Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development
Open accessAbstract
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.
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Due to the lack of commensal microbes, GF animals have impaired immune systems, dysregulated hormone signaling, altered metabolism, and differences in neurotransmission from conventional counterparts.
“Due to the lack of commensal microbes, GF animals have impaired immune systems, dysregulated hormone signaling, altered metabolism, and differences in neurotransmission from conventional counterparts (Kawase et al., 2017;Neufeld et al., 2011;Pan et al., 2018;Sudo et al., 2004;Weger et al., 2019).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Pan et al., 2018
The Results section ('The gut microbiota and chronological age determine the epithelial transcriptome during postnatal development'; no page given) reports differences in immune-function and metabolic gene expression between germ-free and conventionally raised mice. These findings support immune and metabolic differences, but they do not establish an impaired immune system or altered whole-animal metabolism. The paper does not report dysregulated hormone signaling or differences in neurotransmission. (LLM, conf=0.87)
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- Authors
- Pan, W.-H., Sommer, F., Falk-Paulsen, M., Ulas, T., Best, L., Fazio, A., Kachroo, P., Luzius, A., Jentzsch, M., Rehman, A., Müller, F., Lengauer, T., Walter, J., Künzel, S., Baines, J. F., Schreiber, S., Franke, A., Schultze, J. L., Bäckhed, F., & Rosenstiel, P.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- University of Bonn (DE)
- Max Planck Institute for Informatics (DE)
- Saarland University (DE)
- University of Copenhagen (DK)
- Corresponding author
- Rosenstiel, Philip
- ORCID
- Venue
- Genome Medicine
- Published
- 2018-04-13
- Volume
- 10
- Issue
- 1
- Pages
- 27-27
- ISSN
- 1756-994X (ISSN-L)
- PMC
- PMC5899322
- OpenAlex
- W2802827720
- Cited by
- 157
- References
- 77
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 16 · 2023: 24 · 2022: 21 · 2021: 20 · 2020: 29 · 2019: 15 · 2018: 6
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Max Planck Digital Library (submittedVersion, other-oa)
- DZNE Pub (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (RTG 1743/1, CRC877 B9, ExC 306 Inflammation at Interfaces, ExC 1023 ImmunoSensation, CRC1182 C2)
- BMBF (DEEP IHEC network grant (TP5.2 and 2.3))
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- gut microbiota, DNA methylation, intestinal epithelial cells, postnatal development, transcriptome, immune pathways, metabolism, intestinal development
- MeSH terms
- Gastrointestinal Microbiome, Animals, Epithelial Cells, Female, Intestines, Mice, Inbred C57BL, RNA, Transcription, Genetic, Gene Expression Regulation, Developmental, DNA Methylation, Growth and Development, Genetic Loci, Transcriptome
About these checks
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