Fusobacterium nucleatum Induces Premature and Term Stillbirths in Pregnant Mice: Implication of Oral Bacteria in Preterm Birth

Abstract

Fusobacterium nucleatum is a gram-negative anaerobe ubiquitous to the oral cavity. It is associated with periodontal disease. It is also associated with preterm birth and has been isolated from the amniotic fluid, placenta, and chorioamnionic membranes of women delivering prematurely. Periodontal disease is a newly recognized risk factor for preterm birth. This study examined the possible mechanism underlying the link between these two diseases. F. nucleatum strains isolated from amniotic fluids and placentas along with those isolated from orally related sources invaded both epithelial and endothelial cells. The invasive ability may enable F. nucleatum to colonize and infect the pregnant uterus. Transient bacteremia caused by periodontal infection may facilitate bacterial transmission from the oral cavity to the uterus. To test this hypothesis, we intravenously injected F. nucleatum into pregnant CF-1 mice. The injection resulted in premature delivery, stillbirths, and nonsustained live births. The bacterial infection was restricted inside the uterus, without spreading systemically. F. nucleatum was first detected in the blood vessels in murine placentas. Invasion of the endothelial cells lining the blood vessels was observed. The bacteria then crossed the endothelium, proliferated in surrounding tissues, and finally spread to the amniotic fluid.

Identification and Characterization of a Novel Adhesin Unique to Oral Fusobacteria

“…nucleatum invades epithelial and endothelial cells in vitro, a mechanism presumably employed for its spreading into deeper tissues (25,26). Invasion of F. nucleatum into endothelial cells was observed in vivo in the mouse placenta (25).…”

“…F. nucleatum may originate in the oral cavity and be transmitted to the uterus via a hemotogenous route. It has been shown in mice that, once in the bloodstream, F. nucleatum colonizes specifically in the placenta, causing preterm and term stillbirths (25).…”

“…F. nucleatum is recognized as an "adhesive" organism because it binds to a variety of host mammalian cells, including epithelial and endothelial cells, polymorphonuclear leukocytes, monocytes, erythrocytes, fibroblasts, and HeLa cells, as well as salivary macromolecules, extracellular matrix proteins, and human immunoglobulin G (IgG) (2,25,26,50,59,62,63). It also coaggregates with a wide array of microorganisms in the oral cavity and plays an important role in plaque formation (1, 7, 20, 22, 29, 36-38, 46, 53).…”

Can Oral Anaerobic Bacteria cause Adverse Pregnancy Outcomes?/ Дали Оралните Анаеробни Бактерии Можат Да Доведат До Лоши Опстетрички Исходи?

“…Hill demonstrated that Fusobacterium nucleatum can be isolated from amniotic fluid cultures of women with preterm labour and intact membranes suggesting the transient bacteraemia had originated from the mouth via haematogenous spread and infection of the amniotic fluid through the placenta [28]. More recently, Han and colleagues have reported a term stillbirth case by association was caused by Fusobacterium nucleatum, she had previously demonstrated that Fusobacterium nucleatum induced premature and term stillbirths in pregnant mice [29,30].…”

Efficient gene transfer and targeted mutagenesis in Fusobacterium nucleatum

“…In addition, it is the most common of the periodontal species found in extraoral infections, including blood, brain, chest, lung, liver, joint, abdominal and obstetrical and gynecological infections and abscesses (5,6,9,10,16,20,21,31). F. nucleatum infections of the vagina and amnionic fluid are associated with adverse pregnancy outcomes (19,20,39) and recent studies demonstrated that F. nucleatum induces premature delivery, stillbirths and non-sustained live births in a rodent model system (17).…”