What is the microbiome?
=======================

* Protima Amon
* Ian Sanderson

*   Microbiome
*   Metagenomics
*   Paediatric diseases

## Introduction

There has been an explosion in our understanding of the human microbiome (the genome of all our microbes) in the recent years. Advances in genome sequencing technologies and metagenomic analysis (genetic study of genomes taken directly from environmental samples) have enabled scientists to study these microbes and their function and to research microbiome–host interactions both in health and disease. The human microbiome has an estimated 100 trillion microbes, the bulk of which live in our gut. This summary gives an overview about what is known about the microbiota (microbial community) in paediatric practice. This short article is written for the practising paediatrician. For a scientific overview, the reader is referred to reviews.1 ,2 An understanding of this complex ecological community is important as it affects our patients, and manipulation of the gut microbiome has the potential to be used in the treatment of childhood diseases in the future.

## The human microbiome: an organ in its own right

The human microbiome is composed of communities of bacteria (and viruses and fungi) that have a greater complexity than the human genome itself. Large-scale metagenomic projects (community and environmental genomics), such as the European Metagenomics of the Human Intestinal Tract and the Human Microbiome Project, have reported 3.3 million unique protein-encoding genes as compared with the entire human genome, which has around 23 000 genes. These studies have described the beneficial functions of the normal gut microbiota on health down to the genetic level.3 The human microbiome has extensive functions such as development of immunity, defence against pathogens, host nutrition including production of short-chain fatty acids important in host energy metabolism, synthesis of vitamins and fat storage as well as an influence on human behaviour, making it an essential organ of the body without which we would not function correctly (figure 1).

![Figure 1](http://ep.bmj.com/https://ep.bmj.com/content/edpract/102/5/257/F1.medium.gif)

[Figure 1](http://ep.bmj.com/content/102/5/257/F1)

Figure 1 
The human microbiome plays an important role in control of vital homeostatic mechanisms in the body. These include enhanced metabolism, resistance to infection and inflammation, prevention against autoimmunity as well as an effect on the gut–brain axis. SCFA, short-chain fatty acid.

## Microbiome composition

Unlike the host genome, which is relatively constant, the microbiome is dynamic and changes with early development, environmental factors such as diet and use of antibiotics and especially in response to disease.4 The most dramatic changes in composition occur in infancy and early childhood.5 The intestinal microbiome of an infant is affected by gestational age (full term or premature), mode of delivery (vaginal birth or caesarean section), type of feed (breast milk or formula feeds), maternal nutritional status (overweight or undernourished) and use of antibiotics.6 The complexity and plasticity of the infant microbiota during this early-life development is believed to be important in maintaining homeostasis with the host's immune system and has an impact on health later in life.7 

A healthy human gut can house at least 1000 different species of bacteria, comprising of two major phyla, namely Bacteroidetes and Firmicutes. Elucidating the microbiome composition in healthy individuals is important to understanding what consequences changes in microbiome composition may have to human health and disease susceptibilities.

Other microbes also live in the gut including viruses, fungi and archaea. However, research on them has been small compared with that on bacteria.

## The human microbiome and disease

The relationship between changes in microbiome composition and disease pathogenesis is uncertain. The challenge is to identify whether microbial imbalance is related to disease, sometimes termed ‘dysbiosis’, and to be able to distinguish between cause and effect. The following section highlights some conditions seen in paediatrics that have been associated with changes in the gut microbiota (table 1).8–16 

View this table:
[Table 1](http://ep.bmj.com/content/102/5/257/T1)

Table 1 
Alterations in gut microbiota exert an influence on organ systems in the body leading to disease

*Inflammatory bowel disease (IBD)*—This is one of the most extensively studied human conditions associated with the gut microbiota. The composition of the gut microbiota differs between healthy individuals and patients with IBD both in terms of species richness (ie, numbers of bacterial species) and species abundances (ie, number of individuals per species). As bacteria are identified by sequencing, rather than by functional characteristics in the culture laboratory, the individual bacterial species or genus (depending on the classification of sequence data) are commonly referred to as operational taxonomic units in microbiota research.

