Abstract
Caesarean section delivery (CSD) disrupts mother-to-neonate transmission of specific microbial strains and functional repertoires as well as linked immune system priming. Here we investigate whether differences in microbiome composition and impacts on host physiology persist at 1 year of age. We perform high-resolution, quantitative metagenomic analyses of the gut microbiomes of infants born by vaginal delivery (VD) or by CSD, from immediately after birth through to 1 year of life. Several microbial populations show distinct enrichments in CSD-born infants at 1 year of age including strains of Bacteroides caccae, Bifidobacterium bifidum and Ruminococcus gnavus, whereas others are present at higher levels in the VD group including Faecalibacterium prausnitizii, Bifidobacterium breve and Bifidobacterium kashiwanohense. The stimulation of healthy donor-derived primary human immune cells with LPS isolated from neonatal stool samples results in higher levels of tumour necrosis factor alpha (TNF-α) in the case of CSD extracts over time, compared to extracts from VD infants for which no such changes were observed during the first year of life. Functional analyses of the VD metagenomes at 1 year of age demonstrate a significant increase in the biosynthesis of the natural antibiotics, carbapenem and phenazine. Concurrently, we find antimicrobial resistance (AMR) genes against several classes of antibiotics in both VD and CSD. The abundance of AMR genes against synthetic (including semi-synthetic) agents such as phenicol, pleuromutilin and diaminopyrimidine are increased in CSD children at day 5 after birth. In addition, we find that mobile genetic elements, including phages, encode AMR genes such as glycopeptide, diaminopyrimidine and multidrug resistance genes. Our results demonstrate persistent effects at 1 year of life resulting from birth mode-dependent differences in earliest gut microbiome colonisation.
Highlights
The rate of caesarean section delivery is constantly increasing worldwide, which is partly driven by increases in overall income and access to health facilities.[1]
Birth mode-dependent gut microbiota differences during the first year We previously described the initial seeding and colonisation processes within the human gut microbiome and identified differences in microbiome structure and function as well as linked immunogenicity and immune system priming, which stratified according to birth mode.[8,39]
Pro-inflammatory immune responses elevated in Caesarean section delivery (CSD) after 1 year of life In the early stages of neonatal development, we found that the immune activation potential of LPS was significantly increased in samples from vaginal delivery (VD) neonates,[8] whereby the isolated LPS triggered the secretion of TNF-α and IL-18 by monocyte-derived dendritic cells (MoDCs) from four healthy adult donors
Summary
The rate of caesarean section delivery is constantly increasing worldwide, which is partly driven by increases in overall income and access to health facilities.[1]. Shao et al reported that CSD may predispose individuals to colonisation by opportunistic pathogens including those carrying antimicrobial resistance (AMR) genes.[15] On the one hand, several reports including our previously published study[8] addressed questions concerning the very early development of the neonate’s gut microbiomes[14,16] and immune system priming[3] in relation to disease development.[17,18] On the other hand, only few reports[19,20,21,22] follow the effects of birth mode during the first year of life especially in relation to immune system priming, development and evolution of AMR, and the contribution of mobile genetic elements to the persistence of AMR genes. Aside from this, it is generally accepted that birth mode, i.e. vaginal delivery (VD) or CSD, has a pronounced impact on early microbiome structure.[3,8,11,26,27] While the majority of these studies focus on overall microbiome structure, analyses of Received: 27 October 2020 Revised: 9 December 2020 Accepted: 2 January 2021
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