“How Colonization by Microbiota in Early Life Shapes the Immune System” (2016), by Thomas Gensollen, Shankar S. Iyer, Dennis L. Kasper, Richard S. Blumberg

In 2016, researcher Thomas Gensollen and colleagues published “How Colonization by Microbiota in Early Life Shapes the Immune System,” hereafter, “Microbiota Shapes the Immune System,” in Science. The article reviews what is known about how microbial colonization impacts immune development in newborns. Because the immune system protects the body from infection, an individual’s microbiome composition also affects susceptibility to certain diseases. Specifically, the authors discuss microbe colonization during early life, a time they refer to as the window of opportunity for future disease susceptibility. That window of opportunity is a period where environmental influences more easily shape the infant’s immune cells and their functions. In turn, the authors present that window as an optimal time for treating disorders associated with the microbiome and the immune system. “Microbiota Shapes the Immune System” reviewed data from dozens of articles to show that there is a narrow window during infancy where microbiome interactions directly or indirectly influence immune development, a potential area for interventional methods to target immune development.

1. Background and Context
2. Article Roadmap
3. Detailed Content
4. Impact

Background and Context

The article centers on the lasting impacts of the microbiome on early development. The microbiome is a collection of microorganisms, mostly bacteria, that colonize the gut, skin, and airways because of daily environmental exposures. In the human gut, there are roughly 100 trillion bacterial cells, which is approximately ten times more than the total number of human cells in the body. Although there are harmful bacteria that infect the body, most microbiota are commensal, which means that they are not harmful to the host. In fact, they contribute to the host’s physiological functions, such as energy metabolism and protection against infection. Different factors such as diet and lifestyle can shape the composition of the microbiome. Within the first year of life in humans, microbiome composition fluctuates in diversity, which results in different adults having their own unique set of microbiota.

Like the microbiome, development of the immune system during early infancy relies on environmental exposures. The immune system consists of a variety of different cells and tissues that provide immunity, which means that they protect the body against infection. Immune cells recognize foreign proteins called antigens, and then either alert nearby cells or kill the invader directly. While the whole body has an immune system, there are also various mucosal membranes throughout the body that have local immune systems. Mucosal membranes are surfaces that line body cavities and canals, such as the gut and oral cavity, which makes them especially prone to infection since they are barriers to the body’s interior. One of the main characteristics of mucosal immune cells is that they are tightly controlled to avoid improper immune system reactions to foreign food antigens. The gut mucosal immune system is one of the most complex in the body. Because the gut is also home to a complex microbiome, the proximity between microbiome and immune cells allows for interaction and cross-talk.

All authors of “Microbiota Shapes the Immune System” were affiliated with the Brigham and Women’s Hospital at Harvard Medical School in Boston, Massachusetts, at the time of publication. Gensollen, Shankar S. Iyer, and Richard S. Blumberg were a part of the Department of Medicine, specifically the Division of Gastroenterology, Hepatology, and Endoscopy. Dennis L. Kasper worked in the Department of Microbiology and Immunobiology under the Division of Immunology. Gensollen, the primary author of “Microbiota Shapes the Immune System,” had worked on antigens and T cell regulation as a research fellow at Brigham and Women’s Hospital since 2014.

“Microbiota Shapes the Immune System” is a review article that examines the role of microbial colonization during early development of the mammalian immune system. One of the first documented reports of bacterial colonization in the gut was in 1842 when John Goodsir, a surgeon from Edinburgh, Scotland, found a colonizing bacteria called Sarcina ventriculi in the stomach fluids of a patient. During that time period, scientists questioned whether the bacteria was pathogenic or commensal. Then, in the late nineteenth century, Theodor Escherich, who conducted research in Germany, studied gut bacteria in infants and hypothesized that bacterial colonization influenced breakdown of food and other physiological functions. In 2007, the National Institutes of Health started the Human Microbiome Project with the primary goal of characterizing the human microbiome and understanding how microbiome composition impacts human health. One study conducted by Sahar El Aidy, who worked in the Netherlands, and team, in 2013 showed that in mice, microbial colonization during early development shaped the host’s immune system. However, El Aidy also found that microbial colonization during adulthood did not have the same effect on immune development. “Microbiota Shapes the Immune System” reviews a collection of studies on humans and rodents that demonstrate microbial colonization during a specific window of opportunity can impact how the immune system develops, which in turn dictates the diseases to which an individual is susceptible.

