Nutrients and Microbiota in Lung Diseases of Prematurity: The Placenta-Gut-Lung Triangle

Abstract

Cardiorespiratory function is not only the foremost determinant of life after premature birth, but also a major factor of long-term outcomes. However, the path from placental disconnection to nutritional autonomy is enduring and challenging for the preterm infant and, at each step, will have profound influences on respiratory physiology and disease. Fluid and energy intake, specific nutrients such as amino-acids, lipids and vitamins, and their ways of administration —parenteral or enteral—have direct implications on lung tissue composition and cellular functions, thus affect lung development and homeostasis and contributing to acute and chronic respiratory disorders. In addition, metabolomic signatures have recently emerged as biomarkers of bronchopulmonary dysplasia and other neonatal diseases, suggesting a profound implication of specific metabolites such as amino-acids, acylcarnitine and fatty acids in lung injury and repair, inflammation and immune modulation. Recent advances have highlighted the profound influence of the microbiome on many short- and long-term outcomes in the preterm infant. Lung and intestinal microbiomes are deeply intricated, and nutrition plays a prominent role in their establishment and regulation. There is an emerging evidence that human milk prevents bronchopulmonary dysplasia in premature infants, potentially through microbiome composition and/or inflammation modulation. Restoring antibiotic therapy-mediated microbiome disruption is another potentially beneficial action of human milk, which can be in part emulated by pre- and probiotics and supplements. This review will explore the many facets of the gut-lung axis and its pathophysiology in acute and chronic respiratory disorders of the prematurely born infant, and explore established and innovative nutritional approaches for prevention and treatment.

Placental microbial–metabolite profiles and inflammatory mechanisms associated with preterm birth

“…(9) Research suggests a possible contribution from a deranged maternal gut microbiota in the development of atopy, the genetic tendency to develop allergic diseases such as rhinitis and asthma and autoimmune phenotypes in the neonate (4), along with an increased risk of necrotising enterocolitis and sepsis. (10) Furthermore, emerging evidence of the interactions between placental and fetal gut and lung microbiomes highlights that dysregulation of these fetal microbiomes related to placental dysbiosis may influence short-and long-term neonatal complications such as bronchopulmonary dysplasia and necrotising enterocolitis amongst other morbidities. (10) Nonetheless, whether the maternal gut microbiota, and the subsequent impact on metabolic, hormonal and immunological factors during gestation, exerts any influence on the pregnancy itself remains unclear.…”

“…(10) Furthermore, emerging evidence of the interactions between placental and fetal gut and lung microbiomes highlights that dysregulation of these fetal microbiomes related to placental dysbiosis may influence short-and long-term neonatal complications such as bronchopulmonary dysplasia and necrotising enterocolitis amongst other morbidities. (10) Nonetheless, whether the maternal gut microbiota, and the subsequent impact on metabolic, hormonal and immunological factors during gestation, exerts any influence on the pregnancy itself remains unclear. (11) However, there is consensus on the role of the vaginal microbiome in health with a dominance of protective Lactobacillus species, which make up >70% of resident bacteria, found in the vagina of healthy, reproductive-age women.…”

Evidence for the Management of Bronchopulmonary Dysplasia in Very Preterm Infants

“…The complex interaction of microbiome of intestines and lungs with the developing immune system and organ development will likely provide further insight in the development of BPD [ 153 ]. Microbial dysbiosis may be associated with BPD progression and severity [ 145 ].…”

“…Individualized fortification, which is adjustable fortification (by measuring the infant’s blood urea nitrogen) or targeted fortification (measuring the macronutrient content of human milk), seems to be superior compared to standardized fortification regarding the gain of growth parameters in a recent Cochrane meta-analysis, but the included seven studies did not present data on the development of BPD or long-term outcomes [ 202 ]. Last, human milk has an important influence on the immature microbiome, which is an important focus of very recent research [ 153 ].…”

Perspectives on Probiotics and Bronchopulmonary Dysplasia

“…The gut-lung axis hypothesis, which involves a complex crosstalk between lung/gut disease and gut/lung microbiota dysbiosis, has been extensively tested (34)(35)(36)(37). Newborn mice that have been depleted of gut microbiota with antibiotics become more susceptible to Streptococcus pneumoniae infection, however, restoring intestinal microbiota increases neonatal and germfree (GF) mice resistance (38) and potentiates phagocytosis of alveolar macrophages (39), thus protecting lungs from bacterial infection.…”