Multi-omic analysis unveils biological pathways in peripheral immune system associated to minimal hepatic encephalopathy appearance in cirrhotic patients
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PROVIDER: PRJNA629828 | ENA |
REPOSITORIES: ENA
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Project description:Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) which affects their quality of life and life span. It has been proposed that a shift in peripheral inflammation triggers the appearance of MHE. However, the mechanisms involved in this immune system shift remain unknown. In this work we studied the broad molecular changes involved in the induction of MHE with the goal of identifying (1) altered genes and pathways in peripheral blood cells associated to the appearance of MHE, (2) serum metabolites and cytokines with modified levels in MHE patients and (3) MHE-regulated immune response processes related to changes in specific serum molecules. We adopted a multi-omic approach to profile the transcriptome, metabolome and a panel of cytokines of blood samples taken from cirrhotic patients with or without MHE.
2021-01-27 | GSE149741 | GEO
Project description:Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) which affects their quality of life and life span. It has been proposed that a shift in peripheral inflammation triggers the appearance of MHE. However, the mechanisms involved in this immune system shift remain unknown. In this work we studied the broad molecular changes involved in the induction of MHE with the goal of identifying (1) altered genes and pathways in peripheral blood cells associated to the appearance of MHE, (2) serum metabolites and cytokines with modified levels in MHE patients and (3) MHE-regulated immune response processes related to changes in specific serum molecules. We adopted a multi-omic approach to profile the transcriptome, metabolome and a panel of cytokines of blood samples taken from cirrhotic patients with or without MHE. Transcriptomic analysis supports the hypothesis of alternations in the Th1/Th2 and Th17 lymphocytes cell populations as major drivers of MHE. Cluster analysis of serum molecules resulted in six groups of chemically similar compounds, suggesting that functional modules operate during the induction of MHE. Finally, the multi-omic integrative analysis suggested a relationship between cytokines CCL20, CX3CL1, CXCL13, IL-15, IL-22 and IL-6 with alteration in chemotaxis, as well as a link between long-chain unsaturated phospholipids and the increased fatty acid transport and prostaglandin production. We found altered immune pathways that may collectively contribute to the mild cognitive impairment phenotype in MHE. Our approach is able to combine extracellular and intracellular information, opening new insights to the understanding of the disease.
| S-EPMC7820002 | biostudies-literature
Project description:Aims: Hepatic encephalopathy (HE) is a serious neurological complication in patients with liver cirrhosis. Nothing is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE. Methods: A 4-week bile duct ligation (BDL) model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated using archived GSE41919. Motor function of rats was assessed by the rotarod test. AAV8-VEGF-C was injected into the cisterna magna of BDL rats one day after surgery to induce meningeal lymphangiogenesis. Results: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (p<0.001) as well as increased neuroinflammation as indicated by significant increases in IL-1, INF, TNF and Iba1 expression in at least one of the three regions of the cortex. Motor function was also impaired in rats with HE (p<0.05). Human brains of cirrhotic patients with HE also exhibited upregulation of pro-inflammatory genes (NF-κβ, Iba1, TNFα and IL-1β) (n=6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (p=0.035) and tracer dye uptake in the anterior and middle regions of the cortex (p=0.006 & 0.003, respectively), their corresponding meninges (p=0.086 & 0.006, respectively) and the draining lymph nodes (p=0.02). Further, AAV8-VEGF-C decreased microglia activation (p<0.001) and neuroinflammation, and ameliorated motor dysfunction (p=0.024). Conclusion: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.
2023-04-23 | GSE149227 | GEO
Project description:The psychometric hepatic encephalopathy score (PHES) is the gold standard for diagnosing minimal hepatic encephalopathy (MHE). Screening for MHE is frequently overlooked in clinical practice due to time constraints. Furthermore, the simplified animal naming test (S-ANT1) is a new simple tool for evaluating MHE in cirrhotic patients. The purpose of this study was to standardize the PHES in a healthy Thai population, assess the prevalence of MHE, and validate the S-ANT1 in detecting MHE in patients with cirrhosis. The study included 194 healthy controls and 203 cirrhotic patients without overt HE. Psychometric tests and the S-ANT1 were administered to all participants. Multiple linear regression was used to analyze factors related to PHES results, and formulas were developed to predict the results for each PHES subtest. In healthy controls, age and education were predictors of all five subtests. The PHES of the control group was -0.26 ± 2.28 points, and the threshold for detecting MHE was set at ≤ -5 points. The cirrhotic group had PHES values of -2.6 ± 3.1 points. Moreover, MHE was found to be present in 26.6% of cirrhotic patients. S-ANT1 had a moderate positive correlation with PHES (r = 0.44, p < 0.001). S-ANT1 < 22 named animals detected MHE with a sensitivity of 71.2%, specificity of 65%, and area under the receiver operating curve of 0.68 (p < 0.001). In conclusion, Thai PHES normative data have been developed to detect MHE in cirrhotic patients who do not have overt HE. The optimal cutoff for detecting MHE in Thai cirrhotic patients was PHES ≤ -5 points and S-ANT1 < 22 named.