Article Roadmap

The authors divide the article into seven sections. In the untitled introduction, the authors explain the process of microbial colonization and the potential implications it has on development and health. In the second section, the authors introduce the history behind animal experiments in microbiome research. The third section details how neonatal immune cells are more adaptable to change than adult immune cells, which makes early life a critical period for development. In the fourth section, Gensollen and colleagues examine specific types of immune cells and the general impact of microbial colonization on each type of cell. Then, through the fifth section, the authors discuss microbial colonization and immune cells, but in the context of the first two weeks after birth. The sixth section outlines how because the immune system protects against disease, the effect of microbial colonization on immune development may dictate what types of diseases an individual is at risk for. In the seventh and last section, the authors emphasize that because the microbiome influences disease susceptibility, it is a potential area of study for disease intervention and prevention.

Detailed Content

In the untitled introduction, the authors briefly describe the microbiome in early life and how it adapts to environmental influences. They state that commensal microbiota, which are the harmless bacteria that reside inside the body, colonize most body surfaces such as the skin, oral mucosa, and gastrointestinal tract. The authors explain that the composition of a mammal’s gut bacteria may begin developing before birth, since researchers have found maternal gut bacteria in the amniotic fluid that surrounds the fetus in mice and in the first stool of a premature human newborn after birth. After birth, environmental factors such as delivery method, the infant’s diet, and other exposures influence the introduction of new microbial species. For example, infants born via Cesarean section, which is when a surgeon delivers the infant by cutting into the mother’s abdomen, lack the vaginal microbes that infants born vaginally acquire during delivery. The authors note that prior to the age of three, the microbiome is highly variable and sensitive to the environment. The team notes that during early development, the immune system learns to recognize and react to microbial substances that can have long lasting effects such as an individual’s immune responses later in life. They also state that changes to the microbiome composition early in life may alter the behavior of immune cells, highlighting the potential implications of the infant microbiome on susceptibility to certain diseases in adult life.

In the second section, “Evidence That the Microbiota Influences the Immune System: Lessons from Germ-Free Animal Studies,” Gensollen and colleagues summarize past experiments that studied the relation between microbiota and the immune system. They explain that in 1885, Louis Pasteur, a microbiologist who conducted research in France, proposed the idea of using germ-free, or GF, animals to research the effects of microbe colonization. GF animals are animals raised in a sterile environment and so do not possess a microbiome, which allows researchers to conduct experiments to see how the microbiome affects health. According to the authors, then, in 1896, George H. F. Nuttall and Hans Thierfelder created the first GF animals by delivering guinea pigs via Cesarean section to prevent colonization by vaginal microbes during delivery, and then raising them in germ-free conditions. Following the creation of GF rats and mice, various researchers throughout the 1900s found physiological differences between GF animals and animals with normal, harmless microorganism colonization. The authors state that because GF animals lost the microbiota that contributed to essential functions, they presented with dysfunctional gastrointestinal symptoms. For example, researchers found that GF animals had impaired digestive function, which led to a buildup of mucus and enlarged organs. In addition, various researchers in the late 1900s reported that GF animals had impaired tissue development in the spleen, thymus, and lymph nodes, which are tissues that participate in immune system function. The authors of “Microbiota Shapes the Immune System” explain that most of the abnormalities existed at mucosal surfaces, which is where colonizing bacteria reside, indicating that the loss of microbial diversity was likely the reason for those irregularities.

The third section, “Microbial Colonization Modulates Early Development of the Immune System in Mucosal Tissues,” specifically looks at how the microbiome influences early immune system development according to past studies. The authors write that the first few years of life mark the period of greatest fluctuation in microbial diversity. They then speculate that the variability of microbial colonization directs the immune system in its development of cell structures and functions. The authors state that unlike adult immune cells, neonatal immune cells tolerate exposure to unknown molecules or organisms, such as commensal bacteria. Adult immune cells are more reactive against foreign antigens whereas neonatal immune cells are geared towards developing tolerance. They explain that tolerance during the neonatal stage, where there is a sudden exposure to many new antigens, is necessary so that the immune cells do not attack the commensal microbes that are colonizing the body. Receptors on the neonatal immune cells recognize the antigens from the commensal bacteria, which leads to development of the immune cells and their functions. The authors state that because GF animals lack microbial colonization, they present with various immune defects. They discuss two categories of those immune defects. The first is age-independent, where artificially introducing commensal bacteria to the GF animal can rectify the immune defect. The second is age-dependent, meaning that if the GF animal does not possess a normal microbiome during early stages of life, then the immune defect will remain permanent through adult life. The authors thus emphasize the importance of early life microbial colonization for proper immune development.

