Rapid Gut Adaptation to Preterm Birth Involves Feeding-Related DNA Methylation Reprogramming of Intestinal Genes in Pigs

Xiaoyu Pan,Per T Sangild,Thomas Thymann,Fei Gao

doi:10.3389/fimmu.2020.00565

Abstract

Following preterm birth, the immature gut function and immunology must rapidly adapt to cope with bacterial colonization and enteral milk feeding. We hypothesized that intestinal epigenetic changes are involved in the gut response to preterm birth and the first feeding. Using piglets as models for infants, preterm, and term pigs were fed total parenteral nutrition (TPN) or partial enteral feeding for 5 days, followed by exclusive enteral feeding with bovine milk until day 26 (weaning age). Intestinal structure, function, microbiome, DNA methylome, and gene expressions were compared between preterm and term pigs on days 0, 5, and 26 (n = 8 in each group). At birth, the intestine of preterm pigs showed villus atrophy and global hypermethylation, affecting genes related to the Wnt signaling pathway. Hypermethylation-associated lowered expression of lipopolysaccharide-binding protein and genes related to the Toll-like receptor 4 pathway were evident during the first 5 days of life, but most early methylation differences disappeared by day 26. Regardless, sucrase and maltase activities (adult-type brush border enzymes) remained reduced, and the gut microbiota altered (fewer Akkermansia, more Lachnoclostridia and Lactobacilli) until day 26 in preterm pigs. During the 0- to 5-day period, many new preterm–term methylation differences appeared, but mainly when no enteral feed was provided (TPN feeding). These methylation differences affected intestinal genes related to cell metabolism, including increased GCK (glucokinase) expression via promoter hypomethylation. In conclusion, the immature intestine has a remarkable capacity to adapt its gene methylation and expression after preterm birth, and only few preterm-related defects persisted until weaning. Early enteral feeding may be important to stimulate the methylation reprogramming of intestinal genes, allowing rapid intestinal adaptation to preterm birth.

Highlights

Preterm birth accounts for ∼10% of all live births and remains a major global health problem [1]
We previously showed that formula feeding and bacterial colonization have marked shortterm effects on intestinal DNA methylation in preterm pigs [18, 20], but it is not known if such changes are stable more long-term and enteral nutrition (ENT)-dependent
Except that early ENT feeding significantly increased the relative intestinal weight in both groups on day 5 (28.30 ± 1.09 vs. 22.77 ± 0.76 for preterms and 32.23 ± 0.80 vs. 26.23 ± 1.09 for terms, both p < 0.001), none of the other measured phenotypic characteristics of the gut were consistently affected by ENT vs. total parenteral nutrition (TPN) feeding

Summary

Introduction

Preterm birth accounts for ∼10% of all live births and remains a major global health problem [1]. For survival after preterm birth, the structure and function of the immature gut must rapidly adapt to the new nutritional and microbial environment. This adaptation may fail, or take some time to develop, as indicated by a high sensitivity to feeding intolerance, gut inflammation, and necrotizing. Children born preterm may show elevated risks of neurologic and metabolic disorders [4,5,6,7], whereas persistent gut complications are less often reported Both short- and long-term gut complications may result from a combination of three critical factors, shortened gestational age at birth, premature transition to enteral feeding, and inappropriate bacterial colonization. A better understanding of how the immature gut interacts with environmental factors, such as nutrition and microbes, is required to define how early feeding strategies can best secure optimal adaptation of the preterm infant to postnatal life

Methods

Results

Conclusion