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RNA-seq of WT ileum with DEX, Zn and untreated controls

ABSTRACT: The cytokine TNF drives inflammatory diseases, e.g. Crohn disease. In a mouse model of TNF-induced systemic inflammatory response syndrome (SIRS), severe impact on intestinal epithelial cells (IECs) is observed. Zinc confers complete protection in this model. We found that zinc no longer protects in animals which lack glucocorticoids (GCs), or express mutant versions of their receptor GR in IECs, nor in mice which lack gut microbiota. RNA-seq studies in IECs showed that zinc caused reduction of expression of constitutive (STAT1-induced) interferon-stimulated response (ISRE) genes and Interferon Regulatory Factor (IRF) genes. Since some of these genes are involved in TNF-induced cell death in intestinal crypt Paneth cells, and since zinc has direct effects on the composition of the gut microbiota (such as several Staphylococcus species) and on TNF-induced Paneth cell death, we postulate a new zinc-related anti-inflammatory mechanism. Zinc modulates the gut microbiota, causing less induction of ISRE/IRF genes in crypt cells, less TNF-induced necroptosis in Paneth cells and less fatal evasion of gut bacteria into the system.

ORGANISM(S): Mus musculus

PROVIDER: GSE156119 | GEO | 2020/09/07

REPOSITORIES: GEO

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Project description:The mammalian gut harbors a diverse microbial community (gut microbiota) that mainly consists of bacteria. Their combined genomes (the microbiome) provide biochemical and metabolic functions that complement host physiology. Maintaining symbiosis seems to be a key requirement for health as dysbiosis is associated with the development of common diseases. Previous studies indicated that the microbiota and the hostM-bM-^@M-^Ys epithelium signal bidirectional inducing transcriptional responses to fine-tune and maintain symbiosis. However, little is known about the hostM-bM-^@M-^Ys responses to the microbiota along the length of the gut as earlier studies of gut microbial ecology mostly used either colonic or fecal samples. This is of importance as not only function and architecture of the gut varies along its length but also microbial distribution and diversity. Few recent studies have begun to investigate microbiota-induced host responses along the length of the gut. However, these reports used whole tissue samples and therefore do not allow drawing conclusions about specificity of the observed responses. Which cells in the intestinal tissue are responsible for the microbially induced response: epithelial, mesenchymal or immune cells? Where are the responding cells located? We used using extensive microarray analysis of laser capture microdissection (LCM) harvested ileal and colonic tip and crypt fractions from germ-free and conventionally-raised mice to investigate the microbiota-induced transcriptional responses in specific and well-defined cell populations of the hostM-bM-^@M-^Ys epithelium. Ileum and colon segments were dissected from germ-free and conventionally-raised 10-12 weeks old female C57Bl/6 mice, washed and frozen as OCT blocks. Cryosections were prepared from these OCT blocks and tip/crypt fractions isolated using laser capture microdissection. To investigate the microbiota-induced transcriptional responses specific for specific subpopulations of intestinal epithelial cells, tip and crypt fractions of ileal and colonic epithelium of germ-free and conventionally-raised 10-12 weeks old female C57Bl/6 mice were harvested using laser capture microdissection and probed in an extensive microarray analysis.

Project description:The mammalian gut harbors a diverse microbial community (gut microbiota) that mainly consists of bacteria. Their combined genomes (the microbiome) provide biochemical and metabolic functions that complement host physiology. Maintaining symbiosis seems to be a key requirement for health as dysbiosis is associated with the development of common diseases. Previous studies indicated that the microbiota and the hostM-bM-^@M-^Ys epithelium signal bidirectional inducing transcriptional responses to fine-tune and maintain symbiosis. However, little is known about the hostM-bM-^@M-^Ys responses to the microbiota along the length of the gut as earlier studies of gut microbial ecology mostly used either colonic or fecal samples. This is of importance as not only function and architecture of the gut varies along its length but also microbial distribution and diversity. Few recent studies have begun to investigate microbiota-induced host responses along the length of the gut. However, these reports used whole tissue samples and therefore do not allow drawing conclusions about specificity of the observed responses. Which cells in the intestinal tissue are responsible for the microbially induced response: epithelial, mesenchymal or immune cells? Where are the responding cells located? Furthermore, the gut microbiota has been implicated in epigenetic regulation of the hostM-bM-^@M-^Ys transcriptional profile. We used using extensive microarray analysis of laser capture microdissection (LCM) harvested ileal and colonic tip and crypt fractions from germ-free mice before and during the time course of colonization with a normal microbiota (on days 1, 3, 5 and 7) to investigate the microbiota-induced transcriptional responses and their kinetics in specific and well-defined cell populations of the hostM-bM-^@M-^Ys epithelium. Ileum and colon segments were dissected from germ-free 10-12 weeks old female C57Bl/6 mice and on day 1, 3, 5 and 7 after colonization, washed and frozen as OCT blocks. Cryosections were prepared from these OCT blocks and tip/crypt fractions isolated using laser capture microdissection. To investigate the microbiota-induced transcriptional responses specific for specific subpopulations of intestinal epithelial cells and their kinetics, tip and crypt fractions of ileal and colonic epithelium of germ-free 10-12 weeks old female C57Bl/6 mice before and during the time course of colonization with a normal microbiota (on days 1, 3, 5 and 7) were harvested using laser capture microdissection and probed in an extensive microarray analysis.

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RNA-seq of WT ileum with DEX, Zn and untreated controls

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