Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth

Abstract

Delivery via caesarean section, maternal antibiotic prophylaxis and colonization by opportunistic pathogens associated with the hospital environment affect the composition of the gut microbiota of children from birth until infancy.

Full text

LETTER https://doi.org/10.1038/s41586-019-1560-1
Stunted microbiota and opportunistic pathogen
colonization in caesarean-section birth
Yan Shao1, Samuel C. Forster1,2,3, Evdokia Tsaliki4, Kevin Vervier1, Angela Strang4, Nandi Simpson4, Nitin Kumar1,
Mark D. Stares1, Alison Rodger4, Peter Brocklehurst5, Nigel Field4* & Trevor D. Lawley1*
Immediately after birth, newborn babies experience rapid
colonization by microorganisms from their mothers and the
surrounding environment
1
. Diseases in childhood and later in life
are potentially mediated by the perturbation of the colonization
of the infant gut microbiota2. However, the effects of delivery
via caesarean section on the earliest stages of the acquisition
and development of the gut microbiota, during the neonatal
period (≤1month), remain controversial3,4. Here we report the
disrupted transmission of maternal Bacteroides strains, and high-
level colonization by opportunistic pathogens associated with the
hospitalenvironment (including Enterococcus, Enterobacter and
Klebsiella species), in babies delivered by caesarean section. These
effects were also seen, to a lesser extent, in vaginally delivered babies
whose mothers underwent antibiotic prophylaxis and in babies
who were not breastfed during the neonatal period. We applied
longitudinal sampling and whole-genome shotgun metagenomic
analysis to 1,679gut microbiotasamples (taken at several time points
during the neonatal period, and in infancy) from 596full-term
babies born in UK hospitals; for a subset of these babies, we collected
additional matched samples from mothers (175mothers paired with
178babies). This analysis demonstrates that the mode of delivery is a
significant factor that affects the composition of thegut microbiota
throughout theneonatal period, and into infancy. Matched large-
scale culturing and whole-genome sequencing of over 800bacterial
strains from these babies identified virulence factors and clinically
relevant antimicrobial resistance in opportunistic pathogens that
may predispose individuals to opportunistic infections. Our findings
highlight the critical role of the local environment in establishing
the gut microbiota in very early life, and identify colonization with
antimicrobial-resistance-containing opportunistic pathogens as a
previously underappreciated risk factor in hospital births.
The acquisition and development of the gut microbiota during early
life follow successive waves of exposures to and colonization by micro-
organisms, which shapes the longer-term composition and function of
the microbiota
5
. Events in early life—including delivery by caesarean
section
1,4,6–8
, formula feeding
7,9
and antibiotic exposure
7,10
—that could
perturb the composition of the gut microbiota are associated with the
development of childhood asthma and atopy11–13. Although recent
studies7,8,10,14,15 have provided substantial insights into the development
of the gut microbiota during the first three years of life, many of these
studies have been limited by the taxonomic resolution provided by 16S
rRNA gene profiling, small sample size or limited sampling during the
first month of life (the neonatal period). High-resolution metagenomic
studies of large, longitudinal cohorts are required to establish the effects
of events in early life on the assembly of the gut microbiota, and any
associated risks—particularly for the neonatal period, during which
pioneering microorganisms could influence the subsequent develop-
ment of the microbiota and immune system16,17.
To characterize the trajectory of the acquisition and development of
the gut microbiota during the neonatal period, we enrolled 596healthy,
full-term babies (39.5±1.37weeks of gestation, 314vaginal births
and 282births via caesarean section) (Fig.1a, Extended Data Table1,
Supplementary Table1) through the Baby Biome Study (BBS). Faecal
samples were collected from all babies at least once during their neo-
natal period (≤1month) and 302babies were resampled later, dur-
ing infancy (8.75±1.98months). Maternal faecal samples were also
obtained, from 175mothers paired with 178babies. Metagenomic anal-
ysis of the 1,679faecal samples taken in total revealed the temporal
dynamics of the development of the gut microbiota (Fig.1b), as well as
increased diversity of the microbiota with age (Extended Data Fig.1a).
The gut microbiota exhibited substantial heterogeneity between indi-
viduals, and substantial instability (intra-individual variability) during
the first weeks of life (Extended Data Fig.1b). Inter-individual differ-
ences explained 57% of the variation in microbial species composition
(permutational multivariate analysis of variance (PERMANOVA),
P<0.001, 1,000 permutations); this was followed by age at sampling,
which explained 5.7% of the variance (P<0.001). These results indicate
that the gut microbiota is highly dynamic and individualized during
the neonatal period—even more so than was observed during infancy
(Extended Data Fig.1c).
To determine the effect of clinical covariates on the composition of
the gut microbiota, we performed cross-sectional PERMANOVA and
stratified by age. The mode of delivery was the most significant factor
to drive variation in the gut microbiota during the neonatal period
(Fig.2a, Supplementary Table2). Breastfeeding, as well as clinical
covariates that are associated with hospital birth (such as the use of
perinatal antibiotics and the duration of the stay in hospital), exhibited
smaller effects (Supplementary Note1). The largest effect of the mode
of delivery was observed on day 4 (R2=7.64%, P<0.001) (Extended
Data Fig.2); this effect dissipated with age but remained significant at
the point of sampling in infancy (R2=1.00%, P=0.002). No differ-
ences were observed between thematernal gut microbiotas by mode
of delivery, or between theneonatal gut microbiotas after elective and
emergency births via caesarean section (Supplementary Table2).
Given the significant effect of the mode of delivery during the
neonatal period, we next sought to understand how the composi-
tion and developmental trajectory of the microbiota were altered.
Samples from babies delivered vaginally were enriched with species of
Bifidobacterium (such as Bifidobacterium longum and Bifidobacterium
breve), Escherichia (Escherichia coli), Bacteroides (Bacteroides vulgatus)
and Parabacteroides (Parabacteroides distasonis), and these commensal
genera comprised 68.3% (95% confidence interval, 65.7–71.0%) of the
neonatal gut microbiota (Fig.2b, Supplementary Table3), consistent
with recent observations in other cohorts
4,8
. By contrast, the gut micro-
biotas of babies delivered by caesarean section were depleted of these
commensal genera and instead were dominated by Enterococcus faeca-
lis, Enterococcus faecium, Staphylococcus epidermis, Streptococcus paras-
anguinis, Klebsiella oxytoca, Klebsiella pneumoniae, Enterobacter cloacae
and Clostridium perfringens, all of which are commonly associated
with thehospital environment18 and hospitalized preterm babies19–21.
1Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK. 2Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria,
Australia. 3Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia. 4Institute for Global Health, University College London, London, UK. 5Birmingham
Clinical Trials Unit, University of Birmingham, Birmingham, UK. *e-mail: nigel.field@ucl.ac.uk; tl2@sanger.ac.uk
3 OCTOBER 2019 | VOL 574 | NATURE | 117
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