The Human Microbiome in Early Life: Implications to Health and Disease

The Human Microbiome in Early Life: Implications to Health and Disease presents recent research advances that have highlighted the significance of early life, possibly beginning before birth, in the establishment of both the microbiome and its role in health and disease. The book reviews current knowledge on the origins of the human microbiota in early life, presents exposures which may disturb normal microbial colonization, and covers their implications to the risk of disease. Finally, emerging means to modify the early human microbiome to improve health are discussed.

• Examines the timeline of the human microbiome, from before conception to infancy, with an emphasis on clinical implications
• Evaluates the effort to understand not only the composition but also the origin of the microbiome
• Proves the emerging means to modify the human microbiome and particularly ‘the first 1000 days of life’ improve human health and prevent disease
• Generates resources to facilitate characterization of the human microbiota to further our understanding of how the microbiome impacts human health and disease

• Language: English
• Publisher: Academic Press
• Release date: Sep 18, 2020
• ISBN: 9780128180983

Book preview

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Section I

Pregnancy and fetal life

Outline

Chapter 1 The microbiome in a healthy pregnancy

Chapter 2 The microbiome and pregnancy complications

Chapter 3 Microbial signatures of preterm birth

Chapter 4 Prenatal origins of the infant gut microbiome

Chapter 1

The microbiome in a healthy pregnancy

Hadar Neuman¹ and Omry Koren²,    ¹1Zefat Academic College, Safed, Israel,    ²2Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel

Abstract

The human microbiome plays fundamental roles in host metabolism, immunity, and overall health. In many disease states, the microbial composition is altered (dysbiosis), usually exacerbating the clinical condition. However, during pregnancy, the changes in the microbiome are essential for healthy pregnancy progression and outcome. Alterations in microbial compositions are evident in the gut, oral cavity, and the vagina of pregnant women. The microbial changes during pregnancy are correlated with and enhance the gestational immune, hormonal, and metabolic changes that occur during pregnancy, including weight gain. Understanding the extent of the changes in the microbiome that occur in healthy pregnancy and the full effects of the maternal microbiome on the offspring is expected to have an important impact when considering antibiotics and nutritional decisions during pregnancy.

Keywords

Microbiome; pregnancy; progesterone; hormones; immunity

Introduction

The human microbiome, comprising hundreds of microbial species residing within the human body, has been shown to have essential roles in promoting and maintaining health. These include effects on immunity, metabolism, and even involvement in the endocrine system and behavior.

Drastic changes to microbial composition and diversity are typically correlated with disease conditions and are termed dysbiosis. Such changes have been observed in autoimmune diseases, diabetes, obesity, and metabolic syndrome [1–4]. However, during healthy pregnancies, distinct changes are observed in the microbiome, some of which resemble the changes observed in disease states. This phenomenon is not coincidental, but rather essential for the progression of a healthy pregnancy. Thus pregnancy is unique as a positive and physiological example of dysbiosis. In this chapter, we will describe the overall microbial changes during pregnancy and relate these changes to their functional significance. The spectrum of functional effects ranges between influencing the maternal immune system, promoting weight gain, and altering metabolism. Pregnancy complications are correlated with additional distinct microbial alterations, emphasizing the potential roles of the microbiome in both healthy pregnancies, and in the case of complications (discussed in the following chapters). Finally, the maternal microbiome has clear effects on the offspring, as manifested by the initial infant microbiome, and the consequences of antibiotic exposure during gestation.

Understanding the functional changes in the pregnancy microbiome is important for obtaining a full picture of the physiological processes that occur during pregnancy, for evaluation of the state of the pregnancy, and for deciphering potential risk factors for the pregnant mother and developing fetus. It appears evident that the complex immune, hormonal, metabolic, and microbial alterations that occur during pregnancy are correlated with one another, forming a network of physiological processes.

