title: Epigenome-Microbiome crosstalk: A potential new paradigm influencing neonatal susceptibility to disease.
abstract: Preterm birth is the leading cause of infant morbidity and mortality. Necrotizing enterocolitis (NEC) is an inflammatory bowel disease affecting primarily premature infants, which can be lethal. Microbial intestinal colonization may alter epigenetic signatures of the immature gut establishing inflammatory and barrier properties predisposing to the development of NEC. We hypothesize that a crosstalk exists between the epigenome of the host and the initial intestinal colonizing microbiota at critical neonatal stages. By exposing immature enterocytes to probiotic and pathogenic bacteria, we showed over 200 regions of differential DNA modification, which were specific for each exposure. Reciprocally, using a mouse model of prenatal exposure to dexamethasone we demonstrated that antenatal treatment with glucocorticoids alters the epigenome of the host. We investigated the effects on the expression profiles of genes associated with inflammatory responses and intestinal barrier by qPCR-based gene expression array and verified the DNA modification changes in 5 candidate genes by quantitative methylation specific PCR (qMSP). Importantly, by 16S RNA sequencing-based phylogenetic analysis of intestinal bacteria in mice at 2 weeks of life, we showed that epigenome changes conditioned early microbiota colonization leading to differential bacterial colonization at different taxonomic levels. Our findings support a novel conceptual framework in which epigenetic changes induced by intrauterine influences affect early microbial colonization and intestinal development, which may alter disease susceptibility.
authors.affiliation: a Section of Neonatology, Department of Pediatrics, The University of Chicago , Chicago , IL , USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Cortese
authors.affiliation: a Section of Neonatology, Department of Pediatrics, The University of Chicago , Chicago , IL , USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Lu
authors.affiliation: a Section of Neonatology, Department of Pediatrics, The University of Chicago , Chicago , IL , USA.
authors.forename: Yueyue
authors.initials: Y
authors.lastname: Yu
authors.affiliation: b Department of Obstetrics and Gynecology and Institute of Environmental Health Sciences (IEHS), Wayne State University , Detroit , MI , USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Ruden
authors.affiliation: a Section of Neonatology, Department of Pediatrics, The University of Chicago , Chicago , IL , USA.
authors.forename: Erika C
authors.initials: EC
authors.lastname: Claud
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000235:genetics*; D003907:Dexamethasone / Q000008:administration & dosage; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology; D020895:Enterocytes / Q000187:drug effects / Q000382:microbiology; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D007234:Infant, Premature / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D064307:Microbiota / Q000187:drug effects / Q000235:genetics*; D010802:Phylogeny; D011247:Pregnancy; D019936:Probiotics / Q000008:administration & dosage; D012336:RNA, Ribosomal, 16S / Q000235:genetics
chemical_list: D012336:RNA, Ribosomal, 16S; D003907:Dexamethasone
keywords: Antenatal glucocorticoid treatment; DNA modification profiling; developmental origin of disease; epigenome; intrauterine influence; microbiome; transcriptomic profiling