GUT PERTURBATION AND PROBIOTICS IN NEONATOLOGY

Recent studies suggest that fetal colonization begins prior to birth [1]. Besides a possible prenatal transfer of maternal bacteria to fetus, other major determinants for neonatal gut colonization are mode of delivery, mode of feeding and perinatal antibiotic exposure. Generally, vaginally born infants are first colonized by bacteria from the maternal vagina, also including bacteria present in the maternal gut, while the gut microbiota of infants born by Cesarean (C)-section more often resembles maternal skin and oral microbiota, with delayed colonization of Bacteroides, and lower microbial diversity throughout the first 2 years of life. It has been suggested that the early gut colonization may have long-term medical consequences: indeed, C-section delivered babies seems to display higher incidence of celiac disease, obesity and asthma, with some implications on the maturation of the immune system, in terms of lower blood levels of T-helper cell-related chemokines, possibly due to the reduced gut colonization of Bacteroides genus. Perinatal antibiotic exposure is another major determinant of early gut microbial composition in newborns. Thanks to new molecular techniques currently available, we now have proof for antibiotic-induced intestinal dysbiosis, in turn associated with intestinal and plasma lipid profile alterations. Several studies have also demonstrated that antibiotic exposure in early infancy is associated with increased risk of developing overweight/obesity, as well as asthma, wheezing and inflammatory bowel disease later in life [2]. Finally, mode of feeding also plays an important role in influencing early intestinal microbiota. Breastfeeding is undoubtedly the best way to promote the healthy development of human offspring, modulating infant’s early gut colonization both by human milk microbioma and by other unique nutritional components of human milk, such as oligosaccharides and lactoferrin, also known as prebiotic or bifidogenic factors. As a consequence, there are significant differences in the gut microbiota composition of breast-fed vs formula-fed infants. Several studies have pointed out that Bifidobacteria are the most abundant organisms in breast-fed infant guts, whereas the gut microbiota of formula-fed infants is dominated by Enterococci and Clostridia, with more species diversity. In summary, neonatal early gut microbial colonization seems to be a crucial step at a critical age for modulating infant’s healthy immunological, hormonal and metabolic development. Thus, according to the perinatal programming hypothesis, its perturbation might induce long-term negative effects. In this light, premature babies are particularly exposed to several risk factors such as gut immaturity, higher rates of maternal infections, perinatal antibiotics and other disturbing drugs and C-sections, as well as lower rates of breastfeeding. Overall, prematurity affects the microbiota as indicated by a reduced percentage of Bacteroidaceae during the first months of life and by a higher initial percentage of Lactobacillaceae in preterm infants compared with full term infants [3]. Perinatal antibiotics, including intrapartum antimicrobial prophylaxis, also affect the gut microbiota by increased Enterobacteriaceae organisms in the infants, with reduced Bifidobacteriaceae and Lactobacilli [4]. In the wake of this, the possible role and functions of early probiotics supplementation to modulate and reduce gut perturbations and dysbiosis has been extensively investigated. According to the definition of “live microorganisms that when administered in adequate amounts confer a health benefit on the host”, probiotics promote microbial homeostasis rather than change its composition, through different mechanisms of action, such as competitive exclusion of pathogens, direct antagonism, gut barrier reinforcement and production of specific bioactives with immunological and endocrinological effects. Some of them, namely of Lactobacilli, Bifidobacteria and Saccharomyces genera, have been reported to prevent necrotizing enterocolitis, reduce time to full enteral feeding and mortality in very low birth weight infants [5], especially when associated to breastfeeding, as well as to reduce crying time in colicky babies and antibiotic associated diarrhea [6]. In contrast, probiotics supplementation is not linked to significant improvement of postnatal growth of preterm infants, as reported so far. Although the risk of sepsis may be an issue in some predisposed subjects, in general the use of probiotics can be considered safe also in premature babies. By the way, it’s worth pointing out that clinical trial results from one probiotic strain in one population cannot be automatically generalized to other strains or to different populations and that the beneficial effects reported in the vast majority of clinical trials refer to a very limited number of strains. REFERENCES [1] Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The Placenta Harbors a Unique Microbiome. Sci Transl Med. 2014;6(237):237ra65. [2] Faa G, Gerosa C, Fanni D, Nemolato S, van Eyken P, Fanos V. Factors influencing the development of a personal tailored microbiota in the neonate, with particular emphasis on antibiotic therapy. J Matern Fetal Neonatal Med. 2013;26(S2):35-43. [3] Gritz EC, Bhandari V. The human neonatal gut microbiome: a brief review. Front Pediatr. 2015;3:17. [4] Arboleya S, Sánchez B, Solís G, Fernández N, Suárez M, Hernández-Barranco AM, Milani C, Margolles A, de los Reyes-Gavilán CG, Ventura M, Gueimonde M. Impact of Prematurity and Perinatal Antibiotics on the Developing Intestinal Microbiota: A Functional Inference Study. Int J Mol Sci. 2016;17(5):E649. [5] AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2014;(4):CD005496. [6] Johnston BC, Goldenberg JZ, Parkin PC. Probiotics and the Prevention of Antibiotic-Associated Diarrhea in Infants and Children. JAMA. 2016;316(14):1484-5