The importance and roles of a healthy microbiome

In the healthy state, our microbiome includes highly diverse populations of bacteria residing in a variety of body sites and niches. These bacterial populations have different characteristics—some are aerobic, whereas others are anaerobic; they can thrive at a variety of pH values and within a range of nutritional milieus [5]. The bacterial populations are also greatly affected by immune and hormonal factors. This explains why the gut microbiota significantly differs from the vaginal or the oral one, why the microbial populations are not identical between individuals, and emphasizes the importance of rich populations of microbes adapting to the changing surroundings during dynamic homeostatic conditions. On a functional level, it is assumed that microbes residing in different body sites also serve different roles in maintaining overall health. While the gut microbiome may play the most essential roles regarding human metabolism, as well as affecting immunity and hormones, the microbiome of the skin, vagina, and oral cavity contributes directly to the immune system in its defense against outside pathogens [6].

The many metabolic roles of the microbiota include food digestion, fermentation of carbohydrates into short-chain fatty acids (SCFAs), digestion of proteins into amino acids, production of vitamins, and metabolism of drugs and xenobiotics [7]. The microbiota has also been implicated in lipid metabolism, conversion of bile acids, and breakdown of polyphenols.

The immunological roles of microbiota are numerous. They help form a barrier for repressing pathogens and modulate the host immune response by affecting both innate and adaptive immune system components [8]. The presence of the microbiota maintains a balance in the abundance of immune cell populations, such as Treg cells versus T helper 17 (TH17) cells [9]. Moreover, levels of pro-inflammatory cytokines have been shown to depend on the microbial composition.

Additional effects of the microbiome on their hosts include altering hormone levels and affecting brain function and behavior [10–12]. A close interplay between the microbiome and the host endocrine system has been described [13]. While host hormones affect the growth of certain bacteria and their function, bacteria can produce and modulate hormones influencing behavior, appetite, metabolism, gender, and immunity.

Similarly, the microbiome is both affected by the brain and can affect the brain development as well as impact appetite, emotions, stress response, cognition, and behavior, such as anxiety and aggression [14]. To this end, the gut microbiome has been shown to be altered in various psychiatric disorders including major depression, schizophrenia, and autism [13,15,16]. One potential mechanism for this effect is the capacity of gut microbiota to produce several human brain neurotransmitters [14]. Other components that might link the microbiome and behavior include hormones and immune parameters.

While alterations in microbiome are associated with developmental changes across our lifetime (e.g., from infancy to childhood, and later, old age), with dietary changes, and with other environmental factors, most divergence from steady-state microbial populations (dysbiosis) has been associated with disease states. Dysbiosis usually includes a decline in microbial diversity and may have long-term consequences leading to disease or enhancing a disease state. Examples of diseases associated with dysbiosis include obesity, inflammatory bowel disease, diabetes, and metabolic syndrome [3]. In fact, it has been suggested that almost all diseases are characterized by a perturbation of the healthy microbiome into an unbalanced diseased state, so that our overall fitness and health are closely intertwined with our microbiome composition [17].

Some of the microbial changes that occur during pregnancy may seem identical to those seen in disease states. However, in their precise developmental context, they do not lead to morbidity, but rather promote necessary functions, including a more flexible immune state and altered metabolism, and may therefore be considered beneficial.

The gut microbiome is altered during pregnancy

Pregnancy leads to dramatic changes in the gut microbiome. These alterations include a distinct reduction in bacterial diversity and richness within individuals (decreased α diversity), less similarity in microbial composition between different women (increased β diversity), and an increase in the bacterial load [18,19]. In addition, alterations in species abundance are observed, with some bacterial species being overrepresented and others being underrepresented as compared to the nonpregnant state [19].

Interestingly, most of the pregnancy-related microbial changes are seen at late stages of pregnancy, in the third trimester. This is also the time when other physiological parameters such as weight gain, insulin insensitivity, inflammation, and changes in hormonal levels reach a peak [20,21]. A recent study found that progesterone has a direct effect on the microbial composition, specifically increasing the richness of several species including Bifidobacterium in the gut microbial composition of women and mice during late pregnancy [22].

