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REVIEW ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 1  |  Page : 5-9

Neonatal microbiome: A complex, invisible organ and its evolving role in neonatal illness and beyond


Department of Neonatology, Homerton University Hospital, London, UK

Date of Web Publication29-Jan-2019

Correspondence Address:
Dr. Shivashankar Diggikar
Homerton University Hospital, London
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_98_18

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  Abstract 


Neonatal microbiome is a complex amalgamation of millions of organisms harboring inside and outside the body with a pivotal role in neonatal physiology and pathology. Yet it is a relatively less-discussed topic in day-to-day practice. With its origin right from the womb, it has its own genetics, weight and is responsible to maintain homeostasis. As the field of neonatology has grown exponentially over the last few decades, the understanding of neonatal microbiome has grown on par with it. With more and more evidence revealing its seminal role during the neonatal period and beyond, it is not only leaving us amazed but also cautious. How far we realize this super organ's importance in our patient cohort and what role should we play assisting this large family with millions of members to grow symbiotically and prevent posing any threat our tiny little babies need to be discussed. This article was written to make the neonatologist aware of the neonatal microbiome, how it develops right from the womb and its evolution over a period. The article also sensitizes the reader on its role in various neonatal diseases, especially necrotizing enterocolitis and what neonatologist should be doing in the intensive care unit while this is happening.

Keywords: Microbiome, neonate, preterm


How to cite this article:
Diggikar S. Neonatal microbiome: A complex, invisible organ and its evolving role in neonatal illness and beyond. J Clin Neonatol 2019;8:5-9

How to cite this URL:
Diggikar S. Neonatal microbiome: A complex, invisible organ and its evolving role in neonatal illness and beyond. J Clin Neonatol [serial online] 2019 [cited 2019 Jun 18];8:5-9. Available from: http://www.jcnonweb.com/text.asp?2019/8/1/5/250990




  Introduction Top


The word “microbiome” was first coined by Nobel Laureate Joshua Lederberg in 2001[1] which subsequently lead to human microbiome project in 2007. Neonatal microbiome comprises all the organisms living inside or on the surface of newborns. With the evolution in the field of genomics and understanding of meta-genetics, its role in maintaining a healthy ecosystem from “womb to tomb” is much better understood than before. Its immense role in altering or maintaining neonatal immunology, metabolic, and nutritional aspects is quite surprising. It alters itself depending on many internal and external factors to maintain the homeostasis. The most intriguing part is how it plays a significant role during the neonatal period and beyond. The purpose of this article is to make the neonatologist familiar about the neonatal microbiome, its significance during the early human development, and its role in various diseases.[2],[3]


  Neonatal Microbiome Top


What is neonatal microbiome?

Neonatal microbiome constitutes all the genomes and genetic products of the microorganism living inside and on the surface of the neonate. They constitute a huge number varying between 10 and 100 trillion outnumbering human cells significantly.[4] It is regarded as an “invisible organ” with its own genetics, weight, immunology, and its role in maintaining the homeostasis. This vast family is mainly constituted by bacteria, and the gastrointestinal (GI) system is the home to majority of them. It includes members of phyla Actinobacteria, Proteobacteria, Bacteroidetes, Firmicutes, and Tenericutes. It differs significantly in term and preterm babies, babies who are born vaginally and by C section, babies who are fully fed and nil orally, and babies on antibiotics.[4],[5] Over the past few years, the understanding of neonatal microbiome has reached its peak, and the technological advancement has made it easier to identify even at the species level [Table 1].
Table 1: Various phyla of microbiome in neonates and their characteristics

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Evolution during prenatal, perinatal, neonatal period, and role of meta-genetics in identifying microbiome