| S-EPMC9864758 | biostudies-literature
Project description:RNA-seq analysis of brain tissue treated by VEGFC in BDL-induced cirrhotic rat with hepatic encephalopathy
| PRJNA627703 | ENA
Project description:AIM:To evaluate the reversibility of minimal hepatic encephalopathy (MHE) following liver transplantation (LT) in Egyptian cirrhotic patients. METHODS:This prospective study included twenty patients with biopsy-proven liver cirrhosis listed for LT and twenty age- and sex-matched healthy control subjects. All underwent neuro-psychiatric examination, laboratory investigations, radiological studies and psychometric tests including trail making test A (TMT A), TMT B, digit symbol test and serial dotting test. The psychometric hepatic encephalopathy score (PHES) was calculated for patients to diagnose MHE. Psychometric tests were repeated six months following LT in the cirrhotic patient group. RESULTS:Before LT, psychometric tests showed highly significant deficits in cirrhotic patients in comparison to controls (P < 0.001). There was a statistically significant improvement in test values in the patient group after LT; however, their values were still significantly worse than those of the controls (P < 0.001). The PHES detected MHE in 16 patients (80%) before LT with a median value of -7 ± 3.5. The median PHES value was significantly improved following LT, reaching -4.5 ± 5 (P < 0.001), and the number of patients with MHE decreased to 11 (55%). The pre-transplant model for end-stage liver disease (MELD) score ? 15 was significantly related to the presence of post-transplant MHE (P = 0.005). More patients in whom reversal of MHE was observed had a pre-transplant MELD score < 15. CONCLUSION:Reversal of MHE in cirrhotic patients could be achieved by LT, especially in those with a MELD score < 15.
| S-EPMC5084057 | biostudies-literature
Project description:Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is seen as the clinical manifestation of a low grade cerebral edema associated with oxidative-nitrosative stress, however, comprehensive data on HE-associated molecular derangements in human brain are lacking. In the present study we used a whole human genome micro-array approach for gene expression profiling in post mortem brain samples from cirrhotic patients with or without HE and non-cirrhotic controls. Altered expression levels were found for a total of 1012 genes in liver cirrhotic patients without and with HE and HE-characteristic gene expression changes were identified. Genes with altered expression pattern in HE were related oxidative stress, microglia activation, inflammatory signalling pathways, cellular proliferation and apoptosis. Despite an up-regulation of genes associated with microglia activation, pro-inflammatory cytokine mRNA profiles remained unchanged in the brain of patients with liver cirrhosis and HE as compared to controls. Interestingly, many genes counteracting pro-inflammatory signalling and inflammatory cytokine expression were up-regulated in the cerebral cortex of patients with liver cirrhosis and HE. It is concluded that pathogenetic mechanisms of HE deduced from cell culture and animal experiments, such as oxidative stress, altered Zn2+-homeostasis and microglia activation also apply to human brain from cirrhotic patients with HE. The study also revealed a not yet recognized increased expression of genes antagonizing pro-inflammatory signalling and inflammatory cytokine expression. The dataset comprises 19 samples divided into three sample groups each representing a certain liver disease condition of humans.
2013-05-01 | E-GEOD-41919 | biostudies-arrayexpress
Project description:Normal and cirrhotic LSECs can influence hepatic stellate cells (HSCs) differently. This project aims to determine the set of proteins secreted by LSECs from healthy and cirrhotic livers, and identify the protein(s) that promote HSC activation.
2018-11-06 | PXD009010 | Pride
Project description:Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is seen as the clinical manifestation of a low grade cerebral edema associated with oxidative-nitrosative stress, however, comprehensive data on HE-associated molecular derangements in human brain are lacking. In the present study we used a whole human genome micro-array approach for gene expression profiling in post mortem brain samples from cirrhotic patients with or without HE and non-cirrhotic controls. Altered expression levels were found for a total of 1012 genes in liver cirrhotic patients without and with HE and HE-characteristic gene expression changes were identified. Genes with altered expression pattern in HE were related oxidative stress, microglia activation, inflammatory signalling pathways, cellular proliferation and apoptosis. Despite an up-regulation of genes associated with microglia activation, pro-inflammatory cytokine mRNA profiles remained unchanged in the brain of patients with liver cirrhosis and HE as compared to controls. Interestingly, many genes counteracting pro-inflammatory signalling and inflammatory cytokine expression were up-regulated in the cerebral cortex of patients with liver cirrhosis and HE. It is concluded that pathogenetic mechanisms of HE deduced from cell culture and animal experiments, such as oxidative stress, altered Zn2+-homeostasis and microglia activation also apply to human brain from cirrhotic patients with HE. The study also revealed a not yet recognized increased expression of genes antagonizing pro-inflammatory signalling and inflammatory cytokine expression.
2013-05-01 | GSE41919 | GEO
Project description:Patients with liver cirrhosis may have minimal hepatic encephalopathy (MHE) with cognitive and motor impairments that reduce life quality and span. MHE onset is associated with a shift in peripheral inflammation in which CD4+ lymphocytes play a key role but the underlying mechanisms remain unclear. We aimed to identify in CD4+ lymphocytes from patients with and without MHE: (1) gene expression changes and associated biological pathways using RNA-seq; (2) alterations in miRNA levels using miRNA-seq; (3) miRNAs and transcription factors regulating key mRNAs and (4) signalling pathways contributing to the peripheral inflammation shift associated to MHE onset. Additionally, we recovered T-cell receptor (TCR) repertoires from RNA-seq dataset to understand the immune status of control patients and cirrhotic patients with or without MHE.
2022-04-01 | GSE184200 | GEO