Available online at www.sciencedirect.

com

Role of vertical and horizontal microbial transmission of

antimicrobial resistance genes in early life: insights from
maternal-infant dyads☆
Manuel Bernabeu 1,⁎, Elena Cabello-Yeves 2,⁎, Eduard Flores 1, ]]
]]]]]]
]]

Anna Samarra 1, Joanna Kimberley Summers 3,

Alberto Marina 2,† and M Carmen Collado 1,†

Early life represents a critical window for metabolic, cognitive bacterial infections [1]. According to the World Health
and immune system development, which is influenced by the Organization (WHO), antibiotic resistance is one of the
maternal microbiome as well as the infant gut microbiome. top-ten global public health threats facing humanity
Antibiotic exposure, mode of delivery and breastfeeding today [2]. In the early stages of pregnancy, expectant
practices modulate the gut microbiome and the reservoir of mothers may be administered antibiotics to safeguard
antibiotic resistance genes (ARGs). Vertical and horizontal against bacterial infections in the genital tract, which
microbial gene transfer during early life and the mechanisms could potentially harm the child [3]. Following child­
behind these transfers are being uncovered. In this review, we birth, statistics indicate that in high-income countries,
aim to provide an overview of the current knowledge on the approximately 70% of infants undergo at least one course
transfer of antibiotic resistance in the mother–infant dyad of antibiotics to address infections, whereas in low-in­
through vertical and horizontal transmission and to highlight the come countries, the average number of antibiotic courses
main gaps and challenges in this area. administered to infants is notably higher [4]. Despite its
use, sepsis remains a significant contributor to morbidity
Addresses in newborns and young infants. The escalating threat of
1
Institute of Agrochemistry and Food Technology - National Research antimicrobial resistance (AMR) poses a substantial risk
Council (IATA-CSIC), 46980 Valencia, Spain
2 to the efficacy of antibiotics, particularly in low- and
Instituto de Biomedicina de Valencia-Consejo de Investigaciones
Científicas (IBV-CSIC), CIBER de Enfermedades Raras (CIBERER), middle-income countries. In these regions, neonatal
46010 Valencia, Spain deaths linked to AMR are estimated to reach up to 214
3
Wellington Lab, School of Life Sciences, University of Warwick, CV4 000 annually [5,6]. Hence, the transmission of antibiotic
7AL Coventry, United Kingdom resistance genes (ARGs) via vertical transmission and
Corresponding authors: Bernabeu, Manuel ([email protected]),
also via horizontal gene transfer (HGT) plays a sig­
Cabello-Yeves, Elena ([email protected]) nificant role in the widespread dissemination of anti­
⁎
Equal contribution. biotic resistance among bacterial populations [7]. In early
†
Senior authors. life, particularly in the infant gut microbiome, HGT
plays a significant role in the acquisition and dis­
Current Opinion in Microbiology 2024, 77:102424 semination of ARGs [8]. The microbial communities
This review comes from a themed issue on Microbiota present in the gut, including commensal and pathogenic
Edited by Christopher Stewart and Maria Carmen Collado bacteria, interact within this ecosystem, facilitating the
exchange of genetic material. This exchange can occur
through mechanisms such as transduction, conjugation
Available online xxxx
or transformation enabling the transfer of ARGs between
different bacterial species [9].
https://doi.org/10.1016/j.mib.2023.102424
1369–5274/© 2023 The Author(s). Published by Elsevier Ltd. This is The ubiquity of plasmids and bacteriophages and the
an open access article under the CC BY-NC-ND license (http:// broad phylogenetic distribution of natural transformation
creativecommons.org/licenses/by-nc-nd/4.0/).
means that these ancient agents of HGT operate in a
vast array of environments and ecosystems. This in­
cludes clinical environments, human hosts, human
Introduction communities and almost all natural environments [10].
Antibiotic resistance is a significant and growing global Plasmids, integrons, transposons and bacteriophages are
problem that threatens our ability to effectively treat a diverse group of mobile genetic elements (MGEs) that

☆
Given the role as Guest Editor, Maria Carmen Collado had no involvement in the peer review of the article and has no access to information
regarding its peer-review. Full responsibility for the editorial process of this article was delegated to Christopher Stewart.

