This post was written by JC Gutierrez-Ramos, CEO of Synlogic, as part of the From The Trenches feature of LifeSciVC.
When I was a graduate student, I listened to the famous developmental biologist Lewis Wolpert say, “It is not birth or marriage or even death that are ‘the’ key milestones of our life, it is gastrulation.” At that time, I smiled proudly as I was dedicating my pre-doctoral life to study drosophila blastulas and their future “consequential” steps. Now that I am in my 50s, I found myself re-examining key milestones in life. This was a thorough and painful process of which I will spare you the details, but after all that middle-age drama, my scientific mind took over and brought me to a good, comfortable place. I concluded that I disagreed with Professor Wolpert because I believe the most important milestone in life is birth.
This is not because birth marks the beginning of our conscious life as an independent being, or because our mother loves us very much, or the pink little dresses that we get, but because birth is the start of a massive bacterial colonization, it is the moment when we stop being just human. In fact, it is almost scary…what happens in the hours, days, and weeks after we exit the birth canal and the womb of our mother. In my mind, it is similar to one of those scenes in Star Wars where millions of Stormtroopers are invading the planet Endor or when the vast armies of Sauron Orcs invade the beautiful Rohan in Lord of the Rings.
You may think I’m exaggerating, but I don’t think so because this is such an epic moment! One hundred percent of the cells we are made of when we start life are human. That is the case during the nine months that span from oocyte fertilization to the time when there is a breach in the protective amniotic sac that allows us to exit the womb to the external world (when our mother’s “water breaks”). These are the only nine months of our entire life when we are just simply and straightforwardly human. Yet from the moment of birth we are to be soon colonized by so many microorganisms that by the end of this process, only 10% of our cells are human with microbes accounting for the remaining 90%. Isn’t that truly epic??
As unborn babies, we live in an environment that is completely germ-free. For nine months, we have no contact with the outside world except through our mother. Our food is pre-digested, our oxygen is pre-breathed, and our mother’s lungs and gut filter everything before it reaches us. We are more sterile than an operating room in the best hospital in Boston. This situation is unusual because never again in our lifetime we will be so protected and isolated. However, like all good things in life, this protection does not last long.
The first bacteria to invade us are from the vaginal flora of our mother. About half of these bacteria are from the genus Lactobacillus, and they have one main job: to produce lactic acid. All this lactic acid results in the pH of our tiny belly going way down which leads in a very strict environment for colonization and survival (only a dozen acid resistant bacteria live there at that time). For comparison, I would like to point out that just in our nose we harbor between 800 and 1,000 species of bacteria. By the time we are wrapped and immobilized with a blanket and a silly hat in the delivery room, we have a good initial set of microbial colonies dividing exponentially about every 20 minutes. While everyone is smiling, kissing and recovering from the pain, bacteria are going wild colonizing our human bodies.
In addition to our mother’s vaginal flora that we mentioned above, some of her gut flora mixed with a few skin dwelling germs and possibly a few others from the hospital’s repertoire are the mixture that we start with. This acid army protects us from harmful bacteria and yeast, while other bacteria begin to train our immune system (which will be a major part of their job throughout the rest of our life), and even start to help us deal with indigestible components of our mother’s milk by breaking it down to manageable pieces.
Several academic groups have reported that it can take one to three years to reach some sort of steady state of stable colonization. Until then, our gut is a dramatic environment of bacterial battles and struggles, where power and supremacy change hands unpredictably and often. For example, in the first days of our human life, bacteria that find their way into our mouth will spread quickly throughout the gut, only to disappear as quickly as they came. Other bacteria come and remain with us for the rest of our life.
