The Microbiome in Prenatal and Neonatal Life

By Josef Neu

The Microbiome in Prenatal and Neonatal Life clarifies that the microbiome in the maternal fetal unit and immediate changes that occur as new microbes are acquired postnatally play major roles in subsequent health and disease. Rapidly developing technologies for multi-omic analyses and systems biology are shifting paradigms in both scientific knowledge and clinical care with regard to this topic. In essence, we are changing the idea that newborns emerge from sterile environments. As such, in-utero colonization may have impacts on the development of immunity and metabolism that, with epigenetic modifications, will lead to diseases in later life.

In addition, the microbial profile that develops during and after birth depends on mode of delivery, type of feeding (human milk versus formula), and various other environmental factors to which the newborn is exposed.

• Discusses the critical nonredundant timeframe in a newborn's life during which many factors drive immune and tissue maturation and influence the susceptibility to immune-mediated and other diseases in adult life
• Proves that the fetus and uterine membranes are exposed to not only microbes in close proximity but also to microbial products from metabolism of microbes in the mother
• Shows that since early life periods are a critical window for development, epigenetic and/or immunologic alterations may occur that can affect not only the infant during his/her lifetime but also subsequent generations
• Gives insight into factors that may affect the newborn microbiome and subsequent development

• Language: English
• Publisher: Academic Press
• Release date: Jan 13, 2021
• ISBN: 9780128206096

Josef Neu

Dr. Neu is Professor, Department of Pediatrics, Division of Neonatology; he received his Bachelor of Arts Degree in 1971, at Wisconsin State University, Whitewater, WI. In 1975 he received his Medical Doctorate, University of Wisconsin, Madison, WI. Dr. Neu completed his Pediatrics Residency at John Hopkins Hospital, Baltimore, MD from 1975-1978, 1978-1980 Postdoctoral Fellow in Neonatology, Stanford University Medical Center, Stanford, CA. In 1987 he completed his Sabbatical, Inselspital, at the University of Bern, Switzerland. Dr. Neu has received during his career several honors and awards. He Chairs and is involved on National and International Committees. Dr. Neu is active on several Society Membership, Editorial boards, journal reviewer, Service to the Community, Service to schools. He is well known for his lectures here and aboard. Dr. Neu has received many appointments as Assistant Professor, Director, Division of Neonatology, Milwaukee Children’s Hospital Milwaukee, WI, Associate Professor, and Associate Division Chief for Neonatology, College of Medicine, University of Florida, Director/Neonatology Fellowship Program and Director of Neonatal Intensive Care Unit.

Book preview

Introduction

If you don’t like bacteria, you’re on the wrong planet.

Stewart Brand—Writer and editor of the Whole Earth Catalog.

Over the past two decades, an increasing number of scholarly research articles, reviews, and books related to human microbial ecology and/or the human microbiome have been published. Excitement about this emerging field has been fueled by its potential in helping us better understand human health and disease and the development of numerous preventative and therapeutic strategies. We no longer look upon microbes as merely pests that cause disease, but in many cases old friends that improve our survival and enhance our lives. This book will focus on highly relevant stages of microbial-human interactions: pregnancy, the immediate perinatal period, and infancy.

Why would this short epoch that only represents about 13% of the human lifespan deserve an entire book? Let’s start with the commonly held concept that the mother and fetus exist as a dyad during pregnancy with microbes’ major roles as agents of diseases that can cause the pregnant mother or fetus great harm. While partially true, pathogenic microbes contribute a very small proportion to our entire microbial environment. The vast majority can be classified as commensals, symbionts, or mutualists. In other words, they either just live in concert with the human host or play a role where either the microbe or host benefit or both mutually benefit.

This leads us to the Old Friends Hypothesis, popularized by Dr. Graham Rook.¹ In this hypothesis, humans are not individuals, but rather ecosystems with microbial partners that especially in early life are involved in development of every organ system in our body. In fact, we are composed of more microbial DNA and genes than those we consider human, in other words, derived from a sperm and an egg. This can be interpreted as the human body serving as a farm for our microbial partners. They, for the most part, simply just grow, proliferate, and thrive with us. Some may serve important functions by protecting us either directly from pathogenic microorganisms or training our immune systems to control pathogens. Occasionally, this control overreaches and results in collateral damage via massive inflammatory responses or autoimmunity.

The microbe-host ecosystem (sometimes also termed a holobiont) is highly relevant to the main theme of this book.², ³ We will discuss how interactions within this ecosystem in early life affect development during the entire lifetime of the individual and likely even effect subsequent generations through epigenetic mechanisms.

Much of the excitement about concepts related to friendly microbes during the perinatal period and early life have emerged over the past two decades largely because of new technologies that are now helping us to be better able to understand the microbial world around us. Some of the enthusiasm is driven by commercial interests which include use of microbial therapeutics such as probiotics in the promotion of health or even prevention of disease.

Classic technologies involved examining microbes under a microscope and/or culturing them in a broth or gelatinous substance usually derived from seaweed (agar) that promotes the growth of these microbes. Of interest is the fact that it was often noted that a large variety of microbes could be seen under a high power microscope, but often only a small percentage of these microbes could actually be cultured. This was a phenomenon some referred to as the great plate count anomaly and suggested that there were many microbes that were just simply difficult to culture by common means.⁴

The techniques developed in the past couple of decades involve DNA sequencing-based technologies, many of which resulted from the Human Genome Project which was initiated in the late 1980s and resulted in sequencing of the Human Genome in the early 2000s. This catalyzed the Human Microbiome Project,⁵ focused primarily on the microbiome, and more recently the Integrated Human Microbiome project,⁶ which integrates several types of -omic studies including proteome, metabolome, transcriptome, etc. Of note is that these technologies are being used to not only identify and characterize microbes in humans, but certain environmental niches such as soil and bodies of water. In the human, body regions and organs such as the intestine, skin, and vagina are being intensively investigated.

