The maternal gastrointestinal flora is involved in modulating health-from mother to the fetus even though it is frequently assumed that the fetus lives and grows in uterus in a sterile environment protected by maternal barriers against potentially pathogenic bacteria. Recent evidence indicates that that is indeed a myth to a great extent.
While the maternal environment protects the fetus against a barrage of bacterial load when it is not capable of handling such attack, the developing fetus is actually selectively exposed to bacteria and bacterial products in a controlled manner.
Bacteria-From mother's gut to fetus
- Bacterial translocation across the gut wall is physiological event which is significantly increased during pregnancy and lactation.
- Fetus is exposed to maternal gut bacteria via the placenta and the amniotic fluid. Vaginal delivery results in a massive bacterial exposure of the newborn. In addition, bacteria and/or their products may translocate across the intestinal wall and secreted via the breast milk on to the baby. The maternal bacteria are further transfered to the baby via skin-to-skin contact during loving/bonding.
- According to Dr. Mold and colleagues from the University of California in San Fransisco, large number of maternal cells cross into placenta and settle in fetal lymph nodes. They induce regulatory T lymphocytes that suppress fetal anti-maternal immunity.
Potential modes of entry of bacteria into amniotic cavity
- Ascending through birth canal
- Hematogenous access through placenta
- Retrograde entry from fallopian tubes
Human data based on hygiene hypothesis supporting bacteria-fetus connection
- Maternal exposure to farms, a microbial rich environment modulates innate immunity, and protects against atopic sensitization in school age kids. According to Dr. Ege and colleagues, the changes of atopic sensitization have actually been documented in cord blood during fetal life.
- Dr. Roduit of the PASTURE group documented that pregnant mom's with farm animals and cats protects against atopic eczema in child after birth.
- Dr. Conrad and colleagues from the Philipps-University of Marburg, Marburg, Germany, conducted a study of prenatal exposure to the cowshed bacteria A. lwoffii F78 with a mouse model of allergic airway inflammation, and demonstrated that such a prenatal exposure to farming-related microbial environment protects against development of allergic manifestations in the child after birth and beyond in adult life. The protective mechanisms involve a low level maternal immune response, and the transference of the protective immunity from the mother to the fetus.
Direct evidence for bacterial contact with fetus
- Human uterus/endometrium is not sterile but contains microbial flora.
- Recent polymerase chain reaction based studies indicate that the prevalence of microbial invasion of the amniotic cavity may be 30-50% higher than that detected by conventional techniques.
- DNA from normal inhabitants of human gut like Bifidobacterium and Lactobacillus can be identified in most human placenta.
- Studies by Bearfield and colleagues from the Queen Mary's School of Medicine and Dentistry in London, certain bacteria like streptococci seen in the amniotic fluid may have an oral origin. Bacterial invasion of the amniotic cavity by species like P. gingivalis suggest a role for periodontal pathogenic bacteria in pregnant women bringing into focus the importance of teeth and health and sickness.
- Women who test positive for bacteria in amniotic fluid by PCR have higher levels of pro-inflammatory cytokines and suffer greater number of pregnancy and delivery related complications.
- Adminstration of preconceptional antibiotics at risk for preterm delivery actually does not have any impact on preterm delivery, although it causes increased incidence of low birth weight infants.
- According to Tita and colleagues at the University of Alabama in Birmingham, AL, interconception antibiotics prevents the acquisition and promotes the resolution, but not eradication, of endometrial microbial organisms
- Andrews and colleagues have shown that many as 82% of women demonstrates endometrial cultures positive for at least one bacteria approximately 3 months after delivery. As such, the mere presence of bacteria in uterus is by itself not harmful.
Implications of fetal microbial exposure
- The clinical implication of selective bacterial exposure means that these bacteria can impact important organs and systems of body during early developmental phase when they are susceptible or "naive" thus determining health and sikness later on after birth not just as kids but also as adults.
- Maternal infections and passage of maternal antibodies across placenta not just causes inflammatory immune activation of placenta but can also alter the composition of the initial load of bacteria to the new born as well as immunological composition of breast milk the baby is fed.
- Studies by Fichorova and colleagues from Harvard Medical School show that mcroorganisms present in the placenta provoke distinct inflammatory responses in the newborn and that the presence of Lactobacillus is associated with reduced inflammatory reaction.
- Even mode of delivery may via gut microbiota development have significant impact on immune system of the infant.
- Studies by Rautava et al have shown that probiotic supplementation to the mother modulates fetal innate immune gene expression profiles in the placenta and the fetal gut.
Perinatal bacterial exposure and risk of illness
- Colonization with U. urealyticum as a result of transmission from mom to preterm infant carries a high risk of Chronic lung disease including brochopulmonary dysplasia in infants.
- Low-virulence microorganisms isolated from the placenta are associated with placental inflammation and ultrasound evidence of brain lesions and cerebral palsy in the very preterm infant.
- Results of ORACLE II trial have shown that administeration of antibiotics to women in spontaneous preterm labour with intact membranes is associated with an increase in functional impairment among their children at 7 years of age along with incraesed risk of cerebral palsy.
Manipulation of maternal microbial environment offers an attractive therapeutic target using probiotics for modulation of immune system during fetal life in order to reduce risk of diverse immunoinflamamtory disease processes in later life.