Interactions with our mother are key in shaping the collection of bacteria that will live with us for the coming months and prepare our gut for the arrival of an adult bacterial population. One common interaction is breast feeding, which promotes the establishment of a bacteria that are instrumental in the development of immune and metabolic system: Bifidobacteria. Children with an insufficiency in Bifidobacteria in their gut during the first year of life are more prone to obesity later in life. There is also circumstantial evidence that a breast feeding induced shift in bacterial flora has a correlation to later gluten intolerance. A baby’s first population of gut bacteria prepares the way for a more mature population by removing oxygen and electrons from the intestine. The shift from breast feeding to baby formula and later to junior food supply, is another key inflection point but is more gradual. The first bacterial colonizers just described are able to break down simple carbohydrates such as those in rice. When we proudly buy the first baby meals with garden peas, or spinach, etc., we are triggering significant selective pressure because the baby is going to quickly need new kinds of digestive bacteria.
Fortunately, bacteria will adapt to the type of foods that are supplied. For example, studies have shown that if you compare the microbiome of a one-year-old African baby with that of one from a western country, the former contain several species of bacteria that are able to break down very fibrous plant based foods that are absent in the later. Another great story of how this selection pressure forces bacteria to adapt, even at the genetic level, is found in Japanese microbiome studies. The human gut microbiome in Japan has picked up genes from bacterial marine microbes that allow the Japanese to digest seaweed more efficiently than those of us living here in Boston. Thus, as much as I love sushi, I may not be getting the most out of it, or at least not as much as my Japanese friend, Akira, does. He probably has the right bugs to deal with seaweed because his mother was born and raised in Japan, and he is very likely to still have them despite arriving in Boston in the early 90’s and eating many nights at McDonald’s with me at the Longwood Galleria.
Another aspect of our childhood that is operationally important, or at least more than I realized at the time, is that on the way to a relatively mature gut flora in our third year we go through a phase where we stick all sorts of things into our mouths, which turns out to be a good thing. By doing this, we acquire more and more microorganisms that help to build up our population diversity, some of which will stay and enrich us. As we build our population diversity, we evolve from having a couple hundred species of bacteria (the first 3 to 6 months of life) to several thousand. Most of the inhabitants of our gut belong to one of five different Phyla: mainly Bacteroidetes and Firmicutes, with important selected subpopulations of Actinobacteria, Proteobacteria and Verrucomicrobia. Within each one of these phyla, we have families with numerous members and species that vary among each other.
All these new data on how do we acquire our microbiome and the value of its diversity put Cesarean section births under a different light. More than a third of all children in the western industrialized world are born by C-section. Since these children do not get maternal bacteria from a vaginal birth, they will get it mainly from skin contact. Skin bacteria is not as strictly controlled as the birth canal contingency, so whatever gathers on the skin could end up in the baby’s belly. These bacterial characters may include pathogens or weird types of bacteria that might not train an immature immune system in the proper way. Babies born by C-section take more years to develop a normal population of bacteria than babies born vaginally. However, several studies have shown that by the age of seven, there is barely any discernable difference between the gut flora of children born vaginally or by C-section. The problem is by that age the ability to modulate and shape the immune and metabolic systems are over or almost over. These are the facts, but as to the consequences? I am not an expert and cannot evaluate the literature, but there are hundreds of peer reviewed articles establishing solid correlations between the type of birth with autoimmune and metabolic diseases. I am hopeful that the scientific community will learn more and help us make intentional and active decisions about the consequences of electing a C-section. For example, one American study has shown that administration of Lactobacillus to C-section babies can reduce their risk of developing allergies, while the same treatment has no effect on children born vaginally.
From the age of three, we shape our bacterial microbiome based on our diet (I drink way too much coffee), our lifestyle (sports, stress, pets), where we live, and more. Defining a normal healthy microbiome is a matter of extensive scientific research, and many academic and industrial groups are focused on understanding and establishing what is a normal ‘baseline.’ Each one of us has a quite unique “bacterial fingerprint” in our gut that helps us to stay healthy or can trigger trouble, whether big or small. Our bacterial composition is shaped by what we do every day, but it was determined in that first EPIC day; the day that we were colonized, the day we went from being just human to being an ecosystem, the day we became a hybrid being full of diversity and acquired functions by virtue of a massive invasion of the bacterial hordes. That day, Professor Wolpert, was birth. Gastrulation was a just another boring day.