Immediately after birth, newborn babies experience rapid colonization by microorganisms from their mothers and the surrounding environment1. 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.
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This work was supported by the Wellcome Trust (WT101169MA) and Wellcome Sanger core funding (WT098051). Y.S. is supported by a Wellcome Trust PhD Studentship. S.C.F. is supported by the Australian National Health and Medical Research Council (1091097, 1159239 and 1141564) and the Victorian Government’s Operational Infrastructure Support Program. We thank the participating families for their time and contribution to the BBS; the research midwives at recruiting hospitals for recruitment and clinical metadata collection; N. Moreno, H. Ali, S. Bibi and A. Takyi for raw-sample processing; the Core Sequencing and Pathogen Informatics teams at the Wellcome Sanger Institute for informatics support; and H. Browne and A. Almeida for critical feedback of the manuscript.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Peer review information Nature thanks Serena Manara, Xavier Ramnik, Nicola Segata and Paul Wilmes for their contribution to the peer review of this work.
Extended data figures and tables
a, Microbiota alpha diversity (Shannon diversity index) increased over developmental time. The violin plot outlines the kernel probability density; the width of the shaded area represents the proportion of the data shown. Centre line shows median; box limits indicate the 25th and 75th percentiles; whiskers extend 1.5× the interquartile range from the 25th and 75th percentiles; and outliers are represented by dots. The gut microbiotas of babies on day 4 (n = 310 individuals), 7 (n = 532 individuals) and 21 (n = 325 individuals), and in infancy (n = 302 individuals), as well as from matched mothers (n = 175), are plotted. b, c, Stability of the gut microbiota, stratified by inter-individual (day 4, n = 310 individuals; day 7, n = 532 individuals; and day 21, n = 325 individuals) and intra-individual comparisons in sliding time windows (day 4 to 7, n = 274 individuals and day 7 to 21, n = 285 individuals) during the neonatal period (b), in the context of the overall infancy period (c). Microbiota stability measurements from the TEDDY15 study (the earliest measurements on day 90, and at year 3) are plotted in crosses. Solid lines show the median per time window. Shaded areas show the 99% confidence interval, estimated using binomial distribution. Error bars indicate median absolute deviation. The significance of the difference between groups was determined by two-sided Wilcoxon rank-sum test.
Extended Data Fig. 2 Microbiota variation associated with mode of delivery in the neonatal period and infancy.
Non-metric multidimensional scaling ordination of Bray–Curtis dissimilarity between the species relative-abundance profiles of the gut microbiota sampled from babies on day 4 (vaginally delivered, n = 157 babies; delivered by caesarean section, n = 153 babies), day 7 (vaginally delivered, n = 280 babies; delivered by caesarean section, n = 252 babies), day 21 (vaginally delivered, n = 147 babies; delivered by caesarean section, n = 178 babies) and during infancy (vaginally delivered, n = 160 babies; delivered by caesarean section, n = 142 babies). The microbial variation explained by the mode of delivery is represented by the PERMANOVA R2 value (bottom left), and is significant across four cross-sectional PERMANOVA tests. False-discovery-rate-corrected P values are reported in Supplementary Table 2.
Extended Data Fig. 3 Microbial succession in the neonatal gut microbiota of vaginally delivered babies.
Bar plots show longitudinal changes in the mean relative abundance of faecal bacteria at the genus level on day 4, day 7 and day 21, for genera with >1% mean relative abundance across all neonatal samples. Left, n = 316 samples from 160 vaginally delivered babies detected with Bacteroides. Right, n = 290 samples from 154 vaginally delivered babies with the low-Bacteroides profile (defined in ‘Classification of babies with the low-Bacteroides profile’ in Methods).
Transmissions of maternal microbial strains across 178 mother–baby pairs (for 112 vaginally delivered babies, and 66 babies delivered by caesarean section) who sampled at least once during the early neonatal period. Only the frequently shared species that were detected with sufficient coverage for strain analysis in more than ten pairs are shown. The neighbour-joining tree is constructed on the basis of the pairwise mash distances of the respective reference genomes. Phylogenetically related species shared a similar pattern for the timing of transmissions; for example, the frequent transmission of Bacteroides spp., Parabacteroides spp. and Bifidobacterium spp. in vaginally delivered babies and the lack of species of these genera in babies delivered by caesarean section, and the fact that most Streptococcus species were transmitted from environmental sources other than the maternal gut microbiota.