www.sciencedirect.com Current Opinion in Microbiology 2024, 77:102424

2 Microbiota

collectively form the ’mobilome’, the study of which Neonatal microbiota evolution: influences shaping ARGs
offers valuable ecological insights into the mechanisms and MGEs
of adaptation and speciation [11]. MGEs are the main The neonatal microbiota is a complex and dynamic mi­
actors in the transmission of ARGs by HGT from the crobial ecosystem, initiated with the maternal microbial
maternal to the infant gut microbiome. While these inoculum, that plays essential roles in nutrition, metabo­
elements can be inherited vertically, their significant role lism and immune system stimulation during diverse stages
in HGT underscores substantial heterogeneity even of development. The establishment and assembly of the
within an individual species [12]. This process estab­ infant microbiome are particularly critical for long-term
lishes a diverse pool of non-ARGs that can impact the health outcomes [23]. Following birth, the neonatal gut
infant’s metabolic potential and immune system devel­ microbiota begins to form and diversify over the first few
opment [13]. Thus, the maternal gut microbiome acts as months of life [24], this vertical transmission is influenced
a reservoir of ARGs and MGEs, which can be transferred by external factors: breastfeeding type and duration, de­
vertically and horizontally between bacteria and plays a livery mode, skin-to-skin care, infant weight, antibiotic
critical role in the gut microbiome of infants [14]. Un­ usage, diet, exposure to the external environment [25] and
derstanding the intricate interplay and dynamics within physiological factors [26]. Finally, perinatal factors such as
maternal-infant pairs is vital for developing effective consumption of solid food by infants, or antibiotic use
strategies to combat antibiotic resistance [15]. during pregnancy, may also influence the patterns of ARGs
and MGEs [27].
What about the transmission of antibiotic
resistance genes (ARGs) and mobile genetic Infants share a higher percentage of microbiome [28],
elements (MGEs) early in life? and therefore ARGs and MGEs, with their mothers, than
Role of the maternal microbiota as a source of ARGs with other individuals, even before undergoing any an­
and MGEs tibiotic treatment, demonstrating the vertical transfer of
The mother’s microbiota is considered the main source these elements. This process occurs through mother–­
of microbes and ARGs and MGEs for infants, which are infant contact and, notably, through breastfeeding, pro­
vertically transferred to newborns at birth and during viding the bacteria that will colonise the infants’
lactation. During pregnancy, metabolites from the ma­ microbiota [29]. A recent study has highlighted the role
ternal microbiome significantly influence the develop­ of MGEs in shaping offspring gut microbiomes via the
ment of the foetal immune system and metabolic transfer of genetic material from mother-to-infant bac­
pathways [16], but no data are available about the ARGs teria, which may have implications for immune system
and MGEs in women’s guts during pregnancy and their development [15]. However, despite the inoculum from
role in foetal development. Pregnant women frequently their mothers, the microbiota of infants in early stages
experience infections with pathogenic microorganisms show a higher prevalence of bacteria carrying ARGs and
(bacteria, viruses, fungi or parasites), mainly treated with MGEs compare to their mother’s microbiota [29,30],
antibiotics, that could favour the presence of ARGs and potentially leading to a higher frequency of HGT among
imbalance the microbiota. Furthermore, the presence of commensal bacteria. Furthermore, the infant gut mi­
those potential pathogens increases the risk of compli­ crobiota shares genes with their mothers’ microbiota.
cations such as preterm birth [17]. For example, Group- However, the specific strain that initially had these
B Streptococcus (GBS), as representative Streptococcus genes isn’t transferred vertically. This illustrates the
agalactiae, is a Gram-positive pathobiont that asympto­ complex interplay between vertical and horizontal
matically colonises the vaginal mucosa and/or rectum of transmission during this stage of life [15]. In addition,
approximately 30% of healthy women [18]. These op­ the use of antibiotics, often employed to prevent pre­
portunistic pathogens can be found in the mother’s gut natal or postnatal complications, including neonatal GBS
and vaginal microbiota, potentially exposing the infant to infections, raises concerns about the vertical transmis­
ARGs and facilitating vertical transfer during pregnancy sion of ARGs [17]. Research has demonstrated the
[19]. This exposure may result in GBS colonisation, transmission of antibiotic-resistant bacteria from mothers
occasionally leading to severe infections in humans, to infants during pregnancy, delivery or breastfeeding,
particularly in individuals with weak immune systems, leading to alterations in the maternal microbiome com­
such as the elderly and newborns [20]. Consequently, position [19]. Moreover, neonates subjected to perinatal
pregnant women at risk are tested for GBS in their third antibiotic treatment exhibit a higher abundance of ARGs
trimester in some countries. According to the WHO, the in their gut microbiome compared to their mothers who
administration of prophylactic antibiotics to all women were also exposed to antibiotics [31]. This heightened
undergoing C-section before skin incision can prevent susceptibility to antibiotic resistance in newborns could
the risk of infection [21]. However, this treatment can stem from the limited bacterial species present in the
cause alterations in the composition of the maternal neonatal gut, facilitating the selection and proliferation
microbiome, which have been associated with the de­ of those bacterial strains containing relevant ARGs
velopment of several chronic diseases [22]. that can then spread [32].

