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Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development.

ABSTRACT: BACKGROUND:The interplay of epigenetic processes and the intestinal microbiota may play an important role in intestinal development and homeostasis. Previous studies have established that the microbiota regulates a large proportion of the intestinal epithelial transcriptome in the adult host, but microbial effects on DNA methylation and gene expression during early postnatal development are still poorly understood. Here, we sought to investigate the microbial effects on DNA methylation and the transcriptome of intestinal epithelial cells (IECs) during postnatal development. METHODS:We collected IECs from the small intestine of each of five 1-, 4- and 12 to 16-week-old mice representing the infant, juvenile, and adult states, raised either in the presence or absence of a microbiota. The DNA methylation profile was determined using reduced representation bisulfite sequencing (RRBS) and the epithelial transcriptome by RNA sequencing using paired samples from each individual mouse to analyze the link between microbiota, gene expression, and DNA methylation. RESULTS:We found that microbiota-dependent and -independent processes act together to shape the postnatal development of the transcriptome and DNA methylation signatures of IECs. The bacterial effect on the transcriptome increased over time, whereas most microbiota-dependent DNA methylation differences were detected already early after birth. Microbiota-responsive transcripts could be attributed to stage-specific cellular programs during postnatal development and regulated gene sets involved primarily immune pathways and metabolic processes. Integrated analysis of the methylome and transcriptome data identified 126 genomic loci at which coupled differential DNA methylation and RNA transcription were associated with the presence of intestinal microbiota. We validated a subset of differentially expressed and methylated genes in an independent mouse cohort, indicating the existence of microbiota-dependent "functional" methylation sites which may impact on long-term gene expression signatures in IECs. CONCLUSIONS:Our study represents the first genome-wide analysis of microbiota-mediated effects on maturation of DNA methylation signatures and the transcriptional program of IECs after birth. It indicates that the gut microbiota dynamically modulates large portions of the epithelial transcriptome during postnatal development, but targets only a subset of microbially responsive genes through their DNA methylation status.

SUBMITTER: Pan WH

PROVIDER: S-EPMC5899322 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development.

Pan Wei-Hung WH Sommer Felix F Falk-Paulsen Maren M Ulas Thomas T Best Lena L Fazio Antonella A Kachroo Priyadarshini P Luzius Anne A Jentzsch Marlene M Rehman Ateequr A Müller Fabian F Lengauer Thomas T Walter Jörn J Künzel Sven S Baines John F JF Schreiber Stefan S Franke Andre A Schultze Joachim L JL Bäckhed Fredrik F Rosenstiel Philip P

Genome medicine 20180413 1

<h4>Background</h4>The interplay of epigenetic processes and the intestinal microbiota may play an important role in intestinal development and homeostasis. Previous studies have established that the microbiota regulates a large proportion of the intestinal epithelial transcriptome in the adult host, but microbial effects on DNA methylation and gene expression during early postnatal development are still poorly understood. Here, we sought to investigate the microbial effects on DNA methylation a ...[more]

PMID: 29653584

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Project description:BackgroundLead (Pb) is an environmentally ubiquitous heavy metal associated with a wide range of adverse health effects in children. Both lead exposure and the early life microbiome- which plays a critical role in human development-have been linked to similar health outcomes, but it is unclear if the adverse effects of lead are partially driven by early life gut microbiota dysbiosis. The objective of this study was to examine the association between in utero and postnatal lead levels (measured in deciduous baby teeth) and early life bacterial and fungal gut microbiota in the first year of life.MethodsData from the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort were analyzed. Tooth lead levels during the 2nd and 3rd trimesters and postnatally (<1 year of age) were quantified using high-resolution microspatial mapping of dentin growth rings. Early life microbiota were measured in stool samples collected at approximately 1 and 6 months of age, using both 16S rRNA (bacterial) and ITS2 (fungal) sequencing. Of the 1,258 maternal-child pairs in WHEALS, 146 had data on both tooth metals and early life microbiome.ResultsIn utero tooth lead levels were significantly associated with gut fungal community composition at 1-month of age, where higher levels of 2nd trimester tooth lead was associated with lower abundances of Candida and Aspergillus and higher abundances of Malassezia and Saccharomyces; 3rd trimester lead was also associated with lower abundances of Candida. Though lead did not significantly associate with the overall structure of the infant gut bacterial community, it associated with the abundance of some specific bacterial taxa, including the increased abundance of Collinsella and Bilophila and a decreased abundance of Bacteroides taxa.ConclusionsThe observed associations between lead exposure and infant gut microbiota could play a role in the impact of lead on childhood development. Given the paucity of research examining these associations in humans-particularly for fungal microbiota-further investigation is needed.

Project description:Establishing and maintaining beneficial interactions between the host and associated gut microbiota are pivotal requirements for host health. Autophagy is an important catabolic recycling pathway that degrades long-lived proteins and some organelles by lysosome to maintain cellular homeostasis. Although impaired autophagy is thought to be closely correlated with Crohn's disease (CD), the functional role of autophagy in the maintenance of gut microbiota is poorly understood. As autophagy-related 5 (Atg5) is a key gene associated with the extension of the phagophoric membrane in autophagic vesicles, we established a gut-specific Atg5 knockout mouse model, and we found that the disruption of autophagic flux in the intenstinal epithelium cells dramatically altered the composition of the gut microbiota and reduced alpha diversity. Microbial function prediction indicated that the pathway allocated for infectious diseases was enriched in Atg5-/- mice. "Candidatus Arthromitus" and the Pasteurellaceae family were increased in Atg5-/- mice, whereas Akkermansia muciniphila and the Lachnospiraceae family were reduced. Transcriptome analysis revealed that two key inflammatory bowel disease (IBD)-related transcription factors, RORC and TBX21, of host cells were upregulated in Atg5-/- mice, thus elevating the Muc2-related immunological response. The findings suggest that intestinal autophagy plays a vital role in modulating the diversity and composition of gut microbiota.IMPORTANCE The homeostasis of host-microbiota interactions is of great importance to host health. Previous studies demonstrated that disruption of autophagy was linked to inflammatory bowel disease. However, the interaction mechanism of gut microbiota regulated by autophagy was obscure. In an intestinal epithelium-specific autophagy-related 5 (Atg5) knockout mouse model, we observed a significant alteration and decreased diversity in the gut microbiota of Atg5-deficient mice compared with that of wild-type mice. Although the numbers of some organisms (e.g., Akkermansia muciniphila and members of the Lachnospiraceae family) associated with the control of inflammation decreased, those of proinflammationory bacteria (e.g., "Candidatus Arthromitus") and potential pathogens (the Pasteurellaceae family) increased in Atg5-/- mice. Differential gene expression analysis revealed that two key genes, RORC and TBX21, involved in inflammatory bowel disease were upregulated in Atg5-/- mice. Our study suggests that Atg5 deficiency results in an imbalance of the host-microbe interaction and deterioration of the gut microenvironment.

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Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development.

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Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development.

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