Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections Original paper

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.