment of infections resistant to conventional antibiotics and preserve the microbiome during therapy. The multifactorial action and synergy with antibiotics make Lf-derived peptides strong candidates for next-generation antimicrobials in microbiome-sensitive applications.

What was reviewed?

This systematic review analyzed the antiviral efficacy of orally administered lactoferrin (LF) in human clinical studies. The review encompassed 27 records, including randomized controlled trials, non-randomized trials, and clinical trial protocols, with a focus on various viral infections such as hepatitis C virus (HCV), HIV, SARS-CoV-2, norovirus, rotavirus, and others. The primary goal was to evaluate LF’s role in the prevention or management of confirmed viral infections and to assess clinical and immunological outcomes from oral LF interventions across diverse populations.

Who was reviewed?

Participants included both adults and children across multiple studies involving infections from Flaviviridae (HCV), Retroviridae (HIV), Coronaviridae (SARS-CoV-2), Caliciviridae (norovirus), and Reoviridae (rotavirus). Most studies were conducted in Japan and Italy. Clinical populations ranged from healthy children to immunocompromised individuals and patients with chronic viral conditions. The review incorporated a diverse array of LF sources (e.g., bovine LF, recombinant human LF) and dosages, with durations ranging from 10 days to 15 months.

What were the most important findings?

Findings were highly heterogeneous and largely inconclusive. Some studies reported modest benefits in reducing viral loads (notably in low HCV baseline patients), symptom duration (especially in rotavirus and norovirus infections), and certain immunological markers like IL-6 or CD4+ percentages. However, these effects were not consistent across studies or virus families. For SARS-CoV-2, one preprint study reported shortened PCR conversion time and symptom duration, while another observed symptomatic relief with no significant virological changes. Importantly, lactoferrin showed a strong safety profile with minimal adverse effects, making it a candidate for further investigation.

From a microbiome perspective, oral LF may help preserve epithelial integrity and modulate mucosal immunity during viral infections, though direct evidence of microbiome modulation was lacking in this review. Studies on HIV noted trends in immune modulation, such as skewed T-cell populations and increased phagocytic activity, which suggest lactoferrin's potential to stabilize host immune-microbial interactions indirectly.

What are the implications of this review?

Despite a promising in vitro profile, clinical evidence for oral lactoferrin’s antiviral efficacy remains inconclusive due to poor methodological quality, inconsistent dosing, and heterogeneous protocols across studies. Nonetheless, its safety, tolerability, and hints of symptom alleviation support its exploration as a supportive therapy—especially for viral infections where mucosal integrity and immune tolerance are compromised. For clinicians considering microbiome-centered interventions, lactoferrin’s potential to reduce infection-related inflammation without disrupting microbial communities is an attractive, albeit under-validated, approach.

What was reviewed?

This review evaluated both in vitro and in vivo evidence for lactoferrin’s antiviral activity against common viral infections, particularly respiratory viruses, gastroenteritis viruses, summer cold-related viruses, and herpes viruses. It focused on the efficacy of oral administration of bovine and human lactoferrin in reducing infection rates, severity of symptoms, and host immune responses in animal models and human studies.

Who was reviewed?

The authors synthesized findings from multiple cell-based assays, murine models, and clinical studies in human populations across all age groups. Viral targets included influenza A, respiratory syncytial virus (RSV), parainfluenza virus, rotavirus, norovirus, enterovirus 71, coxsackievirus, adenovirus, and herpes simplex virus types 1 and 2. Study populations encompassed both healthy individuals and those affected by viral illness, with a particular focus on children and immunocompromised patients.

What were the most important findings?

Lactoferrin showed consistent in vitro inhibition of viral attachment and entry across a wide range of viruses by binding to cellular receptors or directly to viral particles. In vivo, orally administered lactoferrin reduced the incidence or severity of common cold symptoms, gastroenteritis episodes, and herpes infections in some clinical cohorts. In norovirus and rotavirus infections, lactoferrin limited disease severity rather than preventing infection outright. Mechanistically, lactoferrin induced interferon-α/β expression and activated natural killer (NK) cells and Th1 cytokines such as IL-12 and IFN-γ, providing mucosal and systemic immune enhancement.

Relevance to microbiome health emerges through lactoferrin’s non-bactericidal antiviral action and immunomodulatory roles. By limiting epithelial inflammation and promoting immune homeostasis without disrupting microbial communities, lactoferrin indirectly supports a balanced mucosal microbiome. This is particularly significant in viral gastroenteritis, where microbial dysbiosis often follows mucosal damage. Lactoferrin’s ability to prevent viral entry and reduce cytokine-driven inflammation positions it as a microbiome-preserving antiviral adjunct.