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 Vertical and Horizontal microbial transmission Bernabeu et al. 3

Preterm neonatal microbiota present even more differences conducted [41], and integrons in faecal E. coli strains
to the adult microbiota and are more vulnerable to changes isolated from mother–child pairs [42]. While the existing
due to their immature gastrointestinal tract and immune literature provides insights, the lack of comprehensive
system. The use of antibiotics is a common practice in studies in this field emphasises the importance of ad­
neonatal intensive care units (NICUs) due to the high in­ vancing knowledge on this topic. Understanding the
cidence of bacterial infections and sepsis in this vulnerable specifics of HGT and the factors that modulate it in
population [33]. Nevertheless, this practice has been asso­ natural microbial communities such as the maternal-in­
ciated with the emergence of antibiotic-resistant bacteria, fant gut microbiome is crucial for developing effective
which can lead to treatment failure and increased mortality strategies to combat antibiotic resistance. This under­
rates. This selective pressure results in a less-complex mi­ standing will allow us to build strategies that aim to re­
crobiota, often dominated by unique species, notably those duce the prevalence of ARGs in the gut microbiome.
from the Enterobacteriaceae family, which are major carriers of
ARGs along with multiple MGEs [34]. Additionally, ex­
posure to antibiotics in the neonatal period has been linked Approaches to study horizontal gene transfer
to long-term health consequences, including alterations in (HGT) in early life
the development of the neonatal microbiome, which can Next-generation sequencing provides an alternative to
impact immune system development and increase the risk culturing of microbes, allowing exploration of those spe­
of non-communicable diseases later in life [35]. Conse­ cies that we are not yet able to culture, facilitating the
quently, careful consideration of antibiotic use during discovery of new microbial species [43], and advancing
pregnancy and breastfeeding is essential to minimise the our comprehension of the human microbiome [44]. Re­
transmission of ARGs to offspring, ensuring the long-term cent advances in sequencing technologies have resulted
health and well-being of infants. in a significant increase in bacterial sequences, and the
decreasing cost of sequencing makes it a viable surveil­
Influential factors in the postnatal transfer of ARGs and lance tool for detecting AMR and MGEs [45]. In recent
MGEs from mother to newborn years, bioinformatics tools have been developed for short
Breastfeeding drives the neonatal gut microbiota evo­ reads, long reads, contigs and metagenome-assembled
lution and modulates the presence of ARGs and MGEs, genomes (MAGs). These employ different approaches,
as well as it is a vehicle of vertical transmission of ARGs such as mapping reads to reference genomes, binning and
and MGEs. Beyond nutritional aspects, breastmilk is a assembly of short reads to form MAGs and using more
source of bioactive components, including microbes accurate short reads to polish scaffolds formed from more
(Staphylococcus, Streptococcus, lactic acid bacteria, error-prone long reads. These new tools allow the iden­
Bifidobacterium and also, some enterobacteria such as tification of absent genomic regions, genomic islands
Escherichia coli, Ralstonia and Klebsiella among others) as (GIs) and virulence genes, often found in poorly char­
well as other microorganisms such as viruses and bac­ acterised regions [46]. As a result, whole-genome shotgun
teriophages [36]. Breastfeeding duration significantly sequencing is a powerful tool for identifying the mobi­
influences the composition of ARGs in the infant gut lome and resistome [47]. However, this approach faces
microbiome, being recommended for at least 6 months, technological limitations in connecting bacterial taxa to
because it reduces ARG abundance, particularly in specific MGEs encoding ARGs. Chromatin conformation
Gammaproteobacteria, accompanied by an increase in capture, a high-throughput culture-independent tech­
beneficial Bifidobacterium species [37]. nique, effectively samples long-range interactions within
bacterial genomes, surveilling MGE carriage [48]. Com­
Along with breastfeeding, the primary factors associated bined with experimental work, these approaches con­
with the presence of ARGs in infants are those linked to tribute to filling the gaps in our understanding of the
vertical transmission, such as the use of antibiotics pre- specific associations between MGEs and bacteria in the
and post partum, the mode of delivery (natural or C- human microbiome. Advances in computational algo­
section) and term or preterm birth [38]. However, due to rithms and experimental approaches have significantly
children having a higher abundance of ARGs than their expanded our knowledge of the genes involved in HGT
mothers, it is also important to consider HGT and the and the ecological dynamics of HGT in natural environ­
role of external factors such as contact with other in­ ments [49], especially in the maternal-infant context.
dividuals and even the environment that may shift the Additionally, these techniques facilitate the characterisa­
microbiota (Figure 1) [29,39]. Despite being a relatively tion of complex selective pressures on MGEs and their
unexplored field, there are studies on ARGs [29], and interaction with bacterial host genomes. Tools such as
MGEs [15], including plasmids and bacteriophages Platon and geNomad [50], which classify, annotate and
highlighting their significant roles in the establishment integrate gene content information with a deep neural
and persistence of ARGs such as glycopeptide and network, are employed for detecting plasmids and other
multidrug resistance [40]. Additionally, research on MGEs [51,52]. Other approaches to consider are new and
virulence factors (VFs) within GBS genomes has been improved classifiers of viruses, such as VirSorter2 [53],

