Intestinal Microbiome: Functional Aspects in Health and Disease

E. Isolauri, P. M. Sherman, W. A. Walker

• Publisher: S. Karger
• Year: 2017
• ISBN:
  9783318060317
• Topic: Medicine
• Subtopic: Gynecology, Obstetrics & Midwifery

The intestinal microbiome is especially important during the first thousand days of life. Exposure to microbes in utero significantly impacts fetal development, in part through epigenetic processes and in part through hormonal influences which cause a change in the mother's intestinal microbiome. The nature of delivery and perinatal antibiotic treatment, as well as diet (especially in the postpartum period), can also influence initial microbial colonization and the development of appropriate intestinal defense mechanisms. These, in turn, can affect the expression of allergy, autoimmune disease, and brain function, among other things, later in life. The first part of this publication focuses on the development of the human microbiome in utero and the importance of normal colonization of the newborn gut in immune development and disease prevention. The second section deals with the normal development of gut microbiota and with clinical conditions associated with dysbiosis. The final chapters cover various aspects of human milk evolution and oligosaccharides.

Normal Development of Gut Microbiota and Dysbiosis

Isolauri E, Sherman PM, Walker WA (eds): Intestinal Microbiome: Functional Aspects in Health
and Disease. Nestlé Nutr Inst Workshop Ser, vol 88, pp 57-65, (DOI: 10.1159/000455215)
Nestec Ltd., Vevey/S. Karger AG., Basel, © 2017

______________________

Dysbiosis in the Neonatal Period: Role of Cesarean Section

Josef Neu

Division of Neonatology, Department of Pediatrics, University of Florida, Gainesville, FL, USA

______________________

Abstract

From epidemiological studies and studies done evaluating microbiomes in infants, there is a strong signal that the infants born by elective cesarean section (C-section) develop microbiota that differs from those babies born by vaginal delivery. Epidemiological studies show increased odds ratios for the development of immunological disorders such as type 1 diabetes, celiac disease, asthma, allergic diseases as well as metabolic diseases such as obesity in babies born by C-section. These are interesting associations, and if supported by additional studies that rigorously control for confounding factors, they will have major public health implications. Such studies represent major challenges because the confounding factors are numerous. The fact that provision of vaginal bacteria to C-section-delivered babies using a mouth swab that may actually transmit these bacteria to the infant is of interest and supports the concept that this can be done to alter the infant microbiota. However, significant caution needs to be taken, and alternative approaches that are safe as well as effective need to be considered; follow-up studies showing efficacy as well as safety need to be evaluated in the long term.

© 2017 Nestec Ltd., Vevey/S. Karger AG, Basel

Introduction

Vaginal birth has been the natural and common mode of newborn delivery until the last century, where cesarean sections (C-sections) have become increasingly common. There are many indications for C-section delivery, both maternal and fetal ones. C-sections can be further classified into planned or emergent C-sections. Emergent C-sections are typically performed when the life of the infant or the mother can potentially be saved. States of emergency can be caused by events such as the prolapse of the umbilical cord and nonreassuring fetal heart rate tracings. Planned C-section deliveries are usually performed prior to the onset of labor and may be either medically indicated or elective. Medically indicated C-sections are generally defined as situations with a significant risk of an adverse outcome for the mother or the baby if the operation is not performed at a given time [1, 2]. Medical indications can be due to situations such as untreated maternal HIV, herpes, a history of prior uterine rupture, fetal anomalies, or abnormal fetal presentation. There are also indications which are clearly not based on medical needs, and these are usually performed secondary to convenience of scheduling for the obstetrician or family.

Although the optimal C-section delivery rate is not clear, in 1985, at a meeting organized by the World Health Organization in Fortaleza, Brazil, a panel of reproductive health experts stated that “there is no justification for any region to have a rate higher than 10-15%” [3]. Despite these recommendations, C-section rates have risen dramatically in the past 2 decades, with rates approaching 50% in some countries, such as Brazil, Iran, and the Dominican Republic. Thus, it is very likely that many of these C-sections may be unnecessary and/or simply based on convenience in countries with a high rate. Although concern should be raised in regard to the effects of these high C-section rates on the mother, their effect on public health as well as the health and maturation of the individual infants should be considered, as will be discussed in this review.

With the advent of the human microbiome project in the past decade, it has become increasingly clear that early microbial colonization will have major effects on the maturing individual. Although the term “dysbiosis” is not clearly defined, it reflects deviations from the normal microbial ecology that result in detrimental health effects on the host. Therefore, early-life perturbations of the microbiota are likely to lead to metabolic, immunological, and epigenetic consequences that have major effects on the developing individual and perhaps may even affect subsequent generations.