Human microbiome development starts very early in life, perhaps even before birth. Womb presumably a sterile environment seems to be a myth. Various studies mainly Aagard et al. have detected commensal microorganisms belonging to phyla Firmicutes, Bacteroidetes, Fusobacteria, Proteobacteria, and Tenericutes in the placenta, amniotic fluid, umbilical cord, and fetal meconium which resembles the oral microbiota of neonates. The major contribution to this is perhaps the “vertical transmission” through respiratory, GI tract, and genital tract.[5],[6] Hence, certainly, the evidence shows there is an exchange of microbiota from mother to the child. Babies born vaginally have diverse pioneer species than those born by C-section. Infants born vaginally have species which resembles that of maternal vaginal flora such as Lactobacillus and Prevotella whereas those born by C-section predominantly colonized by epidermal species such as Staphylococcus, Propionibacterium, Corynebacterium, Clostridium with reduced number of Bacteroides, and Bifidobacterium. These babies do lag in colonization by members of Bacteroidetes phyla, however, they do “catch-up” by 1 year of age.[7],[8] The further development of human microbiome during and beyond neonatal period depends on various factors such as maternal contact, feeding, xenobiotics, infection, new microbes, and many more[9] which will be discussed in the later part of this article.

How is it possible to identify these invisible communities and their members? and the answer is “Metagenetics.” It is defined as the application of modern genetics to recognize microbial communities at their species level in their natural environment without the need for culture. It primarily depends on 16s rRNA retrieval. Second-generation sequencing (SGS) (2005) and single-molecule sequencing (2011) have revolutionized the identification of microbiome.[10] First-generation sequencing (1977), which is also as “Sanger” sequencing[11] is primarily based on denaturing the DNA by gel electrophoresis, was time-consuming and expensive. This led to next-generation sequencing (NGS) in 2005. The basic characteristics of SGS technology are generation of many millions of short reads in parallel, speed up of sequencing the process compared to the first generation, low cost of sequencing and sequencing output is directly detected without the need for electrophoresis, example genome sequencer (GS) FLX + titanium, and GS junior systems, genome IIx, HiSeq, and MiSeq systems. As the genome with many repetitive areas that NGS technologies are incapable to solve them and the relatively short reads made genome assembly more difficult which led to third-generation sequencing (TGS) (single-molecule sequencing) platforms such as PacBio RS and single-molecule real-time systems and single-strand and “Endonuclease” systems. These third generations of sequencing have the ability to offer a low sequencing cost and easy sample preparation without the need polymerase chain reaction amplification in an execution time significantly faster than SGS technologies. In addition, TGS can produce long reads exceeding several kilobases for the resolution of the assembly problem and repetitive regions of complex genomes.[12]

How does it differ in term and preterm babies and why?

There is no signature pattern of microbiome when term and preterm babies are concerned, yet there is a vast difference in the members of their microbiome. Healthy term babies born vaginally are colonized with increased number of Bifidobacterium, Bacteroides, and Atopobium whereas preterm is colonized with an increased number of facultative anaerobes such as Lactobacillus, Enterobacter, Enterococcus, and Staphylococcus [Table 1].[10],[13] This obvious difference could be due to maternal chorioamnionitis, rupture of membranes, maternal antibiotics, C-section, delayed feeding, formula feeding increased duration of postnatal antibiotics, exposure to various organism in hospital environment, and use of ranitidine and many more in preterm babies.[14] Each of the above factor is so common, yet so important for the little ones which can not only alter the whole diversity of their microbiome but also their immunology, ecosystem and make them susceptible to infections, necrotizing enterocolitis (NEC), and disease beyond the neonatal period.

Symbiosis and dysbiosis

By now we have got a fair idea of the microbial ecosystem and how it evolves and maintain a stable relationship with the host. In return, the host is benefitted from this diversity of organisms, known as symbiosis. Neonatal microbiota helps in the development of GI enterocytes, angiogenesis, immune function, intestinal T-cell development, gut-associated lymphoid tissue, and many more. When the host immune system develops a harmonious cross-talk early in the life with the microbiota both help each other, and a world of peace exists in-vivo. This balanced microbial composition may result in “Symbiosis” among the resident microbes, production of immunomodulatory compounds, and subsequent regulation of immune response.[15]

When this ecosystem becomes sick, it is called “Dysbiosis.” It is characterized by more pathogenic organism, less diversity, less resistant to disease, and lack of ability to combat. Various factors which will expedite “Dysbiosis” are gestational age as extreme preterm babies lose their diversity because of prolonged neonatal intensive care unit stay [Table 1], type of feeding, antibiotic exposure, use of H2 blockers, and duration of hospital stay. Antibiotics perturb the early-life microbiota through their effects on the trajectory of microbial colonization leading to reduced pattern of microbial diversity and delayed commensal colonization, especially in preterm infants.[16] “Dysbiosis” exposes these tiny cohorts who are already immunologically handicapped to deadly and more pathogenic organisms which will lead to various pathological diseases such as “NEC” and tragically continues to effect beyond the neonatal period.