www.sciencedirect.com Current Opinion in Microbiology 2024, 77:102424

4 Microbiota

Figure 1

Current Opinion in Microbiology

Gene transmission and influencing factors in mother–newborn dyads. Vertical transmission: microorganisms, ARGs and MGEs are transferred to
newborns during pregnancy and delivery, as well as during lactation. This transmission can be influenced by multiple factors such as breastfeeding,
delivery mode, infant weight, antibiotics, diet or external environment. Horizontal gene transfer (HGT): main mechanisms of mobilisation of DNA.
Transduction: bacteriophage and phage-inducible chromosomal islands (PICI) transfer genetic material between bacteria. Bacterial conjugation: the
most common mechanism of ARG mobilisation. DNA is transferred from a donor to a recipient bacterium by direct contact. Bacterial transformation:
foreign DNA as single strands integrated into a bacterial chromosome. Created with BioRender.com.

phages and prophages — Phanta [54], bacteriophage sa­ advances are needed to elucidate which MGEs are most
tellites — SatelliteFinder [55] and GIs — Genomic Island represented in the maternal-infant environment, which
Prediction Software [56]. MGEs are of great interest since bacteria in this microbiota are naturally competent to
VFs [57] are disproportionately associated with mobile acquire DNA, which factors influence HGT in the early
sequences [58], as well as with certain ARGs [59]. GIs are stages of infant life and which genes are more frequently
known or predicted to have been acquired through HGT mobilised to map these elements in the infant and ma­
events [60]. GIs can arise after MGE integration [52], as ternal gut microbiome. In addition, metagenomic se­
integrons [61], transposons [62] and prophages [63]. Tools quencing and new analytical tools under development
and pipelines are evolving and improving accuracy and will deepen our understanding of the dynamics of MGEs
detection providing novel data on HGT. and the impact of HGT in natural environments. This
information will be of great value and will have to be
Gaps in knowledge, key challenges and future confirmed empirically, thus understanding the mechan­
perspectives isms underlying these complex processes.
Our understanding of the significant phenotypic differ­
ences between strains is clouded by the lack of knowl­ New approaches appear promising, such as the use of
edge of specific HGT within natural microbial phages that could be used to increase antibiotic sensi­
communities due to technical challenges [64]. New tivity of resistant strains and maintain the effectiveness

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 Vertical and Horizontal microbial transmission Bernabeu et al. 5

of antibiotics [65,66]. This would be considered as a acknowledges Generalitat-Valenciana-European Social Fund (ACIF/2021)
treatment approach for preterm infants in the NICU, as for the predoctoral fellowship grant. M.C.C. acknowledges the support by
the European Research Council Starting grant (MAMI grant ref. 639226),
it would influence the neonatal resistome and mobilome, Horizon Europe Program (INITIALISE ref. 101094099), Spanish Ministry
with implications for reducing the risk of necrotising of Science and Innovation (MAMI-Plus ref. PID2022-139475OB-I00), by
enterocolitis and sepsis by reducing pathogen colonisa­ the Joint Action ’European Joint Programming Initiative “A Healthy Diet
tion and growth, and improving microbiota maturation for a Healthy Life” (JPI-HDHL)’ — FOOD-HYPERSENS call
(ECOBIOTIC) and the national funding from Programación Conjunta
and immune system development [30]. Nevertheless, Internacional (PCI) (ref. PCI2021-122059-2A), Spanish Government
we must continue to work towards a deeper under­ (Ministry of Science, Innovation and Universities) and also by Biostime
standing of the environmental factors that influence and Institute Nutrition & Care (BINC) grant. IATA-CSIC authors also ac­
knowledge the Spanish government Ministry of Science and Innovation/
the MGEs that facilitate the transmission of ARGs to State Investigation Agency (MCIN/AEI) to the Center of Excellence
solve this global emergency. Accreditation Severo Ochoa (CEX2021-001189-S/MCIN/AEI/10.13039/
501100011033). A.M. acknowledges the support by grants PID2019-
108541GB-I00 and PID2022-137201NB-I00 from Spanish Government
Concluding remarks (Ministry of Science and Innovation). M.C.C. and A.M. are part of the
There are gaps in our understanding of how ARGs and CSIC’s Global Health Platform (PTI Salud Global).
MGEs are transmitted from the maternal microbiota to
the infant. Risk factors that have been highlighted in­
clude antibiotic exposure, caesarean section, lack of References and recommended reading
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