Xenotransplanted Human Small Intestinal Organoids Reveal the Transepithelial Zinc Transport Pathway as a Key Mediator of Intestinal Adaptation in Short Bowel Syndrome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE271065 | GEO | 2024/08/16
REPOSITORIES: GEO
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Project description:Xenotransplanted Human Small Intestinal Organoids Reveal the Transepithelial Zinc Transport Pathway as a Key Mediator of Intestinal Adaptation in Short Bowel Syndrome
| PRJNA1129535 | ENA
Project description:Numerous cytokines have been shown to affect epithelial cell differentiation and proliferation through epithelial-mesenchymal interaction. Growing evidence suggests that platelet-derived growth factor (PDGF) signaling is an important mediator of these interactions. The purpose of this study was to evaluate the effect of PDGF-α on enterocyte turnover in a rat model of short bowel syndrome (SBS). Male rats were divided into four groups: Sham rats underwent bowel transection, Sham-PDGF-α rats underwent bowel transection and were treated with PDGF-α, SBS rats underwent a 75% bowel resection, and SBS-PDGF-α rats underwent bowel resection and were treated with PDGF-α. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined at sacrifice. Illumina's Digital Gene Expression (DGE) analysis was used to determine PDGF-related gene expression profiling. PDGF-α and PDGF-α receptor (PDGFR-α) expression was determined using Real Time PCR. Western blotting was used to determine p-ERK, Akt1/2/3, bax and bcl-2 protein levels. SBS rats demonstrated a significant increase in PDGF-α and PDGFR-α expression in jejunum and ileum compared to sham animals. SBS-PDGF-α rats demonstrated a significant increase in bowel and mucosal weight, villus height and crypt depth in jejunum and ileum compared to SBS animals. PDGF-α expression in crypts increased in SBS rats (vs sham) and was accompanied by increased cell proliferation following PDGF-α administration. A significant decrease in cell apoptosis in this group was correlated with lower bax protein levels. In conclusion, in a rat model of SBS, PDGF-α stimulates enterocyte turnover, which is correlated with up-regulated PDGF-α receptor expression in the remaining small intestine.
2012-02-29 | GSE36122 | GEO
Project description:Numerous cytokines have been shown to affect epithelial cell differentiation and proliferation through epithelial-mesenchymal interaction. Growing evidence suggests that platelet-derived growth factor (PDGF) signaling is an important mediator of these interactions. The purpose of this study was to evaluate the effect of PDGF-α on enterocyte turnover in a rat model of short bowel syndrome (SBS). Male rats were divided into four groups: Sham rats underwent bowel transection, Sham-PDGF-α rats underwent bowel transection and were treated with PDGF-α, SBS rats underwent a 75% bowel resection, and SBS-PDGF-α rats underwent bowel resection and were treated with PDGF-α. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined at sacrifice. Illumina's Digital Gene Expression (DGE) analysis was used to determine PDGF-related gene expression profiling. PDGF-α and PDGF-α receptor (PDGFR-α) expression was determined using Real Time PCR. Western blotting was used to determine p-ERK, Akt1/2/3, bax and bcl-2 protein levels. SBS rats demonstrated a significant increase in PDGF-α and PDGFR-α expression in jejunum and ileum compared to sham animals. SBS-PDGF-α rats demonstrated a significant increase in bowel and mucosal weight, villus height and crypt depth in jejunum and ileum compared to SBS animals. PDGF-α expression in crypts increased in SBS rats (vs sham) and was accompanied by increased cell proliferation following PDGF-α administration. A significant decrease in cell apoptosis in this group was correlated with lower bax protein levels. In conclusion, in a rat model of SBS, PDGF-α stimulates enterocyte turnover, which is correlated with up-regulated PDGF-α receptor expression in the remaining small intestine. Animals were divided randomly into two experimental groups of 6 rats each. Group A rats underwent bowel transection and re-anastomosis (Sham), Group B animals underwent 75% bowel resection (SBS). Due to the quality of DNA, we performed final analysis from 5 jejunal samples (1 sham and 4 resected rats) and from 7 ileal samples (3 sham and 4 resected rats). Illumina's Digital Gene Expression (DGE) analysis using Illumina Rat Quad BeadChips was used to determine PDGF-related gene expression profiling.
2012-02-29 | E-GEOD-36122 | biostudies-arrayexpress
Project description:Loss of the transcription factor Satb2 converts mouse colonic epithelium into an ileal type. Here, we report that Satb2 gene deletion alleviates SBS by replacing diminished absorptive function and by inducing lymphovascular channels in the proximal colon. Enhanced nutrient absorption following Satb2 loss increased body weight and survival of mice with SBS. Deletion of SATB2 by adeno-associated viral delivery of CRISPR Split Cas9 to human colon organoids, followed by xenotransplantation into mice, resulted in ileal morphology and expression of ileal marker genes. This approach offers a feasible strategy for future treatment of SBS.
