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Page 2 of 22 Borrego-Ruiz et al. Microbiome Res Rep. 2025;4:20 https://dx.doi.org/10.20517/mrr.2024.78

INTRODUCTION
The colonization of the infant gut by microbes during the perinatal period is essential for the future health
of the child, as the interaction between the microbiota and the host plays a key role in the proper
development of homeostatic systems . Therefore, early colonization has a profound impact on subsequent
[1]
health and represents a window of opportunity for modulating the microbiota toward a healthy
[2]
composition, potentially leading to long-term beneficial outcomes .
The initial gut colonization of the infant is strongly influenced by several determinants, such as gestational
age at birth, mode of delivery, neonatal feeding practices, early-life stress (ELS), and exposure to perinatal
antibiotics . The gut microbiome (GM) is established after birth and evolves throughout the lifespan of
[3-6]
the host, from infancy to advanced age . The GM composition ultimately achieves homeostasis,
[7]
establishing complex ecological and trophic interrelationships between its microbial members and the
[8]
human host . However, diverse factors can disrupt the microbial balance of the GM, causing a state of
[17,18]
dysbiosis .
[9]
Several clinical and preclinical studies have suggested that GM dysbiosis during the perinatal period may
play a pivotal role in the onset of various physiological and neurodevelopmental disorders [10-12] .
Consequently, disruptions in the GM during critical developmental stages may have persistent effects on
health, underscoring the need for early interventions to mitigate the risk of chronic conditions and a deeper
understanding of the role of the GM in both physical and mental well-being. In order to provide a
comprehensive overview of the topic, this narrative review synthesizes current knowledge on early-life GM
development and its long-term impact on health outcomes. Specifically, it addresses how early-life GM
dysbiosis may affect the trajectory of physiological processes, predisposing individuals to conditions such as
allergic diseases, metabolic disorders, type 1 diabetes (T1D), inflammatory bowel disorders (IBDs), and
atherosclerotic cardiovascular diseases (ACVDs). In addition, it examines the influence of probiotic and
prebiotic supplementation during pregnancy and early life in shaping infant GM composition, as well as the
impact of ELS-induced GM dysbiosis on mental health, with a particular focus on depression.

EARLY LIFE GM DEVELOPMENT
Until the beginning of the 21st century, the neonatal gut was thought to be a sterile ecosystem (the “sterile
[13]
womb paradigm”) , with microbial colonization believed to commence at birth . However, recent
[10]
findings have challenged this notion, revealing the presence of bacterial cells or DNA in the meconium,
placenta, and umbilical cord blood from healthy newborns delivered via cesarean section [14,15] . Diverse
researchers have postulated the “in utero colonization hypothesis” [13,16] on the basis that probiotics
consumed by expectant mothers were identified in both the placenta and in the meconium of term
infants . Perez-Muñoz et al. analyzed the evidence supporting these two opposing hypotheses based on
(i) the physiological, immunological, and anatomical features of the placenta and fetus; (ii) the
methodological approaches currently used to explore microbial populations in the intrauterine
environment; (iii) the composition of the fecal microbiome during the first days of life; and (iv) the
generation of axenic animals and humans . From this analysis, these authors suggested that the “in utero
[13]
colonization hypothesis” relies on methodologically weak data, likely due to the existence of kitomes. In
addition, the consistent success in generating axenic animals via cesarean section provides strong evidence
for the sterility of the fetal environment in mammals.

During pregnancy, the mother undergoes several endocrine, immunologic, and metabolic changes aimed at
[19]
creating an appropriate intrauterine environment for optimal fetal development . These modifications
promote a pro-inflammatory state, resulting in shifts in the maternal vaginal, intestinal, cutaneous, and oral