  Neonatal Microbiome and Illness Top


Necrotizing enterocolitis-a pentad of “5M's” (microbiome, Mucosal immune system and inflammation, milk, medicines, and mom!)

NEC, one of the most catastrophic conditions in preterm with high mortality, as high as 50%–80% in advanced stages and significant impact on the long-term neurodevelopmental outcome. NEC is multifactorial, various factors, such as excessive inflammation, formula feeding, microorganism, and increased permeability of preterm intestine, have been postulated in the causation [Figure 1].[17]
Figure 1: “PENTAD” of necrotizing enterocolitis (role of 5 M's). *Mother helps in developing a protective and healthy microbiome – signifies role of skin-to-skin contact even in term babies

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Can microbial dysbiosis lead to NEC? and the answer is “Yes.” NEC cannot be produced in a sterile environment in experimental animals. Although there is no signature pattern of microorganism which is consistent with NEC, various studies have shown that preterm babies with NEC have increased the abundance of proteobacteria and decreased relative abundance of firmicutes and Bacteroidetes compared to healthy breastfed preterm babies without NEC who has other way round [Table 1]. This pathogenic deviation occurs 2–3 weeks before the onset of NEC.[18],[19] Is this window of opportunity to intervene is a question to reckon about?

Although antibiotics will sphere head the management of established NEC, ironically their exposure both prenatally and postnatally can act as double-edged sword which can leave a long-lasting effect and disrupt the normal ecosystem and its diversity. They alter the microbial diversity which differs by the route, type of antibiotic, and duration. Prolonged use (>5 days) of empirical antibiotics is associated with an increased risk of NEC and/or death.[20] The role of mother is “critical and phenomenal” in the development of neonatal microbiome from prenatal to neonatal period. Massive colonization in babies occurs during delivery, breastfeeding/Enteromammary route, kangaroo mother care, maternal-infant bonding from maternal oral, respiratory, skin, and vaginal commensals.[21],[22] Hence, her role is unarguably on top of the list in not only establishing a healthy ecosystem but also in preventing NEC.

Role of prebiotics and probiotics in development of microbiome and prevention of necrotizing enterocolitis

It makes sense and logical when probiotics and prebiotics are used for maintaining a stable ecosystem, to prevent sepsis and NEC. No trial has ever proven with robust evidence about their use. Enteral lactoferrin in neonates trial which is one of the largest trials on the use of enteral lactoferrin in preventing sepsis has completed recruitment, and results should be expected soon.[23] On the contrary use of probiotics for the prevention of sepsis/NEC was beneficial as mentioned in ProPrem trial and meta-analysis,[24],[25] until the largest trial ever on the use of probiotics by Costeloe et al.[26] which displayed no benefit on it use. Until a strong evidence is available its use in preterm should be limited.

Other illness beyond neonatal period

It is a matter to worry about that the role of the neonatal microbiome is not limited to the neonatal unit but is carried even after discharge and there is enough evidence for it. It has been implicated various diseases such as skin microbiome alteration is linked to atopic dermatitis, acne, and psoriasis.[27] Similarly, GI microbiome is linked to inflammatory bowel disease, obesity, and type 1 diabetes mellitus[28] babies born by cesarean section are more prone to asthma.[29]


  Conclusion Top


The main purpose of this article was to make the neonatologist aware of growing importance of neonatal microbiome and how it plays a tremendous in normal development and various diseases, especially NEC in the tiny preterm babies. Although it is invisible, we should make all efforts to help it grow symbiotically with the babies and try to avoid unnecessary interventions and disrupt the ecosystem.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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