In the fourth section, “Age-Independent Influences,” the authors examine general age-independent impacts of the microbiome on T cells, B cells, innate lymphoid cells, and epithelial cells. Those cells belong to the immune system and have different functions to defend the body. T cells are immune cells that protect the body against infection by either directly attacking foreign substances or regulating other immune activity. B cells produce antibodies that combat infection by neutralizing foreign proteins. Innate lymphoid cells have similar functions as T cells but recognize more general molecules. Epithelial cells are not immune cells, but they exist at mucosal surfaces and regulate immune functions. The authors state that GF animals present with abnormal numbers or dysfunction in those cells. However, GF animals can regain normal function in those cells through treatment by artificially introducing commensal bacteria into their system at any point in time, which the authors imply is important because an intact immune system is necessary to combat infection. In addition to restoration, they explain that introducing a more diverse microbiome may enhance the function of immune cells. The authors comment that the successful restoration of immune function indicates that some aspects of immune development do not depend on microbiome introduction at an early age.

In contrast, the fifth section, “Age-Dependent Influences,” details immune abnormalities in GF animals that do not correct themselves with microbe colonization due to missing the window of opportunity in early life. The authors discuss immune defects where introducing commensal bacteria is only successful in restoring those defects if the GF animals receive treatment within the first two to four weeks of life. For example, the authors state that IgE, an antibody that B cells secrete in response to allergy, is present in abnormally elevated levels in GF animals. Only animals that received microbiota from birth to four weeks after birth presented with normal levels of IgE in adult life, suggesting that microbial diversity during the neonatal period is required for normal IgE levels. Another example that the authors discuss is the effect of microbial colonization on regulatory T cells, which are a type of T cell that prevent overactivity in the immune system. They state that exposure to the house dust mite microbe in the lung induces the development of a specific group of regulatory T cells, which protect against asthma since asthma results from an overactive immune system. The authors note that development of those regulatory T cells only occurs in the first two weeks of life in mice, and mice with no microbial colonization in the first two weeks had increased cases of asthma. The authors conclude that some immune cell development relies on microbial exposures during early life.

In the sixth section, “Early-Life Perturbations of Microbiota and Their Relationship to Human Disease,” Gensollen and colleagues expand on their discussion of microbial colonization and contextualize it with disease risk. They explain that exposure to environmental factors such as farms, antibiotics, birth delivery method, or breast milk cultivates distinct microbiomes in different individuals. The authors state that children who grow up on farms encounter more diverse microbes, which enhances their immune system. They note that children from farms therefore tend to present with less allergies and asthma. On the other hand, infants exposed to antibiotics, which attack certain microbial cells, have a less diverse microbial composition. The authors cite a 2011 study where children who took antibiotics within the first six months of life had a greater risk of allergy and asthma once they reached six years of age. Thus, the authors claim that there is an association between disruptions to the microbiome and disease susceptibility.

In the last section, “Concluding Remarks,” the authors restate the relationship between microbial colonization and proper immune development. They bring up the window of opportunity in early life where changes to microbial diversity during that time may mold the individual’s disease risk in adult life. The authors state that in rodents, the window of opportunity is the suckling period, which is the first two weeks after birth where the offspring nurses. However, they comment that for humans, the specific time window is unknown. The authors also consider the possibility of microbial colonization during pregnancy affecting the infant’s immune activity. They cite a 2016 study where researchers found maternal transfer of microbial molecules to offspring in mice during pregnancy via the placenta. Those mice had better functioning immune cells when compared to mice born to GF mothers. The authors note that further understanding of the effect of the microbiome on the immune system is necessary for the potential prevention of certain diseases.

Impact

As of 2024, “Microbiota Shapes the Immune System” has been cited over 1,700 times. The primary conclusion that microbial colonization affects immune development has led to further work in Gensollen’s group, as well as other researchers. In 2017, Gensollen published another paper, “Correlation Between Early-Life Regulation of the Immune System by Microbiota and Allergy Development.” In that article, he builds on key concepts from “Microbiota Shapes the Immune System,” but reports on how the microbiome in early life influences allergy development. Several clinical trials have since reported on treatments involving microbe-related supplements to newborns to establish a healthy microbiome. A clinical trial conducted by researchers in Italy and Belgium that ran from 2012 to 2015 showed that infants who took human milk oligosaccharides, a supplement that promotes gut bacterial growth, from birth to six months of age had less reported illnesses and infection-related medication use.

Additionally, another research group published “The Mother-Offspring Dyad: Microbial Transmission, Immune Interactions and Allergy Development” in 2017, which cited “Microbiota Shapes the Immune System,” but extended the topic towards maternal influences during pregnancy and how that may program immune development for the infant before birth. A 2021 study found that taking vitamin D during pregnancy enhanced an infant’s microbial diversity and lowered an infant’s risk for asthma. “Microbiota Shapes the Immune System” reviewed the window of opportunity concept that others have since expanded on for potential therapeutic interventions that may begin before birth. The article provides support for the concept that environmental exposures during early life affect microbiome composition, which in turn has lasting impacts on immune function and disease susceptibility. “Microbiota Shapes the Immune System” helped researchers understand and address microbial colonization as a key factor in immune health.