Gut microbiome is a reality in fetal life also

A study published in the Journal of Clinical Investigation shows that in both mice and humans, the fetal gut has its own microbiome, which is probably derived straight from the maternal organism.

Calling this the end of “a decades long controversy”, the scientists suggest that this could enable the stimulation of the fetal microbiome in case of expected preterm birth could help achieve a higher growth rate as well as prevent several infection-related complications of preterm birth. This can be done easily and rapidly by modulating the mother’s gut microbiome, say the researchers.

The gut microbiome

Microbes are present and flourishing on all the surfaces of the body, both inside and out. These may be found on the skin, the mucosal lining of the nose, the mucous membrane of the gut, and inside the ear.

The gut microbiome refers to the entire collection of living creatures in the gut lumen, whether bacteria, fungi or viruses. These play a number of essential or at least important roles in various physiological processes, and in the health of the gut lining cells which are responsible for digestion and absorption of various nutrients. There are many tens of trillions of single bacterial organisms within the gut microbiome, and bacteria outnumber human cells in the body at least 10 to 1. Certain types of alterations in the gut microbiome confer a danger of diverse conditions such as obesity, allergic conditions, asthma and diabetes, and autoimmune disease. Several cancers have also been traced to specific alterations in the gut microbiome characteristics.

Enterobacteriaceae, gram-negative rod-shaped bacteria, part of intestinal microbiome and causative agents of different infections, 3D illustration. - Illustration Credit: Kateryna Kon / Shutterstock
Enterobacteriaceae, gram-negative rod-shaped bacteria, part of intestinal microbiome and causative agents of different infections, 3D illustration. - Illustration Credit: Kateryna Kon / Shutterstock

The study – is there a fetal microbiome?

Earlier thinking was that the fetus in the womb is in a sterile environment, and the first introduction to bacterial and other microbial life comes from contact with the mother’s birth canal during childbirth, breast feeding, and other contacts after birth. The first line of evidence that this is not so came from the results of next-generation DNA sequencing which showed the presence of genetic matter from an array of bacteria known to colonize humans, in samples from the placenta, amniotic fluid, and meconium or fetal stools. This seemed to prove that microbes are present in the fetal environment even before birth. The nature and timing of such exposure is still not clear, and scientists still don’t know whether the same bacteria are present in the infant microbiome.

The present study looked at pairs of mothers and offspring in both humans and mice to try to resolve the question. Are the bacteria found in fetal life really from that period of life, or are they contaminants from the maternal and other environment?

To answer this, the scientists examined the types and numbers of bacteria in the mother’s vagina, placenta and feces, with those in the baby’s mouth and meconium. 10 mother-infant pairs in humans (5 preterm and 5 full-term) were studied at the time of cesarean delivery in a sterile operating room. The microbiome in fetal life was studied using several methods, namely, sequencing of bacterial DNA, fluorescence in situ hybridization (FISH), and bacterial culture.

The findings

The study showed that the microbes isolated from the uterus and the placenta were different from those obtained from the amniotic membrane and from the maternal fecal organisms. However, they were similar to those cultured from the vagina, the infant’s mouth and the infant’s meconium. The amniotic fluid cultures were more similar to those obtained from the mother’s plasma.

When analyzed by a source tracking software, the placental microbes were predicted to be the common source for the microbiota in the infant’s mouth and meconium.

When the experiment was repeated in pregnant mice delivered at various periods of pregnancy by operative delivery, the overall trends in mid-late to late pregnancy showed that the source of the microbiota in the fetal gut came primarily from the placenta and then from the amniotic membrane. In early pregnancy, the results were more confused. However, the researchers conclude that the fetal gut microbiome changes in composition and source of origin over pregnancy. Bacteria that can grow and proliferate in fetal tissues in mid-pregnancy cannot be induced to grow in culture when tested at later periods of pregnancy. This could be due to alterations in the immune barrier at the junction between maternal and fetal tissue in later pregnancy.

Bacterial cultures were also obtained from pregnant mice and the fetuses, when samples were taken from the fetal gut and uterine, placental and amniotic membrane sites, as well as from the maternal vagina and feces. Bacteria that colonize the pregnant mother in early pregnancy may also be detected in and grown from samples of fetal tissue as well as from the maternal gut, uterus and blood, but not from the vagina. This effect is not seen in later pregnancy.

Implications of a fetal microbiome

The fact that the fetus was proved to have a gut microbiome led the scientists to consider the possibility that this provides a controlled exposure of the fetal organism to microbes. This could be of great service in helping the immature and undeveloped immune system to respond to various types of antigenic challenges in a healthy and useful way. It also trains the fetal metabolic processes to proceed according to the needs of the fast-growing organism.

Researcher Patrick Seed says, “Unlike other studies relying only on next generation DNA sequencing, we validated our sequencing results with microscopy and culture techniques. Now we can pursue ways to boost the development of fetal immune system and metabolism by stimulating mom's microbiome. Our findings point to many promising opportunities for much earlier intervention to prevent future disease.”

However, this is only the starting point, and the scientists point out that much more work will be needed to discover how exactly the fetal microbiome interacts with and modulates fetal growth and development. As this body of knowledge grows, it will hopefully help them to “intervene to improve children's health at the start of life and beyond.”

Journal reference:

Fetal exposure to the maternal microbiota in humans and mice. Noelle Younge, Jessica R. McCann, Julie Ballard, Catherine Plunkett, Suhail Akhtar, Félix Araújo-Pérez, Amy Murtha, Debra Brandon, and Patrick C. Seed. Journal of Clinical Insight 2019;4(19):e127806.https://doi.org/10.1172/jci.insight.127806. https://insight.jci.org/articles/view/127806

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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