Extended Data Fig. 5 Frequency and abundance of opportunistic pathogens in the neonatal gut microbiota.
a, b, Babies delivered by caesarean section, and vaginally delivered babies with the low-Bacteroides profile, more frequently carried opportunistic pathogens (as defined in ‘Classification of the opportunistic pathogen carriage’ in Methods) and at higher level of species relative abundance during the first 21 days of life, as compared to vaginally delivered babies (a) and vaginally delivered babies with the normal Bacteroides profile (b), respectively. There was a significantly different presence in the neonatal samples within each major neonatal-period sampling group (day 4 (n = 310 individuals), day 7 (n = 532 individuals) and day 21 (n = 325 individuals))—in terms of mean relative abundance and frequency—of six known opportunistic pathogens that are associated with the hospital environment, and rarely carried by adults (n = 175 mothers) (b). The numbers of individuals sampled in the neonatal period were 314 (vaginally delivered), 160 (vaginally delivered, and with a normal level of Bacteroides) and 154 (vaginally delivered, with the low-Bacteroides profile). Error bars indicate the 95% confidence interval of the mean relative abundance. The significance (P values indicated to the right of the bars) of the difference in mean species relative abundance and combined-pathogen carriage (defined in ‘Classification of the opportunistic pathogen carriage’ in Methods) frequency was obtained by applying two-sided Wilcoxon signed-rank test and Fisher’s exact test, respectively.
a, Phylogenetic tree of E. faecalis strains of the BBS (n = 282 strains, isolated from 269 faecal samples of 160 subjects). The midpoint-rooted maximum-likelihood phylogeny is based on SNPs in 1,827 core genes. Five major lineages (>10 representatives in strains of the BBS; ST179, n = 60; ST16, n = 30, ST40, n = 27; ST30, n = 21; and ST191, n = 14) were identified within UK hospital collections, distributed across three hospitals in this study and with no phylogroup limited to any single hospital. Solid lines between strains indicate intra-subject strain persistence (n = 92 strains in 67 babies). Dashed lines indicate phylogenetically distinct strains that were isolated from longitudinal samples (n = 18) or mother–baby paired samples (yellow, n = 10); arrows indicate the direction of the potential transmission (early-to-later or mother-to-baby). In situations in which multiple identical strains (no SNP difference in species core genome) were isolated from the same faecal sample, only one representative strain was included in the species phylogenetic tree (total number of strains, n = 356). b–e, Prevalence of virulence-related genes (b, c) and AMR-related genes (grouped by antibiotic class) (d, e) detected in E. faecalis strains of the BBS. Significance results shown are coloured according to the group with higher frequency of detected genes, by two-sided Fisher’s exact test between the groups of the public gut microbiota strains (n = 28) versus strains of the BBS (n = 356), and strains of the BBS versus the epidemic strains in UK hospitals (n = 89; tree branches coloured blue in Fig. 4c). ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05. Virulence-related genes: asa1, EF0149, EF0485 and prgB, aggregation substance; esp, enterococcal surface protein; genes that encode exoenzymes: gelE, gelatinase; EF0818 and EF3023, hyaluronidase (spreading factor); sprE, serine protease; and fsr, quorum sensing system; toxin-encoding gene: cyl, cytolysin. Genes detected across all isolates (dfrE, efrA, efrB, emeA and lsaA) are not shown. AMR-related genes: Am, aminoglycosides (aph3″-III, ant(6)-Ia, aph(2'') and str); Chlor, chloramphenicol (catA); Linc, lincosamides (lnuB); MLSB, macrolide, lincosamide and streptogramin B (ermB or ermT); Tet, tetracycline (tetL, tetM, tetO and tetS); Trim, trimethoprim (dfrC, dfrD, dfrF or dfrG); and Vanc, vancomycin.
