Alcohol feeding promotes colonic permeability and changes in colonic organoid stem cell fate
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE99291 | GEO | 2018/02/14
REPOSITORIES: GEO
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Project description:The etiology of alcohol dependence is not completely understood. Increasing evidence reveals that gut microbiota dysbiosis is associated with certain psychiatric disorders, including alcoholism, through the 'microbiota-gut-brain' axis. The aims were to evaluate the effect of alcohol abuse on the gut microbiota, intestinal permeability and serum metabolic profile and to determine whether alcohol-induced alterations in gut microbiota are correlated with gut permeability and serum metabolic phenotype changes. 16S rRNA gene high-throughput sequencing and nontarget metabolomics techniques were applied in an alcohol-dependent rat model in the present study. The results showed that alcohol intake altered the composition and structure of the colonic microbiota, especially the relative abundance of the commensal microbes <i>Lachnospiraceae</i> and <i>Prevotellaceae</i>, which was significantly decreased. Alcohol-dependent rats developed gut leakiness and a serum metabolic phenotype disorder. The valine, leucine and isoleucine biosynthesis pathways and arginine and proline metabolism pathways were obviously influenced by alcohol intake. Moreover, alcohol consumption disturbed the brain's neurotransmitter homeostasis. The regression analysis showed that alcohol-induced colonic microbiota dysbiosis was strongly associated with increased intestinal permeability and serum metabolic phenotype and neurotransmitter disorders. These results revealed that gut microbiota dysbiosis and serum metabolites alteration might be a cofactor for developing of alcohol dependence. <b>IMPORTANCE</b> The gut microbiota dysbiosis is associated with certain psychiatric disorders through the 'microbiota-gut-brain' axis. Here we revealed that alcohol consumption induced the colonic microbiota dysbiosis, increased intestinal permeability, altered the serum metabolic phenotype in rats, and there were a strong correlation between gut microbiota dysbiosis and serum metabolites disorders. Thus, gut microbiota dysbiosis and serum metabolites alteration may be a cofactor for development of alcohol dependence.
2021-07-30 | MTBLS2688 | MetaboLights
Project description:BackgroundAlcohol increases intestinal permeability to proinflammatory microbial products that promote liver disease, even after a period of sobriety. We sought to test the hypothesis that alcohol affects intestinal stem cells using an in vivo model and ex vivo organoids generated from jejunum and colon from mice fed chronic alcohol.MethodsMice were fed a control or an alcohol diet. Intestinal permeability, liver steatosis-inflammation, and stool short-chain fatty acids (SCFAs) were measured. Jejunum and colonic organoids and tissue were stained for stem cell, cell lineage, and apical junction markers with assessment of mRNA by PCR and RNA-seq. ChIP-PCR analysis was carried out for Notch1 using an antibody specific for acetylated histone 3.ResultsAlcohol-fed mice exhibited colonic (but not small intestinal) hyperpermeability, steatohepatitis, and decreased butyrate/total SCFA ratio in stool. Stem cell, cell lineage, and apical junction marker staining in tissue or organoids from jejunum tissue were not impacted by alcohol. Only chromogranin A (Chga) was increased in jejunum organoids by qPCR. However, colonic tissue and organoid staining exhibited an alcohol-induced significant decrease in cytokeratin 20+ (Krt20+) absorptive lineage enterocytes, a decrease in occludin and E-cadherin apical junction proteins, an increase in Chga, and an increase in the Lgr5 stem cell marker. qPCR revealed an alcohol-induced decrease in colonic organoid and tissue Notch1, Hes1, and Krt20 and increased Chga, supporting an alteration in stem cell fate due to decreased Notch1 expression. Colonic tissue ChIP-PCR revealed alcohol feeding suppressed Notch1 mRNA expression (via deacetylation of histone H3) and decreased Notch1 tissue staining.ConclusionsData support a model for alcohol-induced colonic hyperpermeability via epigenetic effects on Notch1, and thus Hes1, suppression through a mechanism involving histone H3 deacetylation at the Notch1 locus. This decreased enterocyte and increased enteroendocrine cell colonic stem cell fate and decreased apical junctional proteins leading to hyperpermeability.
