A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants

Christophe Lay,Wen Chin Chiang,Ivan Chin Hin Tan,Shuwen Chen,Yanqing Koh,Yanqing Koh,Fiona Wong,Yee Jiun Kok,Rajeshwar Rao,Sachin R Lohar,Sachin R Lohar,Wong Anng Anng,Wong Anng Anng,Nipon Khemapech,Rikky W Purbojati ,Collins Wenhan Chu,Kaouther Ben-Amor,Angela Goh ,Ingrid B Renes,Xinyan Bi ,Chen Jie,Chen Jie,Nana Bartke,Surasith Chaithongwongwatthana,Jié Song ,Eliza Xin Pei Ho ,Voranush Chongsrisawat,Paola Flórez De Sessions ,Rocı́o Martı́n ,Rocı́o Martı́n ,Enzo Acerbi,Guus Roeselers,Guus Roeselers,Mei Chien Chua,Martin L Hibberd,Martin L Hibberd,Daniela I Drautz–Moses ,Ying Swan Ho,Stephan C Schuster,Shi Ya Mak,Jan Knol

doi:10.1186/s12866-021-02230-1

Abstract

BackgroundThe compromised gut microbiome that results from C-section birth has been hypothesized as a risk factor for the development of non-communicable diseases (NCD). In a double-blind randomized controlled study, 153 infants born by elective C-section received an infant formula supplemented with either synbiotic, prebiotics, or unsupplemented from birth until 4 months old. Vaginally born infants were included as a reference group. Stool samples were collected from day 3 till week 22. Multi-omics were deployed to investigate the impact of mode of delivery and nutrition on the development of the infant gut microbiome, and uncover putative biological mechanisms underlying the role of a compromised microbiome as a risk factor for NCD.ResultsAs early as day 3, infants born vaginally presented a hypoxic and acidic gut environment characterized by an enrichment of strict anaerobes (Bifidobacteriaceae). Infants born by C-section presented the hallmark of a compromised microbiome driven by an enrichment of Enterobacteriaceae. This was associated with meta-omics signatures characteristic of a microbiome adapted to a more oxygen-rich gut environment, enriched with genes associated with reactive oxygen species metabolism and lipopolysaccharide biosynthesis, and depleted in genes involved in the metabolism of milk carbohydrates. The synbiotic formula modulated expression of microbial genes involved in (oligo)saccharide metabolism, which emulates the eco-physiological gut environment observed in vaginally born infants. The resulting hypoxic and acidic milieu prevented the establishment of a compromised microbiome.ConclusionsThis study deciphers the putative functional hallmarks of a compromised microbiome acquired during C-section birth, and the impact of nutrition that may counteract disturbed microbiome development.Trial registrationThe study was registered in the Dutch Trial Register (Number: 2838) on 4th April 2011.

Highlights

The compromised gut microbiome that results from C-section birth has been hypothesized as a risk factor for the development of non-communicable diseases (NCD)
The fecal samples collected within the aforementioned clinical trial were analysed through a multi-omics approach (16S rRNA gene amplicon sequencing, shotgun metagenomics, metatranscriptomics and metabolomics) (Fig. 1). These analyses revealed that the compromised microbiome acquired during elective C-section birth reflects a microbiome adapted to a more oxidative environment characterised by functional signatures of reactive oxygen species metabolism, biosynthesis of lipopolysaccharides and the absence of detection of genes, transcripts involved in the metabolism of milk carbohydrates
We demonstrate that a specific synbiotic intervention prevents in elective C-section born infants the establishment of a compromised microbiome in the first days of life

Summary

Introduction

The compromised gut microbiome that results from C-section birth has been hypothesized as a risk factor for the development of non-communicable diseases (NCD). Early life antibiotics exposure or C-section birth have been implicated as risk factors for asthma, eczema, obesity and type 2 diabetes [12, 15,16,17,18]. A recent population cohort study of 7.17 million births described an association between birth by C-section and infection related hospitalisation in early childhood [19]. It appears that a perturbation of the transmission of the maternal microbiome, as well as a compromised development of the infant microbiome because of antibiotic exposure or C-section birth have long-term health consequences. Several studies depicted a delayed colonization by “keystone taxa”, Bifidobacterium and Bacteroides in Caesarean born infants [20,21,22,23,24,25,26,27]

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Discussion

Conclusion