Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review

Abstract

Women's intimate health depends on several factors, such as age, diet, coexisting metabolic disorders, hormonal equilibrium, sexual activity, drug intake, contraception, surgery, and personal hygiene. These factors may affect the homeostasis of the internal environment of the genital tract: the vulva, vagina and cervix. This equilibrium is dependent on strict and complex mutual interactions between epithelial cells, immunocompetent cells and microorganisms residing in this environment. The microbiota of the genital tract in healthy women is dominated by several species of symbiotic bacteria of the Lactobacillus genus. The bacteria inhibit the growth of pathogenic microorganisms and inflammatory processes by virtue of direct and multidirectional antimicrobial action and, indirectly, by the modulation of immune system activity. For the homeostasis of the genital tract ecosystem, antimicrobial and anti-inflammatory peptides, as well as proteins secreted by mucus cells into the cervicovaginal fluid, have a fundamental significance. Of these, a multifunctional protein known as lactoferrin (LF) is one of the most important since it bridges innate and acquired immunity. Among its numerous properties, particular attention should be paid to prebiotic activity, i.e., exerting a beneficial action on symbiotic microbiota of the gastrointestinal and genital tract. Such activity of LF is associated with the inhibition of bacterial and fungal infections in the genital tract and their consequences, such as endometritis, pelvic inflammation, urinary tract infections, miscarriage, premature delivery, and infection of the fetus and newborns. The aim of this article is to review the results of laboratory as well as clinical trials, confirming the prebiotic action of LF on the microbiota of the lower genital tract.

Keywords: antimicrobial activity; lactoferrin; prebiotic activity; probiotics; vaginal microbiota.

Figure 1

The female genital system with the organs of its lower part (genital tract) (A) and the elements of innate immunity in the healthy (B) and infected (C) genital tract. (B) Healthy vaginal and cervical epithelia are protected by a layer of cervicovaginal mucus. Protection against pathogenic viruses, bacteria, fungi and parasites is secured by immune cells (mainly neutrophils, dendritic cells, NK cells and lymphocytes) in the lamina propria of the mucous membrane. The epithelial cells secrete polysaccharides (mucins and glycogen), and the epithelial and immune cells secrete antimicrobial peptides (as LF, SLPI, SP-A and lysozyme), cytokines/chemokines (as IL-1, IL-6, IL-8), and acute phase proteins (such as serum amyloid A and haptoglobin). In the mucus, numerous symbiotic bacteria reside (mainly several genera from Lactobacillus spp.) that metabolize glycogen into lactic acid, which renders the genital tract environment acidic (~pH 3.5–4.5). The immune cells and symbiotic microbiota cooperate to prevent microbial invasion of the uterus and vagina. (C) During bacterial vaginosis/vaginitis, the number of pathogenic bacteria increases and that of symbiotic bacteria decreases; these perturbations of the vaginal microbiota lead to increased vaginal pH > 4.5, as well as concomitant levels of immune cells and antimicrobial proteins, proinflammatory cytokines and acute-phase proteins.

Figure 2

The changes in the uterine mucus (endometrium) during the menstrual cycle. In the proliferative (follicular) phase, the production of estrogen increases, but it decreases in the secretory (luteal) phase. The production of progesterone is high in the secretory phase and low in the proliferative phase. The production of LF is positively correlated with the estrogen level and negatively with the progesterone level. During menstruation, pH in the genital tract increases to 7.3–7.4, but glycogen production by epithelial cells is low, so the population of lactobacilli in the vagina and uterine cervix is low. Under such conditions, the genital tract is particularly prone to infection.

Figure 3

Joint activities of oral and vaginal probiotics and LF in the prophylaxis and cure of feminine genital tract infection and inflammation. Prebiotic and antimicrobial activities of LF are complementary. LF, via several means, destroys/inhibits the growth of pathogenic microorganisms and, at the same time, promotes the growth of symbiotic microorganisms, thus normalizing the composition of the vaginal microbiota. LF has beneficial effects on resident symbiotic bacteria and exogenous probiotic bacteria when applied orally and vaginally. LF is advantageous for the activity of probiotics. Probiotics, in turn, act enzymatically on LF by degrading the protein into more active peptides (lower left part), ↑ increase, ↓ decrease.