Insediamento, sviluppo e ruoli del microbiota intestinale nell’infanzia

Based on the widely accepted sterile womb paradigm, the fetal environment can be regarded as nearly sterile, and the first microbial colonization of the newborn’s gut is believed to occur during delivery and shortly after birth through a combination of vertical transmission from the mother and horizontal acquisition from other humans and the environment. Following the first seeding, the gut microbiota evolves substantially, reaching complete maturation within the first three years of life. However, this process is influenced and can be disturbed by several external factors, such as maternal diet, gestational age, delivery mode, feeding type, and antibiotic use. Given that inadequate gut microbiota development in early life is frequently associated with neonatal and long-term adverse health conditions, understanding the processes that govern initial colonization and development of the infant gut microbial community is of great importance. The aim of this Ph.D. thesis is to explore the engraftment and evolution of the infant gut microbiota by exploiting the most reliable genomic, metagenomic, and phylogenomic approaches. Within this framework, strain-level tracking of gut commensals revealed that beneficial, maternally inherited bifidobacterial species constitute highly stable and resilient communities, identifying host’s sex as a potential variable affecting the long-term persistence of these microorganisms through infancy. In addition to developmental changes in composition, this Ph.D. thesis also explores the functional maturation of the healthy human gut microbiota by tracing the microbial genetic potential for bioactive metabolites from infancy to adulthood, specifically emphasizing the early stages of life. As vaginal-derived microbes can be implicated in the first seeding of the infant gut microbiota, one of the purposes of this Ph.D. thesis is to unravel the composition of the vaginal microbiota across the population, performing detailed genome comparative analyses of Lactobacillus crispatus and Gardnerella vaginalis species, which are notoriously associated with vaginal health and potential dysbiotic status, respectively. As mentioned above, various perinatal factors can significantly impact the developmental trajectories of the nascent gut-associated microbial community. Among these, gestational age at birth is regarded as one of the most impactful, as it dictates the degree of immaturity of several infant’s organs, including intestinal and immune systems. Consistently, premature birth and low birth weight (< 1,500 gr) have been associated with an increased risk of Necrotizing EnteroColitis (NEC). In this context, this Ph.D. thesis explores the gut microbiota composition of preterm infants affected by NEC and prior to NEC onset to identify possible early microbial and functional biomarkers of this severe disease. Given the broadly observed link between early-life depletion of Bifidobacterium genus and host diseases, members of this genus are increasingly used as potential players in restoring gastrointestinal functions. Accordingly, in this Ph.D. thesis, the genetic traits involved in growth, microbe-host, and microbe-microbe interactions of bifidobacterial strains were explored, with a particular focus on B. longum subsp. infantis members. Moreover, common bifidobacterial genomes used in commercial probiotic products were used to build a free-access genomic database named Integrated Probiotic DataBase (IPDB). Finally, considering the bidirectional association between host’s factors and the gut microbiota composition, in this Ph.D. thesis, we determine the impact of different human lifestyles, i.e., sedentary or athletic, on the gut microbiota composition, showing that the host and the bacterial community inhabiting the gut are continuously crosstalking, mutually modulating each other throughout lifespan.