a–f, Midpoint-rooted core-genome maximum-likelihood trees of E. cloacae complex, K. oxytoca and K. pneumoniae strains isolated in this study (a–c) and in the context of public genomes (d–f). a–c, Number of strains of E. cloacae (a) (n = 37, isolated from 37 faecal samples of 30 subjects, 1,861 core genes), K. oxytoca (b) (n = 107, isolated from 90 faecal samples of 62 subjects, 2,910 core genes) and K. pneumoniae strains (c) (n = 53, isolated from 47 faecal samples of 35 subjects, 3,471 core genes) of the BBS. Solid lines between strains indicate the intra-subject strain persistence (E. cloacae, n = 5 strains in 5 babies; K. oxytoca, n = 25 strains in 18 babies; and K. pneumoniae, n = 11 strains in 8 babies. Dashed lines indicate phylogenetically distinct strains isolated from longitudinal samples (E. cloacae, n = 2 strains in 2 individuals; K. oxytoca, n = 7 strains in 6 subjects; and K. pneumoniae, n = 1 strain in 1 individual); arrows indicate the direction of potential transmission (early-to-later samples). In situations in which multiple identical strains (no difference in SNPs in species core genome) were isolated from the same faecal sample, only one representative strain was included in the species phylogenetic tree (number of non-redundant BBS strains: E. cloacae, n = 52; K. oxytoca, n = 150; K. pneumoniae, n = 78). For each species, the main phylogroups identified with UK hospital collections are shown (E. cloacae, III and VIII; K. oxytoca, KoI, KoII, KoV and KoVI; K. pneumoniae, KpI, KpII and KpIII); these were distributed across three hospitals in this study, with no phylogroup limited to any single hospital. d–f, The number of public genomes included in the phylogenetic analysis of E. cloacae (d) (UK hospitals, n = 314; gut microbiota, n = 8; environmental sources, n = 43; 1,484 core genes), K. oxytoca (e) (UK hospitals, n = 40; gut microbiota, n = 9; environmental sources, n = 8; 3,399 core genes) and K. pneumoniae strains (f) (UK hospitals, n = 250; gut microbiota, n = 17; environmental sources, n = 66; 2,510 core genes).
a–d, Frequency and heat maps of isolates for putative AMR-related (a, b) and virulence-related genes (grouped by antibiotic class) (c, d) that are most-frequently detected in strains of the UK hospital collection of E. cloacae (green), K. oxytoca (orange) and K. pneumoniae (blue). Significance results shown are coloured according to the group with higher frequency of detected genes, by two-sided Fisher’s exact test between the groups of the public gut microbiota strains (E. cloacae, n = 8; K. oxytoca, n = 9; and K. pneumoniae, n = 17) versus strains in the BBS (E. cloacae, n = 52; K. oxytoca, n = 150; and K. pneumoniae, n = 78), and strains in the BBS versus strains in UK hospitals (E. cloacae, n = 314; K. oxytoca, n = 40; K. pneumoniae, n = 250). ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05. AMR-related genes: extended-spectrum β-lactamases, SHV (blaSHV), CTX-M (blaCTX-M) and TEM (blaTEM); other β-lactamases, OXA (blaOXA), OXY (blaOXY), ACT (blaACT) and LEN (blaLEN); Tet, tetracycline (tetA and tetR); Am, aminoglycosides (aac(3), aac(6′), aad and str). Virulence-related genes: iron acquisition, fyu; yersiniabactin, ybt; iron transporter permease, kfu; iron regulatory proteins, irp; allatonin metabolism, all; capsule, wzi; aerobactin siderophore receptor, iutA; fimbriae and biofilm formation, mrk; flagella biosynthesis, fli; siderophore production, iro; and fimbrial chaperones, lpf. Genes detected across all isolates are not shown.
This file contains Supplementary Notes 1-6 and Supplementary References.
Clinical metadata of the Baby Biome Study participants included in the analysis.
Variance of species taxonomic profiles (Bray-Curtis dissimilarity) explained by each clinical covariate in cross-sectional PERMANOVA of all subjects, and stratified by vaginal and caesarean section deliveries.
Species associated with clinical covariates in each sampling age group, after accounting for potentially confounding covariates with MaAsLin.
Summary of maternal strain transmission events as inferred by StrainPhAn.
Information on the study isolates and public genomes included in WGS analysis.