Background/Objectives: This study investigated the effects of bovine lactoferrin (LF) on vaginal microbiota in healthy postmenopausal women. Methods: A randomized, double-blind, placebo-controlled trial was conducted. Healthy Japanese postmenopausal women were administered a placebo or bovine LF (300 mg/day) for 12 weeks. The primary endpoint was the Nugent score and the secondary endpoints were the Nugent sub-scores. The exploratory outcomes included vaginal immunoglobulin and urinary deoxypyridinoline levels. Results: Eighty participants were randomized (placebo, n = 40; LF, n = 40), of whom 8 were excluded. The remaining 72 participants (placebo group: n = 36; LF group: n = 36) were included in the per-protocol set. Although the Nugent score was lower in the LF group, the difference was not significant. The Gardnerella/Bacteroides Nugent sub-score was significantly lower in the LF group than in the placebo group. The vaginal immunoglobulin G1 levels were significantly higher in the LF group than in the placebo group. In addition, the urinary deoxypyridinoline levels were significantly lower in the LF group than in the placebo group. Adverse events were comparable between the groups and no adverse drug reactions were observed. Conclusions: Although oral LF supplementation did not significantly affect the primary endpoint (overall Nugent score), a lower Gardnerella/Bacteroides morphotype score and higher vaginal IgG1 levels were observed. As these findings were derived from secondary and exploratory analyses, respectively, they are considered hypothesis-generating and require confirmation in future studies.

Lactoferrin (LF) is present in tears, nasal secretions, saliva, and milk and maintains mucosal homeostasis. The palatine tonsils represent the first immune tissue to recognize pathogens invading the oral cavity via Toll-like receptors (TLRs). We aimed to investigate the effects of bovine LF on tonsillar immune cells stimulated with ligands of TLR7 or TLR9, which recognize viral single-stranded RNA or bacterial unmethylated CpG DNA. Mononuclear cells isolated from palatine tonsils of patients with recurrent tonsillitis or immunoglobulin A (IgA) nephropathy were cultured with LF, TLR7, or TLR9 ligands. Under TLR7 stimulation, LF enhanced the activation of plasmacytoid dendritic cells (pDCs), T-killer cells, and B cells without inducing inflammatory cytokines. In contrast, under TLR9 stimulation, LF suppressed the activation of pDCs, myeloid dendritic cells, T-helper cells, T-killer cells, B cells, and natural killer cells, as well as the production of TNF-α and IL-6. Moreover, LF decreased the production of the B-cell activation factor (BAFF), a proliferation-inducing ligand (APRIL), and galactose-deficient IgA1, all of which are risk factors of IgA nephropathy. Overall, LF may enhance the immune response against viruses and contribute to immune tolerance against commensal bacteria in the palatine tonsils, indicating potential benefits in managing cold-like symptoms, recurrent tonsillitis, and IgA nephropathy.