Studies have reported patients with IBD to have decreased bacterial diversity, and reduced abundances of Firmicutes and Bacteroidetes and an increased abundance of Proteobacteria compared with healthy individuals.17 Latest research suggests that IBD pathogenesis is due to the interaction of environmental factors (eg, smoking, diet and stress) and the host's genetic susceptibility, which is influenced by commensal microbiota, which activates either pathogenic or protective immune responses.18 Evidence from mouse models provides further support for the role of gut microbiota in pathogenesis of IBD.19 

*Necrotising enterocolitis (NEC)*—The pathogenesis of NEC is multifactorial although the gut microbiota is thought to play a crucial role. Studies in both humans and animal models have described changes in the gut microbiota including a reduction in bacterial diversity and increased abundances of Proteobacteria in preterm infants with NEC compared with healthy preterm infants.20 However, the results have been inconsistent across studies, and to date, no single causative set of microorganisms has been identified.

*Atopic diseases*—Conditions such as eczema, asthma and food allergies are increasing in incidence. This is often linked to the hygiene hypothesis. It is thought that the lack of early-life exposure to microbial antigens in hygienic developed countries alters the microbiota composition of the infant gut, which disrupts immune development causing allergic disease.21 For example, species like *Bacteroides fragilis* reportedly induces immunological tolerance through immune receptor signalling pathways.22 Also the infant gut microbiota is affected by environmental factors including pets, residing in rural homes and siblings shown to have protective effects against asthma and allergies.23 The concept that altered microbiome composition influences childhood allergic disease susceptibility is further supported by data from epidemiological studies that report higher prevalence of atopic diseases in infants delivered by caesarean sections, formula fed infants and those exposed to antibiotics.24 

*Type 1 diabetes*—The gut microbiota is involved in regulation of the metabolic–immune axis.8 Research studies speculating the specific causative microbial composition and function have not been consistent. However, Bifidobacteria is believed to be protective, while Proteobacteria is a reported risk factor. Similarly, changes in gut microbiota caused by lifestyle (eg, mode of delivery and diet) are known risk factors for the development of type 1 diabetes, like birth by caesarean section reportedly increases the risk of developing type 1 diabetes by 20%.7 

*Autistic spectrum disorder (ASD)*—The gut microbiota can influence human behaviour by modulating the gut–brain axis via endocrine (cortisol), immune (cytokines) and neural (vagus and enteric nervous system) signalling pathways. Several studies have described an altered gut microbiota in children with ASD compared with developmentally normal children.25 However, more work is needed to establish if this is important in the pathogenesis of the condition.

## Future potential of microbiota manipulation for the treatment of disease

Manipulation of the microbiota as a therapeutic tool is a rapidly advancing field in microbiome research. There is an abundance of data suggesting treatments capable of reversing dysbiosis are effective in managing certain human diseases. Targeted antibiotic use to eliminate select microbiota, probiotics and prebiotics to encourage the expansion of beneficial bacteria and faecal microbiota transplantation to restore bacterial communities are some of the approaches that are currently under investigation or in use. These studies will provide a greater understanding of the host–microbiome interactions that impact on disease.

As paediatricians, we need to keep abreast of the research as within the next decade, it is highly likely that we may be using such treatments in our practice.

## Footnotes

*   Contributors PA wrote the manuscript and IS reviewed and provided critical comments.

*   Competing interests None declared.

*   Patient consent Obtained.

