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A comparison of the intestinal phenotype and transcriptome profile analysis in the oral-fed mice with substances to affect the intestinal homeostasis

ABSTRACT: Epithelial cells in the intestinal mucosa maintain gut homeostasis by interacting with different types of microbiota. Proper appropriate immune responses in the intestinal epithelium are essential for the preservation of the intestinal homeostasis. In the present study, we aimed to identify genotypic and phenotypic changes in mice following oral feeding of various substances which has been shown to differentially affect intestinal homeostasis. We orally fed C57BL/6 mice for either one or seven days with one of the four substances: dextran sulfate sodium (DSS); Typhoid VI Polysaccharide vaccine (Vi vaccine); antibiotic cocktails (AB) of ampicillin, vancomycin, neomycin, and metronidazole; or(probiotics)consisting of Lactobacillus Rhamnosus R0011and L. Acidophilus R0052.While DSS and AB feeding resulted in severe gut pathology characterized by infiltration of inflammatory cells, epithelium shedding, and distortion of paneth cells. Vi vaccine and probiotics feeding resulted in phenotypic improvement of the gut health characterized by epithelial cell proliferation and increased formation of tight junctions between epithelial cells. Interestingly, microarray data showed significant increase in the expression levels of genes regulating cell proliferation and intestinal homeostasis in the gut epithelium of probiotics-and Vi vaccine-fed mice compared to DSS-or AB-fed mice. In addition, expression levels of genes regulating cell death and inflammation were significantly increased in the gut epithelium of DSS- and AB-fed mice. These results suggest that intestinal homeostasis play a pivotal role in maintaining gut health and, subsequently, in protecting host against enteric bacteria and external pathogens infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE84079 | GEO | 2018/07/31

REPOSITORIES: GEO

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Project description:Intestinal homeostasis is dynamically coordinated by various types of epithelial cells fulfilling their specific functions. Tuft cells as chemosensory cells have emerged as key players of the host response, such as innate immunity. Tuft cells are also critical for the restoration of intestinal architecture upon damage, thereby contributing to inflammatory bowel diseases (IBDs) characterized by defective intestinal barrier integrity. However, the molecular mechanism of how tuft cell homeostasis is controlled remains obscure. Recent studies have identified single-nucleotide polymorphisms in the inositol polyphosphate multikinase (IPMK) gene associated with IBD predisposition. IPMK, an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. To investigate the functional significance of IPMK in gut epithelium, we generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMKΔIEC) mice. Whereas IPMKΔIEC mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium (DSS)-induced colitis, with higher clinical colitis scores, and elevated epithelial barrier permeability. Surprisingly, no apparent defects in epithelial growth signaling pathway and inflammation were found in DSS-challenged, IPMK-deficient colons. Rather, Ipmk deletion led to a significant decrease in the number of tuft cells without influencing other intestinal epithelial cells. Ipmk deletion in the gut epithelium was found to reduce choline acetyltransferase but not cytokines (e.g., IL-25), suggesting selective loss of cholinergic signaling. Single-cell RNA-sequencing of mouse colonic tuft cells (EpCAM+/Siglec F+) and immunohistochemistry revealed three populations of tuft cells and further showed that, in IPMKΔIEC mice, a transcriptionally inactive tuft club cell population was markedly expanded, and neuronal-related tuft cells were relatively decreased, supporting the abnormal development of tuft cells without IPMK functions. Thus, IPMK acts as a physiological determinant of colonic tuft cell homeostasis, thereby mediating tissue regeneration upon injury.

Project description:Aim: RNA binding proteins (RBPs) are emerging as critical regulators of gut homeostasis via post-transcriptional control of key growth and repair pathways. IMP1 (IGF2 mRNA Binding Protein 1) is ubiquitously expressed during embryonic development and Imp1 hypomorphic mice exhibit severe gut growth defects. In the present study, we investigated the mechanistic contribution of intestinal epithelial IMP1 to gut homeostasis and response to injury. Method: We evaluated IMP1 expression in patients with Crohn’s disease followed by unbiased ribosome profiling in IMP1 knockout cells. Concurrently, we measured differences in histology and cytokine expression in mice with intestinal epithelial-specific Imp1 deletion (Imp1ΔIEC) following dextran sodium sulfate (DSS)- colitis. Based on ribosome profiling analysis, we evaluated changes in autophagy in Imp1ΔIEC mice as well as in silico and in vitro approaches to evaluate direct protein:RNA interactions. Finally, we analyzed the consequence of genetic deletion of Atg7 in Imp1ΔIEC mice using colitis and irradiation models. Results: IMP1 was robustly upregulated in Crohn’s disease patients and Imp1 loss lessened DSS-colitis severity. Unbiased ribosome-profiling revealed that IMP1 may coordinate translation of multiple pathways important for intestinal homeostasis, including cell cycle and autophagy, which we verified by Western blotting. Mechanistically, we observed evidence for increased autophagy flux in Imp1ΔIEC mice, reinforced through in silico and biochemical analyses revealing direct binding of IMP1 to autophagy transcripts. Finally, we found genetic deletion of Atg7 reversed the phenotype observed in DSS- or irradiation-challenged Imp1ΔIEC mice. Conclusions: IMP1 acts as a post-transcriptional regulator of gut epithelial repair, in part through modulation of autophagy. This study highlights the need for examining post-transcriptional regulation as a critical mechanism in inflammatory bowel disease.

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A comparison of the intestinal phenotype and transcriptome profile analysis in the oral-fed mice with substances to affect the intestinal homeostasis

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