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Antibiotic exposure
We have already discussed how antibiotic use during the antenatal period can influence the neonatal
microbiome. Perhaps unsurprisingly, antibiotic exposure in early life, either administered directly, or
indirectly via breast milk if the mother is taking antibiotics, also reduces the alpha diversity of the
[168]
microbiome . Surprisingly, however, this effect can still be found long after the child stops taking
antibiotics. Unlike in adults, where studies have shown that the microbiome recovers approximately two
weeks after stopping antibiotics , children have a much less stable microbiome during their
[169]
developmental and transitional phases and can take months to years to recover [170,171] . Specific changes to the
microbiome from antibiotic use in children are characterised by reduced Actinobacteria, Bacteroidetes,
[172]
Firmicutes, and Verrucomicrobia populations, which are significant producers of beneficial SCFAs . These
perturbations in the microbiome in early life have been associated with childhood obesity, IBD, asthma, and
allergies [173-176] . Furthermore, there are extensive mechanistic data from animal models supporting the causal
link between the dysbiosis in the microbiome and subsequent pathology [177,178] . In contrast, certain bacterial

cadres have been shown to increase in abundance after antibiotic use, such as E. coli, E. cloacae, K.
pneumoniae, C. difficile, Erysipelotrichaceae spp., and Enterococcus spp., which are considered pathogenic
and are associated with infective diarrhoeal disease, opportunistic infections, and IBD [177,179,180] . The use of
antibiotics also alters the resistome, in that it increases the abundance of antimicrobial-resistant species,
raising the risk of future clinically significant antibiotic-resistant infections . Certain multi-strain
[180]
probiotics may be suitable for rapid replenishment of the microbiome after antibiotic use, with one
randomised control trial showing a significant reduction in antibiotic-related diarrhoea in children under
the age of 18 . Furthermore, evidence summarised in a recent Cochrane review suggests there may be a
[181]
utility for probiotic use in necrotising enterocolitis when used in combination with standard care . While
[182]
no powerful study has looked at the long-term outcomes of children taking probiotics or live bacterial
therapeutics (LBT), there is evidence that Lactobacillus-, Bifidobacterium- and Bacillus-based LBTs can
beneficially modulate the microbiome and reduce atopy, respiratory, ear and gastrointestinal
infections [183-187] . While antibiotic use has a large and perhaps obvious impact on the microbiome, it should
also be noted that the use of gastric acid-suppressing medications (e.g., proton pump inhibitors and
histamine receptor H2 agonists antagonists) that are used in children with symptomatic reflux also
influences the colonisation dynamics of infants. They have been shown to increase the abundance of
Enterobacteriaceae, Clostridium, and Haemophilus, while reducing Firmicutes and Lactobacillus [188,189] .

Gaps in the literature and future research potential
This literature review has described the latest evidence on numerous variables that impact the orchestration
of the infant microbiome during the highly dynamic period of the first half decade of life. It has
documented the evidence for health implications of these variables, and sought clarity on research for
mechanistic causation.

The body of evidence on this topic is large and growing rapidly. PubMed has over 10,500 results for
“paediatric microbiome” from the last decade, and more than half of these were published in the last three
years alone. A significant proportion of these academic papers are based on epidemiological data.
Accordingly, for many of the results presented, causality can only be inferred. To address this, several
research groups have used animal models to control for environmental stimuli. These animal models
require meticulous methodology, and often employ germ-free or gnotobiotic species that are greatly
divorced from natural conditions. As such, the applicability to general human microbiomic dynamics is
hard to fully establish. Consequently, and despite significant research, there are two important deficits in
our understanding of this vital period of microbial colonisation: (i) the causal relationship from a specific
environmental stimulus to establishing a colony in the GIT; and (ii) how specific microbiomes influence
long-term health.