Some of the pregnancy-related microbial alterations seem to correlate with the metabolic state observed in late pregnancy. For example, there is a significant reduction in SCFA producers such as the butyrate-producing bacterium Faecalibacterium, similar to the depletion seen in metabolic syndrome patients [23]. On the other hand, an increased abundance of the Actinobacteria and Proteobacteria phyla is observed [19]. Additional changes include increased abundance of Neisseria, Blautia, and Collinsella as pregnancy progresses and decreased abundance of Clostridium, Dehalobacterium, and an unclassified Bacteroidales [22].

Changes to the vaginal microbiome during pregnancy

The healthy vaginal microbiome plays important roles in protection from pathogen intrusion and infections, decreasing vaginosis and sexually transmitted diseases [24]. The healthy vaginal microbiota is predominantly populated by Lactobacillus crispatus, Lactobacillus jensenii, Lactobacillus johnsonii, and Lactobacillus iners [25]. Functionally, some of the most abundant vaginal species including Lactobacillus species produce lactic acid, which lowers the pH of their surroundings, thereby forming a barrier against pathogenic bacteria. In fact, lactic acid has been shown to have broad-spectrum antimicrobial activity [26]. Specifically, Lactobacillus rhamnosus and Lactobacillus reuteri have been shown to inhibit Candida albicans and decrease expression of the latter’s NF-κB-related inflammatory genes [27]. During pregnancy, the protective functions of the vaginal microbiome, including lowering of the vaginal pH, are enhanced due to an increase in abundance of Lactobacillus species [25,28]. This is accompanied by a significant decrease in overall diversity of the vaginal microbiota [29]. One of the distinct pregnancy-related changes is the development of a dominant Lactobacillus species over the range of Lactobacillus species generally present [30,31]. Mechanistically, this predominance may occur due to bactericidal effects of some Lactobacillus species against competing species [31]. As often occurs in microbiome research, not all studies observed identical microbial changes [32]. This may be due to relatively small cohorts, different detection and analysis methods, and different human subject populations including a variety of ethnic groups studied. Accordingly, it was shown in pregnant African–American women that a significant decrease in vaginal microbial richness and diversity, between the first and second trimesters, is associated with preterm birth [33,34]. A thorough study analyzing the vaginal microbiome of 10 pregnant women sampled every 3 weeks during pregnancy revealed increased diversity of L. iners-dominated communities along gestational age [35]. This study also suggested that analysis at the bacterial strain-level may yield more informative data when trying to understand microbial alterations during pregnancy [35]. Additional features found to be associated with the vaginal microbiome during pregnancy are higher bacterial load and lower prevalence of Mollicutes, specifically Mycoplasma and Ureaplasma [36].

In contrast to the changes observed in late pregnancy in the gut microbial composition, the changes in the vaginal microbiome are most pronounced in early pregnancy [25]. It would be interesting to assess whether this is due to a more direct hormonal effect on the microbiota, or other reasons. Functionally, perhaps the microbial protection from vaginosis is most crucial at early stages of pregnancy, when the developing embryo is most vulnerable. Further indications of hormonal influence on the vaginal microbiome may be seen in studies of the effects of hormonal contraceptives. These studies showed that combined (estrogen and progesterone) oral contraceptives are significantly associated with increased vaginal abundance of lactobacilli and reduced abundance of species associated with bacterial vaginosis [37].

During the postpartum period, the pregnancy profiles are reversed; the vaginal microbiome once again becomes more diverse; Lactobacillus species decrease in abundance; and bacteria such as Peptoniphilus, Prevotella, and Anaerococcus become more abundant as compared to the pregnant state [30].