| S-EPMC5711563 | biostudies-literature
Project description:Background: Alcohol misuse, binge drinking pattern, and gender-specific effects in the middle-aged population has been clearly underestimated. In the present study, we focused on understanding gender-specific effects of alcohol exposure on the gut-liver axis and the role of gut microbiota in modulating gender-specific responses to alcohol consumption. Methods: Fifty-two-week-old female and male C57BL/6 mice were fasted for 12 h, and then administered a single oral dose of ethanol (EtOH) (6 g/kg). Controls were given a single dose of PBS. Animals were sacrificed 8 h later. Alternatively, fecal microbiota transplantation (FMT) was performed in 52-week-old male mice from female donors of the same age. Permeability of the large intestine (colon), gut microbiota, liver injury, and inflammation was thoroughly evaluated in all groups. Results: Middle-aged male mice exposed to EtOH showed a significant increase in gut permeability in the large intestine, evaluated by FITC-dextran assay and ZO-1, OCCLUDIN and MUCIN-2 immuno-staining, compared to PBS-treated animals, whilst female mice of the same age also increased their gut permeability, but displayed a partially maintained intestinal barrier integrity. Moreover, there was a significant up-regulation of TLRs and markers of hepatocellular injury, cell death (AST, TUNEL-positive cells) and lipid accumulation (ORO) in male mice after EtOH exposure. Interestingly, FMT from female donors to male mice reduced gut leakiness, modified gut microbiota composition, ameliorated liver injury and inflammation, TLR activation and the senescence phenotype of middle-aged mice. Conclusion: Our findings highlighted the relevance of gender in middle-aged individuals who are exposed to alcohol in the gut-liver axis. Moreover, our study revealed that gender-specific microbiota transplantation might be a plausible therapy in the management of alcohol-related disorders during aging.
2024-04-18 | GSE263477 | GEO
Project description:Transmissible gastroenteritis virus (TGEV), a member of coronavirus, is the pathogen of TGE. We previously found 123 circular RNAs (circRNAs) were differential expression during activation of mitochondrial permeability transition in porcine intestinal epithelial cells-jejunum 2 cell line (IPEC-J2) in response to TGEV infection. Mitochondrial permeability transition pore (mPTP) is a transmembrane pore of mitochondria and plays a key role in MPT. mPTP abnormal opening causes MPT. Therefore, we postulated that circRNAs might be related to mPTP abnormal opening induced by TGEV. In this study, we found that circBIRC6-2 could inhibit the mPTP abnormal opening induced by TGEV. Interestingly, circBIRC6-2 encodes protein BIRC6-236aa. An open reading frame (ORF) and internal ribosomal entrance site (IRES) of circBIRC6-2 were identified. We also found that BIRC6-236aa rather than circBIRC6-2 inhibited the mPTP opening by overexpression of circBIRC6-2 related vectors. We obtained 91 proteins that interacted with BIRC6-236aa using immunoprecipitation-mass spectrometry (IP-MS). The interaction between voltage-dependent anion-selective channel protein 1 (VDAC1) and BIRC6-236aa was demonstrated through co-immunoprecipitation (Co-IP). Moreover, BIRC6-236aa could inhibit the formation of VDAC1 and Cyclophilin D (CypD) complexes. Overall, these results indicated that BIRC6-236aa antagonized mPTP opening by interacting with VDAC1 to weaken the extent of interaction between VDAC1 and CypD.
2022-10-13 | PXD029055 | Pride
Project description:Endocannabinoid 2-arachidonoylglycerol (2-AG) is an anti-nociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by monoacylglycerol lipase (MAGL). In this study, we investigated the effects of MAGL inhibition on intestinal permeability and explored the possible mechanism. A rat model of severe acute pancreatitis (SAP) was established. Rats were divided into three groups according to treatment. We analyzed intestinal permeability to fluorescein isothiocyanate-dextran and the levels of inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and 2-AG. Hematoxylin and eosin staining was used to assess histological tissue changes. In vivo intestinal permeability was evaluated by transmission electron microscopy. We obtained ileum tissues, extracted total RNA, and applied RNA-sequencing. Sequencing data were analyzed by bioinformatics. Inflammatory factor levels were higher, while 2-AG levels were lower in the SAP group compared with the control group. Administration of JZL184 to rats with SAP increased the levels of 2-AG and lowered the levels of IL-6 and TNF-α. Notably, intestinal permeability was improved by JZL184 as demonstrated by fluorescein isothiocyanate-dextran measurement, hematoxylin and eosin staining, and transmission electron microscopy. RNA-sequencing showed significant transcriptional differences in SAP and JZL184 groups compared with the control group. KEGG analysis showed that the up- or downregulated genes in multiple comparison groups were enriched in two pathways, focal adhesion and PI3K-Akt signaling pathways. Differential alternative splicing (AS) genes, such as Myo9b, Lsp1, and Git2, have major functions in intestinal diseases. A total of 132 RNA-binding proteins (RBPs) were screened by crossing the identified abnormally expressed genes with the reported RBP genes. Among them, Hnrnpdl coexpressed the most AS events as the main RBP. MAGL inhibition improved intestinal mucosal barrier injury in SAP rats and induced a large number of differentially expressed genes and alternative splicing events. Hnrnpdl might play an important role in improving intestinal mucosal barrier injury by affecting alternative splicing events.