*   Provenance and peer review Commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/) 

## References

1.   Schroeder BO , Bäckhed F . Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 2016;22:1079–89. [doi:10.1038/nm.4185](http://dx.doi.org/10.1038/nm.4185) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1038/nm.4185&link_type=DOI) 

2.   Moon Y . Microbiome-linked crosstalk in the gastrointestinal exposome towards host health and disease. Pediatr Gastroenterol Hepatol Nutr 2016;19:221–8. [doi:10.5223/pghn.2016.19.4.221](http://dx.doi.org/10.5223/pghn.2016.19.4.221) 
    
    

3.   Qin J , Li R , Raes J , et al . A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59–65. [doi:10.1038/nature08821](http://dx.doi.org/10.1038/nature08821) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1038/nature08821&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=20203603&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 
    
    [Web of Science](http://ep.bmj.com/lookup/external-ref?access_num=000275117500033&link_type=ISI) 

4.   Lozupone CA , Stombaugh JI , Gordon JI , et al . Diversity, stability and resilience of the human gut microbiota. Nature 2012;489:220–30. [doi:10.1038/nature11550](http://dx.doi.org/10.1038/nature11550) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1038/nature11550&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=22972295&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 
    
    [Web of Science](http://ep.bmj.com/lookup/external-ref?access_num=000308635900030&link_type=ISI) 

5.   Palmer C , Bik EM , DiGiulio DB , et al . Development of the human infant intestinal microbiota. PLoS Biology 2007;5:e177.
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1371/journal.pbio.0050177&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=17594176&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 

6.   Meropol SB , Edwards A . Development of the infant intestinal microbiome: a bird's eye view of a complex process. Birth Defects Res C Embryo Today 2015;105:228–39. [doi:10.1002/bdrc.21114](http://dx.doi.org/10.1002/bdrc.21114) 
    
    

7.   Charbonneau MR , Blanton LV , DiGiulio DB , et al . A microbial perspective of human developmental biology. Nature 2016;535:48–55. [doi:10.1038/nature18845](http://dx.doi.org/10.1038/nature18845) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1038/nature18845&link_type=DOI) 

8.   Sanz Y , Olivares M , Moya-Pérez Á , et al . Understanding the role of gut microbiome in metabolic disease risk. Pediatr Res 2015; 77:236–44. [doi:10.1038/pr.2014.170](http://dx.doi.org/10.1038/pr.2014.170) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1038/pr.2014.170&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=25314581&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 

9.   Smith PA . The tantalizing links between gut microbes and the brain. Nature 2015;526:312–14. [doi:10.1038/526312a](http://dx.doi.org/10.1038/526312a) 
    
    

10.  Betrapally NS , Gillevet PM , Bajaj JS . Changes in the intestinal microbiome and alcoholic and nonalcoholic liver diseases: causes or effects? Gastroenterology 2016;150:1745–1755.e3. [doi:10.1053/j.gastro.2016.02.073](http://dx.doi.org/10.1053/j.gastro.2016.02.073) 
    
    

11.  Lynch SV . The lung Microbiome and airway disease. Ann Am Thorac Soc 2016;13(Suppl 5):S462–5. [doi:10.1513/AnnalsATS.201605-356AW](http://dx.doi.org/10.1513/AnnalsATS.201605-356AW) 
    
    

12.  Kravchenko VV , Kaufmann GF , Mathison JC , et al . Modulation of gene expression via disruption of NF-κB signaling by a bacterial small molecule. Science 2008;321:259–63. [doi:10.1126/science.1156499](http://dx.doi.org/10.1126/science.1156499) 
    
    [Abstract/FREE Full Text](http://ep.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzMjEvNTg4Ni8yNTkiO3M6NDoiYXRvbSI7czoyMzoiL2VkcHJhY3QvMTAyLzUvMjU3LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

13.  Yamashita T , Emoto T , Sasaki N , et al . Gut microbiota and coronary artery disease. Int Heart J 2016;57:663–71. [doi:10.1536/ihj.16-414](http://dx.doi.org/10.1536/ihj.16-414) 
    
    

14.  Herrema H , IJzerman RG , Nieuwdorp M . Emerging role of intestinal microbiota and microbial metabolites in metabolic control. Diabetologia 2016. [doi:10.1007/s00125-016-4192-0](http://dx.doi.org/10.1007/s00125-016-4192-0) 
    
    