What are the implications of this review?

Lactoferrin holds promise as a preventive agent for common viral infections, especially in settings lacking specific antiviral drugs, such as noroviral gastroenteritis. Its ability to modulate immune responses, reduce viral replication, and support epithelial barrier functions suggests a valuable role in microbiome-aligned therapies. However, researchers observe varying outcomes depending on dosage, viral target, and population, and emphasize the need for further controlled human studies. Still, the safety, accessibility, and immunonutritional value of lactoferrin argue strongly for its inclusion in functional food strategies aimed at infection prevention and mucosal immune support.

What was reviewed?

This review examined existing literature on the antimicrobial and prebiotic roles of lactoferrin (LF) in the female reproductive tract, integrating data from in vitro, in vivo, and clinical studies. It emphasized LF's dual functionality: its ability to combat pathogenic microorganisms and its capacity to support beneficial vaginal microbiota, particularly Lactobacillus species.

Who was reviewed?

The review synthesized findings from studies involving human participants, animal models (notably mice and rats), and various probiotic bacterial strains. It focused on healthy women, women with dysbiosis-associated infections (e.g., bacterial vaginosis, vulvovaginal candidiasis, chlamydiosis), and pregnant individuals. The cited research included diverse ethnic populations, particularly regarding vaginal microbiota composition and probiotic strain efficacy.

What were the most important findings?

Lactoferrin acts as a selective antimicrobial agent in the female genital tract. It inhibits the growth of pathogens such as Gardnerella vaginalis, Atopobium vaginae, Escherichia coli, and Candida albicans through mechanisms including iron sequestration, membrane destabilization, biofilm inhibition, and synergistic interaction with immune mediators. Simultaneously, LF supports the growth and biofilm formation of beneficial bacteria such as Lactobacillus acidophilus, L. rhamnosus, and L. crispatus, helping restore eubiosis. It enhances adhesion and colonization of probiotic strains and may be enzymatically processed by probiotics into more active peptides like lactoferricin.

The review also highlights how LF modulates immune responses by suppressing pro-inflammatory cytokines (e.g., IL-6, IL-17, IL-8) and enhancing anti-inflammatory mediators, particularly in infections like C. trachomatis. Importantly, LF's influence on microbiome composition is estrogen-dependent, with higher concentrations observed in the proliferative phase of the menstrual cycle. LF's prebiotic benefit becomes especially relevant in combination with probiotics, forming synbiotic formulations that show enhanced clinical efficacy in reducing infections and promoting vaginal microbial balance.

What are the implications of this review?

Lactoferrin presents as a promising non-antibiotic intervention for female reproductive tract health, offering dual-action antimicrobial and prebiotic benefits. Its ability to suppress infections while promoting Lactobacillus-dominant eubiosis supports its integration into microbiome-focused gynecological therapies, including treatment of recurrent infections and pregnancy-associated complications. Moreover, its safety, hormone-responsive behavior, and synergistic role with probiotics make it highly suitable for use in synbiotic formulations, especially in populations vulnerable to dysbiosis, such as pregnant or immunocompromised individuals. Clinicians should consider LF as a candidate for adjunctive therapy or preventative care in microbiome-sensitive conditions of the female genital tract.

What Was Reviewed?

This paper is a comprehensive review that synthesizes both in vitro and in vivo research on lactoferrin’s (LF) prebiotic, antimicrobial, and immunomodulatory functions. The authors explore lactoferrin's dualistic role, both as a selective antimicrobial agent and as a growth enhancer for specific probiotic strains. The review emphasizes the mechanistic insights behind LF’s function in modulating the gut microbiome, supporting probiotic growth, and providing therapeutic benefit in various disease contexts.

Who Was Reviewed?

The review synthesizes data across diverse studies, including in vitro analyses using various probiotic strains, animal models, and clinical trials involving infants, preterm neonates, and adults. The scope of organisms includes Gram-positive and Gram-negative pathogens, commensals, and probiotics, allowing a broad understanding of LF's selective biological interactions.

What Were the Most Important Findings?

Lactoferrin exhibits a paradoxical yet beneficial role in the microbiome: it selectively inhibits pathogens while preserving or enhancing probiotic viability under certain conditions. Its antimicrobial action stems from iron sequestration and LF-derived peptides like lactoferricin. Importantly, many probiotics, including Lactobacillus and Bifidobacterium species, show resilience to LF's antibacterial effects, and some even demonstrate enhanced growth in its presence, especially under environmental stress like cold temperatures (e.g., 22°C).