In addition to enhancing our ability to being able to identify and classify the microbes present in these sites, it is now also possible to evaluate the entire community of microbes and their capabilities. Meshing the microbial analyses with other techniques such as biochemical analyses to identify and measure metabolites and proteins, using multiomics" it is now possible to determine what these microbes are doing in their environments, and also to evaluate how the human host responds to them. These multiomic techniques combined with evaluation of the health and disease status of the human host over time and how certain perturbations such as nutrition, medications, and other environmental factors interact, now provide the opportunity for developing a much more personalized approach to not only treatment of disease, but also disease prevention strategies.

The overall focus of this book is on pregnancy and early life. In terms of the pregnant woman, her fetus, and baby, it is to be noted that evidence is accumulating that they do not coexist in a sterile environment. Although there is considerable debate whether the womb is sterile under health conditions (to be discussed in Chapter 2), it is clear that the pregnant woman is exposed to a large number of microbes in her environment. It is becoming increasingly evident that these microbes play a vital role in the health of the mother, fetus, and the newborn.

There are several anatomic sites in the pregnant woman that contain microbes and these change during pregnancy. For example, if one uses DNA-based sequencing methodologies to evaluate microbes in the stools of pregnant women during different stages of pregnancy, the microbes found during early pregnancy differ markedly from those near the end of pregnancy.⁷ In fact, if the microbes from early pregnancy are inoculated into mice that have been raised under germ-free conditions, nothing special happens to these animals as they mature. However, if microbes from the third trimester are inoculated into these germ free mice, the mice gain more weight than usual as they mature and also show signs of glucose intolerance, similar to that seen in pregnant women during the third trimester of pregnancy. This suggests a major metabolic role for microbes during different phases of pregnancy.⁷

Vaginal microbes also differ during different phases of pregnancy with certain strains of Lactobacilli dominating the lower vaginal environment during the later phases of a healthy pregnancy. However, in many pregnancies where the babies are born preterm, this phase of Lactobacillus predominance is never reached and other microbes are seen to predominate.⁸

The science of immunology has taught us that we have different components of our immune system that include the capability to mount an effective response to microbes where we largely eliminate these microbes. However, our immune system also has the capability to cause considerable collateral damage to our own tissues, especially at times when we are trying to fight off infections. This systemic inflammatory response can cause death or other major morbidity to the human host. So a balance is needed to counteract brisk inflammatory responses.

The response that balances the brisk response to certain microbial agents, called tolerance requires previous exposure to microbes. If the womb is "sterile’ as suggested by numerous authors, then this tolerizing response would be unlikely. The mother might eliminate the fetus as nonself immunologically. Once the newly born infant emerges from the womb, the baby would potentially respond so strongly to the new microbes in the environment to develop a self-lethal inflammatory response. These are all areas that are now being intensively investigated and will be discussed further in this book.

Babies that emerge from the womb by C-section versus vaginal delivery are thought to collect a different set of microbes early in postnatal life.⁹ If the newborn passes through the vaginal canal and the C-section delivered infant does not, it is likely that the C-section delivered baby will not gather the same vaginally derived microbes. Epidemiologic studies have suggested major differences between individuals born by vaginal versus C-section delivery in terms of various health outcomes such as Type 1 diabetes, celiac disease, obesity, etc.¹⁰ This has been attributed to differences in early microbial exposures and has led to potentially therapeutic approaches such as vaginal seeding or giving probiotics to mothers and babies who deliver by C-section versus vaginal delivery. This will be discussed in greater detail in Chapter 3.

During and after birth, environmental exposures play a major role in acquisition of microbes. How the human host interacts with these plays a major role in health and disease during the individual’s lifetime. In this book we will discuss the role of antibiotics, diet (especially human milk versus formula), and other environmental exposures.

When babies are born preterm, they are highly prone to various problems directly associated with their prematurity. However, studies suggest that diseases such as neonatal necrotizing enterocolitis (NEC), chronic lung disease, and even the development of atopic diseases in these infants may be associated with the types of microbes they are exposed to.

The development of the brain is highly dependent on a large number of factors including nutrition and metabolic status of the mother and infant, and the presence or absence of major acute or chronic inflammation. These factors in turn relate closely to the early microbial ecosystem. In fact, diseases such as autism, schizophrenia, irritable bowel disease, and various other neurodevelopmental disorders have been linked to the interaction between the rapidly developing human fetus, neonate, and infant and their associated microbes. This is not surprising when one considers that major metabolites involved in neurotransmission such as serotonin are derived from these microbes.

Lastly, we will discuss how interactions between microbes and the host result in responses that may not only affect the host during one’s lifetime, but also have effects that can be passed between generations.

From this introduction, it should be clear that a book pertaining to these issues is in order. We will begin this book with a short introduction on evolutionary aspects of the microbiome.

References

1 Rook G.A. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Darwinian medicine and the 'hygiene' or 'old friends' hypothesis. Clin Exp Immunol.