15.  Ahmed I , Roy BC , Khan SA , et al . Microbiome, Metabolome and Inflammatory Bowel Disease. Microorganisms 2016;4:E20. [doi:10.3390/microorganisms4020020](http://dx.doi.org/10.3390/microorganisms4020020) 
    
    

16.  Kong HH , Andersson B , Clavel T , et al . Performing skin microbiome research: a method to the madness. J Invest Dermatol 2017. [doi:10.1016/j.jid.2016.10.033](http://dx.doi.org/10.1016/j.jid.2016.10.033) 
    
    

17.  Manichanh C , Rigottier-Gois L , Bonnaud E , et al . Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 2006;55:205–11. [doi:10.1136/gut.2005.073817](http://dx.doi.org/10.1136/gut.2005.073817) 
    
    [Abstract/FREE Full Text](http://ep.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZ3V0am5sIjtzOjU6InJlc2lkIjtzOjg6IjU1LzIvMjA1IjtzOjQ6ImF0b20iO3M6MjM6Ii9lZHByYWN0LzEwMi81LzI1Ny5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

18.  Sartor RB . Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol 2006;3:390–407. [doi:10.1038/ncpgasthep0528](http://dx.doi.org/10.1038/ncpgasthep0528) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1038/ncpgasthep0528&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=16819502&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 
    
    [Web of Science](http://ep.bmj.com/lookup/external-ref?access_num=000238653200011&link_type=ISI) 

19.  Gkouskou KK , Deligianni C , Tsatsanis C , et al . The gut microbiota in mouse models of inflammatory bowel disease. Front Cell Infect Microbiol 2014;4:28. [doi:10.3389/fcimb.2014.00028](http://dx.doi.org/10.3389/fcimb.2014.00028) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=24616886&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 

20.  Grishin A , Papillon S , Bell B , et al . The role of the intestinal microbiota in the pathogenesis of necrotizing enterocolitis. Semin Pediatr Surg 2013;22:69–75. [doi:10.1053/j.sempedsurg.2013.01.002](http://dx.doi.org/10.1053/j.sempedsurg.2013.01.002) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1053/j.sempedsurg.2013.01.002&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=23611609&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 

21.  Wold AE . The hygiene hypothesis revised: is the rising frequency of allergy due to changes in the intestinal flora? Allergy 1998;53:20–5. [doi:10.1111/j.1398-9995.1998.tb04953.x](http://dx.doi.org/10.1111/j.1398-9995.1998.tb04953.x) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1111/j.1398-9995.1998.tb03769.x&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=9491225&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 

22.  Round JL , Lee SM , Li J , et al . The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 2011;332:974–7. [doi:10.1126/science.1206095](http://dx.doi.org/10.1126/science.1206095) 
    
    [Abstract/FREE Full Text](http://ep.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzMzIvNjAzMi85NzQiO3M6NDoiYXRvbSI7czoyMzoiL2VkcHJhY3QvMTAyLzUvMjU3LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

23.  Ege MJ , Mayer M , Normand AC , et al . Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011;364:701–9. [doi:10.1056/NEJMoa1007302](http://dx.doi.org/10.1056/NEJMoa1007302) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1056/NEJMoa1007302&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=21345099&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 
    
    [Web of Science](http://ep.bmj.com/lookup/external-ref?access_num=000287652500004&link_type=ISI) 

24.  Riiser A . The human microbiome, asthma, and allergy. Allergy Asthma Clin Immunol 2015;11:35. [doi:10.1186/s13223-015-0102-0](http://dx.doi.org/10.1186/s13223-015-0102-0) 
    
    [CrossRef](http://ep.bmj.com/lookup/external-ref?access_num=10.1186/s13223-015-0102-0&link_type=DOI) 
    
    [PubMed](http://ep.bmj.com/lookup/external-ref?access_num=26664362&link_type=MED&atom=%2Fedpract%2F102%2F5%2F257.atom) 

25.  Ding HT , Taur Y , Walkup JT . Gut Microbiota and Autism: Key Concepts and Findings. J Autism Dev Disord 2016.