Transcriptomic data reveal that LF modulates central metabolic and stress-response pathways in L. rhamnosus GG, enabling it to thrive under suboptimal conditions. In vivo, LF supplementation has correlated with shifts in microbiota favoring beneficial taxa, including Lactobacillus and Bifidobacterium, and with decreased levels of Enterobacter and Klebsiella. When paired with probiotics, LF exerts synergistic effects, enhancing pathogen suppression and supporting metabolic and immune resilience, especially in models of NAFLD, sepsis, and bacterial vaginosis. These effects are mechanistically linked to LF’s ability to interact with probiotic surface proteins, influence gene expression, and possibly deliver glycan-bound energy substrates.

What Are the Greatest Implications of This Review?

This review highlights lactoferrin as a promising adjunct in microbiome-targeted interventions (MBTIs). Its ability to differentially influence microbial populations, suppressing pathogens while supporting probiotics, makes it uniquely valuable for targeted microbiota modulation. Mechanistic insights suggest that LF can help restore balance in dysbiotic ecosystems, enhance resilience under physiological stress, and synergize with probiotics to improve outcomes in metabolic, infectious, and inflammatory conditions. The findings justify the inclusion of lactoferrin in clinical protocols aiming to manipulate gut flora for therapeutic benefit, especially in vulnerable populations like neonates, obese individuals, and those with infection-prone immune profiles.

What was studied?

This study investigated the role of lactoferrin (LF) in relation to iron metabolism in women with and without endometriosis by measuring levels of LF, ferritin (FT), transferrin (TF), and iron (Fe) simultaneously in plasma and peritoneal fluid. The authors specifically explored whether the concentrations and ratios of these iron-related proteins in the two biological compartments could distinguish the presence and progression of endometriosis. The goal was to identify noninvasive or minimally invasive biomarkers that may aid in diagnosing or staging the disease based on iron metabolism, especially given endometriosis’ pro-inflammatory, iron-rich microenvironment.

Who was studied?

The study cohort included 90 women of reproductive age undergoing diagnostic laparoscopy, of whom 57 had histologically confirmed endometriosis (stages I–IV) and 33 did not. Plasma and peritoneal fluid samples were collected pre- and intra-operatively. Subjects were classified based on endometriosis diagnosis and stage, and specimens were evaluated for levels of LF, FT, TF, and Fe using ELISA, immunoturbidimetric assay, and colorimetric methods.

What were the most important findings?

Key findings highlight that ferritin and iron concentrations were significantly elevated in peritoneal fluid compared to plasma, especially in patients with advanced-stage endometriosis. In contrast, transferrin was consistently lower in peritoneal fluid. Notably, lactoferrin levels did not significantly differ between women with and without endometriosis when evaluated independently in plasma or peritoneal fluid, but the peritoneal fluid/plasma lactoferrin ratio decreased progressively with increasing disease severity, significantly distinguishing stage I from stage IV. The ferritin ratio was markedly higher in the endometriosis group, underscoring its potential as a disease marker. Correlation analyses revealed that in severe endometriosis, lactoferrin was significantly associated with ferritin and iron in the peritoneal fluid, suggesting a disrupted iron regulation mechanism localized to the disease microenvironment. Importantly, the elevated ferritin concentrations in peritoneal fluid may serve a compensatory, protective role to sequester iron and mitigate oxidative stress, while lactoferrin may lose this protective function as disease progresses.

From a microbiome perspective, this study underscores the iron-dependent ecological shifts that may select for siderophilic pathobionts. The iron overload and pro-oxidative milieu likely fosters the expansion of iron-requiring microbial taxa, potentially including Escherichia, Enterobacter, and Fusobacterium, known to be enriched in some endometriosis microbiome signatures. While microbial profiling was not performed, the metallomic dysregulation described supports the hypothesis that iron availability is a crucial factor in shaping pathogenic microbial communities in endometriosis.

What are the greatest implications of this study?

This study provides compelling evidence that iron-binding proteins—particularly ferritin and lactoferrin—play a localized and differential role in the progression of endometriosis. The findings suggest that peritoneal fluid iron metabolism, and especially the ferritin-to-lactoferrin balance, may be a critical axis of disease progression and potentially a therapeutic target. The study introduces the peritoneal fluid/plasma concentration ratio as a novel diagnostic parameter, offering a more granular assessment than conventional plasma markers. The declining lactoferrin ratio and increasing ferritin ratio with disease severity may signal a transition from iron sequestration and immune modulation toward iron-driven oxidative stress and tissue damage. This may serve as a foundation for the development of metallome-targeted diagnostics and therapies, including exogenous lactoferrin supplementation, which the authors suggest could restore iron balance in advanced disease stages. These findings also have implications for understanding how iron dysregulation may foster microbial dysbiosis, providing a mechanistic link between host iron metabolism and the pathophysiological selection of microbial communities in endometriosis.