The oral microbiome of pregnant women

Perhaps more surprising than the changes caused to the gut and vaginal microbial compositions, are the changes observed in the oral microbiome during pregnancy. First, there appears to be an increase in oral microbial growth during pregnancy. This was observed by viable counts of seven of the most common bacterial species in pregnant versus nonpregnant Japanese women [38]. Moreover, in a study of the supragingival microbiome, increased diversity and alterations in microbial composition were found among the samples of pregnant versus nonpregnant women [39]. Specifically, an increased abundance of Neisseria, Porphyromonas, and Treponema, along with decreased abundance of Streptococcus and Veillonella, was observed in the pregnant group. Furthermore, the growth of pathogenic bacterial species including Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, as well as Candida appears to be elevated during various stages of pregnancy, as supported by multiple studies and the increased rates of gingivitis during pregnancy [40–42]. The oral microbiome shifts back during the postpartum period to once again resemble the nonpregnant state with fewer pathogenic bacteria [42]. In a study comparing the oral microbial populations of pregnant women with gingivitis versus those with healthy gingiva during their third trimester, significant differences in bacterial taxa were found, although no differences in overall diversity were observed [43]. Nonetheless, as there have been relatively few studies to date on the oral microbiome during pregnancy, most of which have included relatively small cohorts, more research is needed in this area. This will allow further analysis of the potential role of dysbiosis during pregnancy in dental pathologies.

It is yet unclear how pregnancy leads to changes in the oral microbiome composition, although several hypotheses have suggested mechanisms based on the overall suppression of immunity during pregnancy [44]. Other potential mechanisms implicate the hormonal changes during pregnancy, specifically the rise in estrogens, which have been shown in previous studies to promote Candida growth [45]. Most intriguing is whether the oral microbial changes have functional significance, or whether they are merely a biomarker for the overall physiological changes.

Microbiome changes correlate with necessary functions during pregnancy

The gut microbial changes observed in late pregnancy correlate with increased weight gain, insulin resistance, and a greater inflammatory response seen in women in the third trimester. In fact, it was shown that this is not merely a correlation, but rather that the gut microbiome during the third trimester can actively enhance the observed physiological effects. When the microbiome from pregnant women in the third trimester was transferred to germ-free (GF) mice, these mice gained more weight, displayed increased insulin resistance, and increased levels of inflammatory serum markers, when compared to mice receiving first trimester microbiome [19]. It is important to realize that the weight gain, reduced insulin sensitivity, and perhaps even low-grade inflammation are all necessary for a healthy pregnancy, in order to enable proper fetal development without harming the mother or the fetus. Reinforcing this notion, maternal gut microbiome in the third trimester of pregnancy has also been associated with proper fetal development, based on correlations with newborn head circumference and weight [46].

The connection between microbial alterations and weight gain and metabolic changes during pregnancy

Perhaps the most dramatic physiological change that occurs throughout pregnancy is weight gain. The weight gain itself is due to the weight of the growing fetus, as well as growth of maternal tissues and elevated fat storage. At early stages of pregnancy, weight gain may only be subtle, whereas the most significant and rapid weight gain occurs during the third trimester.

In many microbiome studies, weight was shown to correlate with microbial populations. One of the most prominent examples of this is a study finding vast differences in microbial compositions in monozygotic twin pairs in which one twin was obese, and the other was of normal weight [47]. The microbial populations of the obese twins were further found to promote weight gain, including both increased body mass and fat mass when introduced into GF mice [48].

The microbiome can induce weight gain, insulin resistance, inflammation, and adiposity by multiple mechanisms. These include stimulation of the immune system or effects on host metabolism including enhanced absorption of glucose and fatty acids, increased fasting-induced adipocyte factor secretion, induction of catabolic pathways, and alterations in host energy harvest, energy expenditure, and fat storage [18,19]. Specific pathways by which microbiota influence weight gain include increased fermentation of polysaccharides, increased SCFA production leading to regulation of metabolic peptide secretion, interaction with TLR5 to regulate appetite, and others [49]. In addition, interaction of the microbiome with endocrine cells can alter signaling of glucagon-like peptides 1 and 2, influencing satiety and insulin secretion [50]. Furthermore, weight gain and the obese state have also been shown to alter gut permeability and increase endotoxemia and bacteremia, thereby promoting systemic inflammation [49].