2022-03-18 | GSE197930 | GEO
Project description:Aspen cell cultures were fed 5 mM salicyl alcohol at the early exponential phase (5 days after subculture). Cells were harvested from fed (SL) or unfed (C) cells after 48 hours. Gene expression changes were analyzed using a custom 7K aspen EST array. RNA was extracted from 3 independent control (C) and 3 salicyl alcohol-fed (SL) samples, and one control and one treated sample were randomly paired for hybridization (3 biological replicates). Dye-swap hybridizations were carried out for each pair of samples.
2010-05-15 | E-GEOD-18360 | biostudies-arrayexpress
Project description:The study describes miRNA expression in intact jejunum following feeding of gluten containing monkey chow to gluten sensitive (GS) rhesus macaques. Gluten feeding induced several inflammation associated miRNAs validated and predicted to directly target intestinal tight junction proteins. Upregulation of these microRNAs was accompanied significantly reduced mRNA expression of claudin-1, claudin-3 and occludin and severe gut dysbiosis. These findings suggest that miRNA mediated downregulation of intestinal epithelial tight junction proteins could increase intestinal permeability and facilitate translocation of dysbiotic bacteria into the systemic circulation.
2016-11-10 | GSE89170 | GEO
Project description:Aspen cell cultures were fed 5 mM salicyl alcohol at the early exponential phase (5 days after subculture). Cells were harvested from fed (SL) or unfed (C) cells after 48 hours. Gene expression changes were analyzed using a custom 7K aspen EST array.
2010-01-21 | GSE18360 | GEO
Project description:Vascular permeability is frequently associated with inflammation and it is triggered by chemokines and by a cohort of secreted permeability factors, such as VEGF. In contrast, here we showed that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and it is independent of VEGF. Both global and endothelial-specific deletion of PR block physiological vascular permeability in the uterus while misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of genome-wide transcriptional profile of endothelium and ChIP-sequencing revealed that PR induces a NR4A1 (Nur77/TR3) specific transcriptional program that broadly regulates vascular permeability in response to progesterone. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely and venule-specific regulation of vascular barrier function. Silencing NR4A1 blocks PR-mediated permeability responses indicating a direct link between PR and NR4A1. These results reveal a previously unknown function for progesterone receptor on endothelial cell biology with consequences to physiological vascular permeability and implications to the clinical use of progestins and anti-progestins on blood vessel integrity. Examination of PR binding sites in HUVEC cells using ChIP-seq (non-infected-negative control, PR infected followed by ligand treatment-PR+P or vehicle PR)
2014-01-01 | E-GEOD-43786 | biostudies-arrayexpress
Project description:Vascular permeability is frequently associated with inflammation and it is triggered by chemokines and by a cohort of secreted permeability factors, such as VEGF. In contrast, here we showed that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and it is independent of VEGF. Both global and endothelial-specific deletion of PR block physiological vascular permeability in the uterus while misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of genome-wide transcriptional profile of endothelium and ChIP-sequencing revealed that PR induces a NR4A1 (Nur77/TR3) specific transcriptional program that broadly regulates vascular permeability in response to progesterone. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely and venule-specific regulation of vascular barrier function. Silencing NR4A1 blocks PR-mediated permeability responses indicating a direct link between PR and NR4A1. These results reveal a previously unknown function for progesterone receptor on endothelial cell biology with consequences to physiological vascular permeability and implications to the clinical use of progestins and anti-progestins on blood vessel integrity. Examination of PR target genes in human umbilical vein endothelial cells (HUVECs) using RNA-seq (PR infected only -PR only and PR infected followed by ligand treatment-PR+P)
2014-01-01 | E-GEOD-43788 | biostudies-arrayexpress