Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 167–176 (DOI: 10.1159/000358465)

The Developing Intestinal Microbiome: Probiotics and Prebiotics Josef Neu  Department of Pediatrics/Neonatology, University of Florida, Gainesville, Fla., USA Reviewed by Johannes B. van Goudoever, Department of Pediatrics, Emma Children’s Hospital Amsterdam, The Netherlands; Hania Szajewska, Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland

Abstract

Emerging non-culture-based technologies derived largely from the Human Genome Project are increasingly being applied to evaluate the intestinal microbiota. The Human Microbiome Roadmap has thus been proposed as a stimulus to evaluate the role of the intestinal microbiome in health and disease [1]. It is becoming increasingly evident that the intestinal microbiota comprises a complex ecosystem that has been shaped by millennia of evolution that usually exists in a symbiotic relationship with the host. During early development, the microbiota undergoes changes based on the individual’s genetic program, diet, and other environmental factors. The resident gastrointestinal microbes play major roles in nutrition and the developing immune system [2, 3]. Previous studies have demonstrated that germ-free animals have extensive defects in the development of gut-associated lymphoid tissue [4], arrested capillary network development in the gut and reduced antibody production. Its role in the de-

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The microbes in the human intestinal tract interact with the host to form a ‘superorganism’. The functional aspects of the host microbe interactions are being increasingly scrutinized and it is becoming evident that this interaction in early life is critical for development of the immune system and metabolic function and aberrations may result in life-long health consequences. Evidence is suggesting that such interactions occur even before birth, where the microbes may be either beneficial or harmful, and possibly even triggering preterm birth. Mode of delivery, use of antibiotics, and other perturbations may have life-long consequences in terms of health and disease. Manipulating the microbiota by use of pro- and prebiotics may offer a means for maintenance of ‘healthy’ host microbe interactions, but over-exuberance in their use also has the potential to cause harm. Considerable controversy exists concerning the routine use of probiotics in the prevention of necrotizing enterocolitis. This chapter will provide a brief overview of the developing intestinal microbiome and © 2014 S. Karger AG, Basel discuss the use of pro- and prebiotics in preterm infants.

Fetal intestine-derived inflammation Bacterial translocation and induction of inflammation

III IV II

Intestinal epithelium I FIRS

Synthesis and release of uterotonins Premature labor

Fig. 1. Model showing how ascending vaginal bacteria translocate through the maternofetal membranes and the fetus swallows the colonized amniotic fluid (left) and how this leads to fetal inflammatory response syndrome (FIRS) that is of fetal intestinal origin (right).

veloping human immune system is well known and much of this interaction occurs in the first years after birth. The microbial composition of the intestine during early development may provide the milieu that prevents or enhances certain diseases such as neonatal sepsis, necrotizing enterocolitis (NEC), type 1 diabetes, asthma, allergies, celiac disease, inflammatory bowel disease and obesity [5–8]. In this chapter, several aspects of the developing intestinal microbiome based on new technologies are discussed in relation to health. We further discuss the role of antibiotics, probiotics and prebiotics, especially as they pertain to the newborn infant and his/her subsequent development.

Fetal Microbial Ecology Although a commonly held belief is that the intestinal tract of the fetus is sterile, recent studies using a combination of culture and non-culture-based techniques suggest that many preterm infants are exposed to microbes found in the amniotic fluid, even without a history of rupture of membranes or culture-positive chorioamnionitis [9]. This has led to speculation that the microbial ecology of the swallowed amniotic fluid may play a role not only in the fetal intestinal physiology and inflammation but perhaps in premature labor (fig. 1) [10]. It needs to be noted that the fetus swallows large quantities of amniotic fluid in the last trimester of pregnancy and the highly immunoreactive intestine is exposed to large quantities of these microbes and microbial components. One study from our

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Neu Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 167–176 (DOI: 10.1159/000358465)

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Development of the Intestinal Microbiota

group used high-throughput 16S-based techniques to analyze intestinal microbial ecology in premature neonates in 23 neonates born at 23–32 weeks’ gestational age [11]. Surprisingly, microbial DNA was detected in meconium, suggesting an intrauterine origin. This suggests the possibility that meconium might be a reasonable source for evaluation of the intrauterine microbial milieu.

Preterm Infant Microbiota As in the neonate born at term, the preterm infants’ gastrointestinal tracts may already have been exposed to an intrauterine microbial milieu that has influenced development prior to birth. Studies on 29 consecutive extremely preterm infants fecal microbiota was collected between 3 and 56 days of life and analyzed using ‘fingerprinting’ (gel separation, elution of bands from gels and subsequent analysis of band sequences) correlated clinical factors such as growth, digestive tolerance, nutrition and antibiotic use to the major taxa present in the feces [14]. The diversity score (related to number of operational taxonomic units) increased 0.45 units/week. Staphylococcus species were by far the as the major group with Bifidobacterium being poorly represented. Gestational age (≥28 weeks) and cesarean delivery independently correlated with better diversity scores during follow-up. The 6-week diversity score inversely correlated with the duration of antibiotic use and parenteral feeding. A predominance

The Developing Intestinal Microbiome: Pro- and Prebiotics Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 167–176 (DOI: 10.1159/000358465)