While weight gain is necessary in all pregnant women, differences in initial weight and body mass index (BMI) of women before pregnancy can further affect the microbial populations during pregnancy, and they even have effects on the microbial compositions of the offspring. Differences in gut microbial composition are seen in overweight versus normal weight women. In overweight as opposed to normal weight pregnant women, there is a significantly higher fecal abundance of Bacteroides and Staphylococcus [18]. Another study in obese and normal weight mothers revealed a positive correlation between pregestational BMI and inflammatory biomarkers during the third trimester [51]. This study also found higher Firmicutes levels and a higher ratio of Firmicutes/Bacteroidetes in overweight and obese subjects, whereas inflammatory markers were correlated with lower microbial diversity. Gestational weight gain has also been associated with maternal gut microbial composition and reduced diversity [52,53]. It was further shown that the prepregnancy maternal BMI correlates with neonatal gut microbial composition in vaginally delivered offspring [54].

The effects of BMI on the pregnancy microbiome are likely interconnected with expression of metabolic hormones. Insulin, gastric inhibitory polypeptide, and adipokine levels were all found to be correlated with alterations in bacterial abundance in overweight and obese women [55]. Additional metabolic changes associated with pregnancy include elevated fasting blood glucose levels, insulin resistance, and glucose intolerance [56–59]. This is of particular interest, as it has been shown that during late pregnancy the expression of carbohydrate-related microbial functions is regulated to conform with the high availability of glucose [60]. Finally, during pregnancy, changes occur in metabolic hormone levels including appetite-related hormones such as leptin, ghrelin, and glucagon-like peptide 1 (GLP1) [55–59], and several findings have correlated specific bacterial species and levels of leptin and ghrelin [61].

The changes described earlier are only part of the changes in the gastrointestinal (GI) tract that are required to meet the increased nutritional demands of the developing fetus during pregnancy. Additional adaptations include enhancement of the villus surface area in the GI tract, as well as increased numbers of sugar and signaling receptors [62]. These may have direct implications on gut microbiome.

Potential effects of diet on the healthy microbiome during pregnancy

Among the environmental effects on the microbiome composition, diet appears to have the most pronounced effect. Many studies in humans or in animal models have shown that dietary changes can further alter the microbiome [63]. Compositional differences are observed between meat eating and vegetarian subjects [64]. While some short-term diets may cause reversible microbial changes, long-term dietary changes may cause stable changes in microbiota composition. High-fat diets (HFDs) have been shown in numerous human and rodent studies to alter the microbial composition, as compared to low-fat diets or normal chow [65]. Most commonly, HFD causes the relative abundance of Firmicutes to increase at the expense of Bacteroidetes [66]. These microbial alterations appear to be independent of BMI, and therefore these are not directly related to obesity. In a similar manner, HFD has strong effects on the microbiome during pregnancy. A human study comparing high-fat versus standard maternal diets during pregnancy revealed that these diets influenced the neonatal microbiome in a manner that persisted even at 6 weeks of age [67]. Even when female mice were fed on HFD only before conception, microbiome compositional effects were observed in later pregnancy [68]. More specifically, the pregnancy microbial alterations following HFD predict gene expression differences in lipid metabolism, glycolysis, and gluconeogenic metabolic pathways. Furthermore, maternal obesity is known to result in metabolic and neurodevelopmental abnormalities in the offspring [69]. When transplanting microbiota from mice fed with HFD or control low-fat diet to female mice, the male offspring of the dams receiving the HFD microbiota showed significant disruptions in exploratory, cognitive, and compulsive behavior. Specifically, decreased representation of specific members of the Firmicutes phylum was linked to behavioral abnormalities in male animals. In addition, the female offspring of HFD dams displayed increased body weight and adiposity [69].

Intake of vitamins and other nutritional supplements during pregnancy may also affect the microbiome. In a cohort of 60 pregnant women, higher dietary intake of fat-soluble vitamins, especially vitamin D, was associated with reduced gut microbial alpha diversity and increased relative abundance of Proteobacteria [70]. Moreover, the diversity of the gut microbiota and the intake of vitamins, n-3 PUFAs, and fiber in overweight pregnant women was associated with decreased serum zonulin concentration, a marker of intestinal permeability. These results suggest that dietary balance during pregnancy may affect microbial compositions in a beneficial manner, leading to improved metabolic health of both the mother and fetus [71]. Vitamin D supplementation has been inversely associated with bacterial vaginosis during pregnancy and with alterations in certain vaginal bacteria