The Microbiota-Gut Axis in Premature Infants: Physio-Pathological Implications

Abstract

Intriguing evidence is emerging in regard to the influence of gut microbiota composition and function on host health from the very early stages of life. The development of the saprophytic microflora is conditioned by several factors in infants, and peculiarities have been found for babies born prematurely. This population is particularly exposed to a high risk of infection, postnatal antibiotic treatment, feeding difficulties and neurodevelopmental disabilities. To date, there is still a wide gap in understanding all the determinants and the mechanism behind microbiota disruption and its influence in the development of the most common complications of premature infants. A large body of evidence has emerged during the last decades showing the existence of a bidirectional communication axis involving the gut microbiota, the gut and the brain, defined as the microbiota-gut-brain axis. In this context, given that very few data are available to demonstrate the correlation between microbiota dysbiosis and neurodevelopmental disorders in preterm infants, increasing interest has arisen to better understand the impact of the microbiota-gut-brain axis on the clinical outcomes of premature infants and to clarify how this may lead to alternative preventive, diagnostic and therapeutic strategies. In this review, we explored the current evidence regarding microbiota development in premature infants, focusing on the effects of delivery mode, type of feeding, environmental factors and possible influence of the microbiota-gut-brain axis on preterm clinical outcomes during their hospital stay and on their health status later in life.

Keywords: gut-brain axis; microbiota; preterm infants.

Figure 1

Microbiota-gut-brain axis (MGBA) in healthy and preterm-associated ASD. After birth, the gut microbiota undergoes changes in composition and function in preterm children as compared to children born at term, as depicted in the graph above. The colors in the graph represent the relevant bacterial dominance in the term and preterm groups. In preterm children developing ASD, dysbiosis may influence MGBA communication via the enhanced production of neuroactive molecules such as phenylalanine and GABA impacting early brain development. Abbreviations: 5HT: 5-hydroxitryptamine, serotonin; GABA: gamma aminobutyric acid; PHE: phenylalanine; PMA = post-menstrual age; ASD = autism spectrum disease.

Figure 2

TLR4’s role in pre- and postnatal age and in preterm NEC. (A) During the normal gestation activation of TLR4 on epithelial intestinal cells by endogenous ligands, such as HSP class, fibrinogen, fibronectin or hyaluronan, ISC proliferation and differentiation is favored via MyD88 and Notch signaling. (B) At term, stimuli associated with vaginal delivery immediately downregulate TLR4 expression in epithelial cells, leading to bacterial tolerance. This protective mechanism is sustained by the inhibitory effect of breast milk−contained EGF on TLR4 signaling. (C) In preterm delivery, the tolerance to luminal microorganisms is not acquired, owing to the absence of vaginal delivery stimuli. A high TLR4−mediated inflammatory response to microbial components ensues via MyD88−Puma signaling, leading to the disruption of the epithelial barrier. Bacterial LPS−induced activation of TLR4 on vascular endothelial cells causes the inhibition of NO release and mesenteric vasoconstriction, paving the way for intestinal ischemia and NEC. Abbreviations: ISC = intestinal stem cell; HSP = heat shock protein; EGF = epidermal growth factor; LPS = lipopolysaccharide; NO = nitric oxide.