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Microbiota Development in Term Infants One of the first comprehensive non-culture-based studies of intestinal microbes in 14 healthy term infants, using a ribosomal DNA microarray-based approach, suggested that the composition of microbes within each baby evolved over time but showed similarity during the first year, but ‘temporal patterns of the microbial communities varied widely from baby to baby, suggesting a broader definition of ‘healthy colonization’ than previously recognized [12]. By 1 year of age, the profile of microbial communities begins to converge toward a profile characteristic of the adult gastrointestinal tract’ [12]. Another study from Norway (the ‘NoMic’ study) evaluated 85 healthy term breastfed infants at 4 and 120 days [13]. These were vaginally delivered, healthy, term infants, who were not exposed to antibiotics, exclusively breastfed during their first month of life and at least partially breastfed up to 4 months. Selected microbial groups were identified by targeting small subunit microbial ribosomal RNA genes. In contrast to more recent studies [12], but in agreement with older culture-based studies, almost all the infants in this study harbored Gammaproteobacteria and Bifidobacterium. The authors found that non-cultivable species belonging to Bacteroides, as well as microbes identified as Lachnospiraceae 2, were highly represented. This study also showed a relative abundance of Staphylococcus genera that decreased over the evaluated time period. Furthermore, the bifidobacteria were represented in relatively high abundance. Whether the differences in bifidobacteria in this study and in the previous study [12] were due to choice of primer (resulting in primer bias), infant health status, use of antibiotics, diet or geographic region remain speculative.

Vaginal delivery Exposure to vaginal microflora

Normal microbial ‘seeding’ of GI tract

Normal development of immunity

Abnormal microbial ‘seeding’ of GI tract

Abnormal development of immunity

Cesarean delivery

Lack of exposure to vaginal microflora

Fig. 2. Colonization after vaginal versus cesarean delivery.

Mode of Delivery During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant’s gut. Microbial colonization after vaginal delivery may be very different than after cesarean delivery (fig. 2) [15]. During vaginal delivery, the contact with the mother’s vaginal and intestinal flora is an important source for the start of the infant’s colonization with predominance of Lactobacillus, Prevotella and other Bifidobacterium [16–27]. During cesarean delivery, direct contact of the mouth of the newborn with the vaginal and intestinal microbiota is absent, and nonmaternally derived environmental bacteria play an important role for infants’ intestinal colonization which has a less diverse flora and a bacterial community similar to those found on the skin surface dominated by Staphylococcus and with a delayed intestinal colonization by Lactobacillus, Bifidobacterium and Bacteroides [8, 17]. With increasing concern over rising rates of cesarean delivery and insufficient exclusive breastfeeding of infants in developed countries, a Canadian group characterized the gut microbiota of healthy Canadian infants and described the influence of cesarean delivery and formula feeding [18]. Fecal samples were collected at 4 months of age, and microbiota composition was characterized using high-throughput DNA sequencing. ‘Compared with breastfed infants, formula-fed infants had increased

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Neu Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 167–176 (DOI: 10.1159/000358465)

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of Staphylococcus seen during this time is of interest since these are the most commonly represented genera with late-onset sepsis in the neonate. It is of interest but speculative that these are organisms that may translocate through the intestinal barrier and cause bacteremia and subsequent sepsis.

richness of species, with overrepresentation of Clostridium difficile. Escherichia-Shigella and Bacteroides species were underrepresented in infants born by cesarean delivery. Infants born by elective cesarean delivery had particularly low bacterial richness and diversity.’ These findings support the accumulating evidence that delivery mode and interaction with infant diet serve as important antecedents to the development of the microbial community. Some authors have suggested that the composition of the very first human microbiota could have lasting effects on the intestine [8]. Of major importance is the evidence that intestinal microbiota’s interaction with the intestinal mucosa plays a critical role in development of the immune system [19]. Thus, depending on the mode of delivery, differences in microbial colonization patterns in the infant’s gastrointestinal tract may lead to differences in the development of immunity. Available epidemiological data show that atopic diseases, asthma, type 1 diabetes and food allergies appear more often in infants after cesarean delivery than after vaginal delivery [20–23]. Studies in adults using non-culture-based analysis of the intestinal microbiota show that antibiotics may perturb the gastrointestinal tract for years [24, 25]. Nevertheless, the increase in cesarean deliveries in many countries could have significant consequences in public health with higher allergies, asthma, celiac and other diseases [15].

Necrotizing Enterocolitis and Intestinal Microbiota

In another study, designed to determine differences in microbial patterns that may be critical to the development of NEC, microbial analysis from fecal samples from NEC patients distinctly clustered separately from controls [26]. As described by the authors, ‘Patients with NEC had less diversity, an increase in abundance of Gammaproteobacteria, a decrease in other bacteria species, and had received a higher mean number of previous days of antibiotics’. These results suggested ‘that NEC is associated with severe lack of microbiota diversity that may accentuate the impact of single dominant microorganisms favored by empiric and widespread use of antibiotics’ [27].

Antibiotics In the USA, a large number of mothers giving birth prematurely are treated with antibiotics. Additionally, most (nearly 90%) of VLBW infants are treated with a course of broad-spectrum antibiotics [28]. Two studies so far have suggested an increased incidence of NEC related to this practice [26, 27]. In studies of adults, the abundance of specific resistance genes to antibiotics was greater in those patients treated with antibiotics [24, 25].

The Developing Intestinal Microbiome: Pro- and Prebiotics Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 167–176 (DOI: 10.1159/000358465)

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Manipulations of the Intestinal Microbiota and Their Consequences

Probiotics and NEC Prospective randomized trials have evaluated the effects of different probiotics on the prevention of NEC [33–43]. A multicenter trial of probiotic suggested a beneficial preventive effect against NEC. However, there was a trend for a higher incidence of sepsis in infants receiving probiotics [34], especially in those with a birth weight

The developing intestinal microbiome: probiotics and prebiotics.

The microbes in the human intestinal tract interact with the host to form a 'superorganism'. The functional aspects of the host microbe interactions a...
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