TY - BOOK

T1 - Early-life gut microbiome development

T2 - Of preterm neonates – a culture-independent insight

AU - Hui, Yan

PY - 2021

Y1 - 2021

N2 - Preterm neonates endure a critical period after birth with high risks of morbidity and mortality. Accumulated evidences have indicated that an aberrant gut microbiota is implicated in many neonatal diseases e.g. sepsis and necrotizing enterocolitis, which have led to an increased interest in investigating novel ways to treat the neonatal health problems through microbiome-targeted strategies.The work presented in this PhD project aims to investigate the effect of multiple intervention strategies on the gut microbiome development of preterm newborns. We have evaluated the effect of probiotics, fecal microbiota transplantation (FMT) and several bioactive proteins, and gathered a comprehensive overview of the factors affecting the preterm neonates’ gutmicrobiome.Paper Ⅰ assessed the effect of probiotic exposure on preterm gut microbiome development in the first month of life. We profiled the microbial communities of the 5, 10 and 30 day-of-life fecal samples from two preterm cohorts recruited before and after probiotic use was introduced as routine treatment. The species to which the two administrated probiotic strains i.e. Lacticaseibacillus rhamnosus GG and Bifidobacterium animalis BB-12 belong, were mainly detected in the gut of those neonates supplemented by the probiotic mixture. During both periods the gut microbiome community structure of these infants were mainly contributed by the hospital environment, oral feeding ratio and whether probiotics were introduced or not. Early probiotic exposure affected the gut colonization of potential hospitalacquired pathogens e.g. Klebsiella, but it didn’t change the longitudinally schemed bacterialprogression in gut, which was likely attributed to the oral feeding.Paper Ⅱ compared the FMT efficiency of two phenotypically similar donors on preterm piglets and indicated the protection against NEC was donor dependent. With high throughput sequencing, we confirmed that the prophylactic effect on NEC prevention of FMT was affected by the donor microbiome characteristics. Even though the donors were phenotypically similar, the two donors led to strain-level difference of lactobacilli engraftment, and also donor-dependent gut microbiome composition and host response among recipients. Genome-resolved analysis further suggested that the superior donor contained specific glycosaminoglycans-degrading Bacteroides.Besides, we evaluated several dietary intervention strategies in the preterm piglet trials, including nutritional fortification with bioactive proteins, nutrient restriction and the effect of host difference. Through comparing term and preterm piglets on the same postnatal age, results from Paper Ⅲ showed that the neonatal gut microbiome was more determined by the postnatal age rather than postconceptional age, suggesting the postnatal nutrition might be adeterminant factor in the neonatal gut microbiome development.In Paper Ⅳ, we concluded that nutrient restriction at an acceptable level didn’t lead todistinct microbial shifts in gut as long as they had the similar as fed basis. This finding was also confirmed in several attempts to fortify infant formula with bioactive proteins including alpha-lactalbumin, osteopontin and casein glycolmacropeptide. Although these bioactive proteins resulted in mild improvements of gut and immunity development, we scarcely found distinct changes in the gut microbiome composition, and their effects on gut microbiome were usually smaller than the sow effect.Our results in this PhD project indicate efficient postnatal intervention is a key factor determining the neonatal gut microbiome even though the preterm gut microbiome is affected by multiple factors in this period. And microbiome-targeted strategies e.g. FMT and probiotic use have shown promising potentials in shifting the preterm gut microbiome, sustaining gut homeostasis and providing protection of the neonates. These practices might be the new solutions to reduce the risk of morbidity and mortality among preterm neonates.

AB - Preterm neonates endure a critical period after birth with high risks of morbidity and mortality. Accumulated evidences have indicated that an aberrant gut microbiota is implicated in many neonatal diseases e.g. sepsis and necrotizing enterocolitis, which have led to an increased interest in investigating novel ways to treat the neonatal health problems through microbiome-targeted strategies.The work presented in this PhD project aims to investigate the effect of multiple intervention strategies on the gut microbiome development of preterm newborns. We have evaluated the effect of probiotics, fecal microbiota transplantation (FMT) and several bioactive proteins, and gathered a comprehensive overview of the factors affecting the preterm neonates’ gutmicrobiome.Paper Ⅰ assessed the effect of probiotic exposure on preterm gut microbiome development in the first month of life. We profiled the microbial communities of the 5, 10 and 30 day-of-life fecal samples from two preterm cohorts recruited before and after probiotic use was introduced as routine treatment. The species to which the two administrated probiotic strains i.e. Lacticaseibacillus rhamnosus GG and Bifidobacterium animalis BB-12 belong, were mainly detected in the gut of those neonates supplemented by the probiotic mixture. During both periods the gut microbiome community structure of these infants were mainly contributed by the hospital environment, oral feeding ratio and whether probiotics were introduced or not. Early probiotic exposure affected the gut colonization of potential hospitalacquired pathogens e.g. Klebsiella, but it didn’t change the longitudinally schemed bacterialprogression in gut, which was likely attributed to the oral feeding.Paper Ⅱ compared the FMT efficiency of two phenotypically similar donors on preterm piglets and indicated the protection against NEC was donor dependent. With high throughput sequencing, we confirmed that the prophylactic effect on NEC prevention of FMT was affected by the donor microbiome characteristics. Even though the donors were phenotypically similar, the two donors led to strain-level difference of lactobacilli engraftment, and also donor-dependent gut microbiome composition and host response among recipients. Genome-resolved analysis further suggested that the superior donor contained specific glycosaminoglycans-degrading Bacteroides.Besides, we evaluated several dietary intervention strategies in the preterm piglet trials, including nutritional fortification with bioactive proteins, nutrient restriction and the effect of host difference. Through comparing term and preterm piglets on the same postnatal age, results from Paper Ⅲ showed that the neonatal gut microbiome was more determined by the postnatal age rather than postconceptional age, suggesting the postnatal nutrition might be adeterminant factor in the neonatal gut microbiome development.In Paper Ⅳ, we concluded that nutrient restriction at an acceptable level didn’t lead todistinct microbial shifts in gut as long as they had the similar as fed basis. This finding was also confirmed in several attempts to fortify infant formula with bioactive proteins including alpha-lactalbumin, osteopontin and casein glycolmacropeptide. Although these bioactive proteins resulted in mild improvements of gut and immunity development, we scarcely found distinct changes in the gut microbiome composition, and their effects on gut microbiome were usually smaller than the sow effect.Our results in this PhD project indicate efficient postnatal intervention is a key factor determining the neonatal gut microbiome even though the preterm gut microbiome is affected by multiple factors in this period. And microbiome-targeted strategies e.g. FMT and probiotic use have shown promising potentials in shifting the preterm gut microbiome, sustaining gut homeostasis and providing protection of the neonates. These practices might be the new solutions to reduce the risk of morbidity and mortality among preterm neonates.

M3 - Ph.D. thesis

BT - Early-life gut microbiome development

PB - Department of Food Science, Faculty of Science, University of Copenhagen

ER -