2025-03-19 | GSE279770 | GEO
Project description:Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases.
| S-EPMC11458589 | biostudies-literature
Project description:Purpose: Most of the morbidity associated with short bowel syndrome (SBS) are attributed to effects of decreased enteral nutrition and administration of total parenteral nutrition (TPN). We hypothesized that acute SBS alone has significant systemic effects, and tested this in a zebrafish SBS model. Methods: With IACUC approval, adult male wild-type zebrafish underwent SBS (laparotomy, proximal stoma, distal ligation,n=3) or sham (laparotomy alone,n=3) surgery. After 2 weeks, the proximal intestine was harvested, RNA isolated and external RNA controls consortium (ERCC) controls spiked into each sample, sequenced and aligned to reference genome with gene ontology (GO) enrichment analysis performed. CyclinD1, CyclinB1, SAA1, IFN-gamma, and CYP7A1 gene expression were confirmed by qPCR. Results: RNA-seq analysis identified 1346 up-regulated genes and 678 down-regulated genes in SBS zebrafish compared to sham. The up-regulated genes were involved in acute phase response signaling, complement system, coagulation, cell proliferation, cellular barrier, production of nitric oxide & reactive oxygen species and bile acid biosynthesis. The down-regulated genes were involved in folate synthesis, gluconeogenesis, glycogenolysis, fatty-acid oxidation & activation, and drug & steroid metabolism. CyclinD1 gene expression was 2-fold higher, CyclinB1 2.8-fold higher, SAA1 4.5-fold higher, IFN-gamma 2.1-fold higher, and CYP7A1 25-fold higher in SBS than sham by qPCR. Conclusion: The gene expression of SBS demonstrates complex and extensive alteration of multiple pathways, some previously implicated as effects of TPN. The systemic complications of SBS alone are significant and extend beyond the complications of therapy.
2017-03-08 | GSE83195 | GEO
Project description:Cyclin Dependent Kinases CDK8 and CDK19 (Mediator kinase) are regulatory components of the Mediator complex, a highly conserved complex that fine tunes transcriptional output. While Mediator kinase has been implicated in the transcriptional control of key pathways necessary for development and growth, its function in vivo has not been well described. Herein, we report the consequences of complete ablation of both Cdk8/19 on tissue homeostasis. We show that intestinal epithelial specific deletion of Mediator kinase leads to a distinct defect in secretory progenitor differentiation with broad loss of the intestinal secretory cell types. Using a phospho-proteogenomic approach, we show that the Cdk8/19 kinase module interacts with and phosphorylates components of the chromatin remodeling complex Swi/Snf in intestinal epithelial cells. Genomic localisation of Swi/Snf and Mediator shows Cdk8/19-dependent genomic binding at distinct super-enhancer loci within key lineage specification genes, including the master regulator of secretory differentiation ATOH1. Using CRISPRi/CRISPRa, we identify a distinct Mediator- Swi/Snf bound enhancer element that is necessary and sufficient for ATOH1 expression in a Mediator-kinase dependent manner. As such, these studies uncover a newly described transcriptional mechanism of ATOH1-dependent intestinal cell specification that is dependent on the coordinated interaction of the chromatin remodeling complex Swi/Snf and Mediator complex.
2023-03-10 | PXD030212 | Pride
Project description:We evaluated the intestinal responses of pigs under zinc restriction and under different zinc sources through RNA-seq of ileal samples. We identified changes in genes related to zinc transport, immune response, cell proliferation, DNA damage and stress resposne. Our findings demonstrate that swine intestine is responsive to zinc restriction and can be a model sentinel tissue for human zinc deficiency. Further research is needed to define the intestinal responses to organic and inorganic zinc sources.
2021-08-05 | GSE181343 | GEO
Project description:Chronic intestinal failure (CIF) is a rare but feared complication of Crohn's disease. Depending on the remaining length of the small intestine, the affected intestinal segment, and the residual bowel function, CIF can result in a wide spectrum of symptoms, from single micronutrient malabsorption to complete intestinal failure. Management of CIF has improved significantly in recent years. Advances in home-based parenteral nutrition, in particular, have translated into increased survival and improved quality of life. Nevertheless, 60% of patients are permanently reliant on parenteral nutrition. Encouraging results with new drugs such as teduglutide have added a new dimension to CIF therapy. The outcomes of patients with CIF could be greatly improved by more effective prevention, understanding, and treatment. In complex cases, the care of patients with CIF requires a multidisciplinary approach involving not only physicians but also dietitians and nurses to provide optimal intestinal rehabilitation, nutritional support, and an improved quality of life. Here, we summarize current literature on CIF and short bowel syndrome, encompassing epidemiology, pathophysiology, and advances in surgical and medical management, and elucidate advances in the understanding and therapy of CIF-related complications such as catheter-related bloodstream infections and intestinal failure-associated liver disease.
| S-EPMC8240052 | biostudies-literature
Project description:Iron or zinc deficiency is one of the most important nutritional disorders which causes health problem. However, food fortification with minerals often induces unacceptable organoleptic changes during preparation process and storage, has low bioavailability and solubility, and is expensive. Nanotechnology surface modification to obtain novel characteristics can be a useful tool to overcome these problems. In this study, the efficacy and potential toxicity of dispersible Fe or Zn supplement coated in dextrin and glycerides (SunActive FeTM and SunActive ZnTM) were evaluated in terms of cytotoxicity, intestinal transport, and bioavailability, as compared with each counterpart without coating, ferric pyrophosphate (FePP) and zinc oxide (ZnO) nanoparticles (NPs), respectively. The results demonstrate that the cytotoxicity of FePP was not significantly affected by surface modification (SunActive FeTM), while SunActive ZnTM was more cytotoxic than ZnO-NPs. Cellular uptake and intestinal transport efficiency of SunActive FeTM were significantly higher than those of its counterpart material, which was in good agreement with enhanced oral absorption efficacy after a single-dose oral administration to rats. These results seem to be related to dissolution, particle dispersibility, and coating stability of materials depending on suspending media. Both SunActiveTM products and their counterpart materials were determined to be primarily transported by microfold (M) cells through the intestinal epithelium. It was, therefore, concluded that surface modification of food fortification will be a useful strategy to enhance oral absorption efficiency at safe levels.
| S-EPMC5408065 | biostudies-literature