In this review, the effects of C-section versus vaginal delivery on the subsequent development of the microbiota, and how this relates to health outcomes, will be discussed. Studies will be presented that suggest that C-section delivery may result in a “dysbiosis” that has detrimental effects on the individual in later life. Various caveats in terms of the interpretation of the results of recent studies suggesting major differences in terms of the microbiota development and associations to subsequent health and disease will be scrutinized. These include the fact that there is considerable evidence suggesting that microbiota exists prior to delivery, and that this may also play a major role in subsequent health and disease. Furthermore, there are various environmental perturbations such as maternal diet, maternal body habitats, such as body mass index, the use of antibiotics as well as various other drugs, introduction of human milk versus donor milk versus formula, early stressors, and other factors that may play a role in confounding results of epidemiological studies as well as studies of microbiota in babies who are delivered by C-section versus vaginal delivery. In this review, we will also discuss recent methods to restore vaginal microbes after C-section delivery.

Mode of Delivery and the Infant Microbiome

Until recently, the fetal-maternal unit was believed to be sterile and only to become colonized at birth through contact with the microbial community in the vaginal canal. Thus, those infants delivered by C-section would not receive this early colonization from the vagina and required other environmental exposures to begin this colonization. However, there is ample evidence that colonization of the fetal-maternal unit begins earlier than birth since microbes have been identified in the amniotic fluid, umbilical cord blood, fetal membranes, meconium, and placenta [4]. These prenatal microbial conditions are seldom mentioned in studies comparing the effects of C-section versus vaginal delivery. In addition, differences have been found in the microbiota of children born vaginally, or by elective or emergency C-section [5]. Many of these studies suffer from interstudy methodology variability such as PCR bias and other confounding factors. Nevertheless, some of the important trends found in the literature regarding microbial composition differences in vaginally versus C-section-delivered children include: (1) children born by C-section, elective C-section in particular, exhibit diminished diversity in their microbiota; (2) less health-inducing bacterial species such as lactobacilli are seen after C-section delivery; and (3) there appears to be a trend toward more pathogenic bacteria (a possible “dysbiosis”) in the developing microbiome of C-section-delivered infants.

In terms of diversity, a few studies have shown evidence of persistent negative associations between C-section delivery and infant microbial diversity and richness. In a study evaluating 16S rRNA genes in 24 healthy term infants’ stool, infants born by C-section had lower total microbial diversity compared to vaginally delivered infants, and these differences persisted through the first 2 years after birth [6]. Another study in Canada using high-throughput DNA sequencing in term infant fecal samples 4 months after birth found that infants born by elective C-section had lower diversity [7]. Other studies have demonstrated higher richness in vaginally delivered infants when evaluating bacteria found in oral swab samples [8].

In 2010, Dominguez-Bello et al. [9] described the microbial communities of 10 mothers and their infants, 6 of whom were delivered by C-section. Using 16S rRNA sequencing of samples, it was found that in vaginally delivered infants, stool sample microbes collected within the first 24 h after birth most resembled their own mother’s vaginal microbes. Babies who were born by C-section were colonized by bacteria that most resembled skin flora. It was suggested from this work that infants delivered by C-section lack exposure found in mother’s vaginal or intestinal environment. The most dominant genera of bacteria in vaginally delivered babies when compared to those delivered by C-section were Lactobacillus, Prevotella, Atopobium, or Sneathia, whereas the most dominant genera in C-section infants was Staphylococcus, a common skin microbe [9]. Lactobacillus microbial communities are found as a dominant group in healthy vaginal communities [10]. Other studies have also found that vaginally delivered infants have more lactobacilli in the gastrointestinal tract than those delivered by C-section [11]. However, not all groups have found differences in bacterial communities in C-section versus vaginally delivered infants. In a study performed in different countries in Europe analyzing 606 infants, mode of delivery had no effect on relative proportions of bifidobacteria in 6-week-old infants [12]. In this study, infants born via C-section also had less Bacteroides than vaginally delivered infants. This is of interest in that Bacteroides may play a beneficial physiological role in the neonatal intestine [13].

There are several confounding factors that need to be taken into account in such studies (Fig. 1). Our group found that the microbiota measured in meconium during the first 48 h after birth was more diverse in preterm infants delivered by C-section [14]. This begs the question of ...