{"id":386540,"date":"2024-10-23T14:00:00","date_gmt":"2024-10-23T12:00:00","guid":{"rendered":"https:\/\/medizinonline.com\/new-findings-through-multi-omics-and-biotechnological-reporter-system\/"},"modified":"2024-10-23T14:39:05","modified_gmt":"2024-10-23T12:39:05","slug":"new-findings-through-multi-omics-and-biotechnological-reporter-system","status":"publish","type":"post","link":"https:\/\/medizinonline.com\/en\/new-findings-through-multi-omics-and-biotechnological-reporter-system\/","title":{"rendered":"New findings through multi-omics and biotechnological reporter system"},"content":{"rendered":"\n

Metabolites in serum, urine and stool samples can identify those with acute-on-chronic liver failure among patients with acute decompensated liver cirrhosis as a basis for early diagnostic and therapeutic measures.\nThis is the conclusion of a current study project.\nIn a project by another research team, the “EXSISERS” reporter system provided interesting insights into the relevance of p53 status in spontaneous bacterial peritonitis, an infectious complication associated with liver cirrhosis. <\/strong><\/p>\n\n\n\n

Advanced liver fibrosis and cirrhosis are summarized as “advanced chronic liver disease” (ACLD).\nAdvanced chronic liver disease is characterized by persistent damage and increasing scarring of the liver.\nThe final stage of liver fibrosis is liver cirrhosis.\nPatients with cirrhosis with acute decompensation (AD) have an increased risk of developing acute-on-chronic liver failure (ACLF).\nACLF is characterized by extrahepatic organ failure and systemic inflammation.\nACLF is associated with a serious risk of infectious complications and high short-term mortality.\nIn order to improve the prognosis of affected patients, early diagnostic and therapeutic measures are required in ACLF [1].\nDechaumet et al.\npresented a research project at this year’s EASL congress in which metabolomic signatures were identified to differentiate between AD patients with or without ACLF.\nThe following is a summary of this and another research project in the field of advanced liver disease [2,3]. <\/p>\n\n

Analysis of data from the MUCOSA-PREDICT cohort <\/h3>\n\n

The entirety of low-molecular substances (metabolites) is called the metabolome.\nThe metabolome can be measured by chromatography, mass spectrometry or nuclear magnetic resonance spectroscopy, for example.\nThe liver is a metabolically highly active organ and liver diseases are increasingly being researched using multi-omics methods (Fig. 1)<\/strong> [10].\nMoreau et al.\nreported in 2020 in the Journal of Hepatology that they were able to identify an ACLF-specific fingerprint of 38 metabolites in the blood using a multi-omics approach in tissue samples, which correlates with systemic inflammation and acts as an indicator of mitochondrial dysfunction in peripheral organs [4]. <\/p>\n

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\"\"<\/a><\/figure>\n<\/div>\n

Study objectives and methodology: <\/strong>The project by Dechaumet et al.\naimed to,\n(i) investigate whether the analysis of metabolites in urine and stool samples has added value for the characterization of the metabolome in decompensated cirrhotic patients and\n(ii) to evaluate how multimatrix metabolomics contributes to improving the stratification of patients with decompensated cirrhosis [2].\nTo this end, the researchers analyzed serum, urine and stool samples from the MUCOSA-PREDICT cohort, in which 93 cirrhotic patients with acute decompensation are followed up, using liquid chromatography coupled with high-resolution mass spectrometry.\nA total of 402 metabolites were detected and identified in the three biological matrices. <\/p>\n\n

Results: <\/strong>The largest number of metabolites whose concentrations are affected by ACLF was observed in serum samples [2].\nInterestingly, the concentrations of some metabolites in urine and feces that were not detected in serum were also found to be affected by ACLF.\nHowever, ROC curve analyses performed for the metabolomics signatures in single or combined matrices showed that the serum signature performed best in discriminating between AD and ACLF.\nThis is a clinically relevant finding, as both clinical pictures overlap in individual cases, but are different entities in terms of pathophysiology and therapy. <\/p>\n\n

Implementation of the “EXSISERS” reporting system<\/h3>\n\n

The gut-liver axis describes the diverse interactions between the gut and liver, including the exchange of cellular and molecular components, and is of central importance for the regulation of essential (patho)physiological processes.\nPatients with liver cirrhosis have reduced mucosal thickness, which facilitates direct contact of bacteria with epithelial cells and the degradation of cellular compounds [5].\nBacterial translocation is considered a crucial step in the pathogenesis of bacterial infections [6].\nFor example, translocation of intestinal bacteria into mesenteric lymph nodes is a key event in spontaneous bacterial peritonitis.\nSpontaneous bacterial peritonitis** is an inflammation of the ascitic fluid that occurs particularly frequently in liver cirrhosis and can have serious consequences. <\/p>\n\n

** The most common bacteria that cause spontaneous bacterial peritonitis are Gram-negative Escherichia coli and Klebsiella pneumoniae and Gram-positive Streptococcus pneumoniae [11].<\/em><\/p>\n\n

Study objectives and methodology: <\/strong>According to Ernst et al.\nthe cellular stress triggered by direct contact with the bacteria affects the p53 family of transcription factors, which act as key regulators of the cell cycle, repair mechanisms and cell death (apoptosis) [3].\nIn its wild-type form, p53 (wtp53) acts as a central tumor suppressor [7].\nThe structurally and functionally homologous proteins p63 and p73 are subsumed into the p53 family of transcription factors.\nThe function of p53 is altered in a large number of tumors (TP53 mutations).\nIn their study, Ernst et al.\ninvestigated the effects of ascites bacteria on the expression of p53 isoforms$<\/sup> in relation to the induction of cell death in epithelial cells.\nThey applied a novel biotechnological reporter system [3].\nThe reporter system called EXSISERS can track the expression of isoforms over time in living cells [8]. <\/p>\n\n

$<\/sup> Isoforms are variants of proteins that arise from a single gene.<\/em><\/p>\n\n

Three exon-specific intein luciferase reporter systems (EXSISERS) have been integrated into exons 2, 4 and 7 of the TP53 gene.\nCleaved inteins allow the cleavage of the enzyme luciferase from the p53 polypeptide while maintaining the structural integrity of the p53 isoforms [9].\nThis method can be used to precisely quantify the ratios of p53 protein isoforms at the cellular level.\nHCT116-EXISERS cells were co-cultured with patient-derived Escherichia coli <\/em>, and the three major groups of p53 isoforms – full-length cell cycle arrest-inducing p53, cell death-inducing \u039440p53, pro-proliferative \u0394133p53\/\u0394160p53 – were measured.\nAt the same time, bacterial-induced cell death was quantified in HCT116 p53 wild-type and p53 knockout cells.\nElectron microscopy was used to determine the type of cell death. <\/p>\n\n

Results: <\/strong>Co-cultivation of patient-derived bacteria with HCT116-EXISERS cells initially led to increased production of the cell death-inducing p53 isoform \u039440p53 within 15 minutes [3].\nThis was followed by a decrease in the pro-proliferative p53 isoforms \u0394133p53\/\u0394160p53.\nAt the same time, apoptosis was observed in response to bacterial contact, which showed morphological features of paraptosis, including mitochondrial swelling and cytoplasmic vacuolization.\nIn parallel to the observed morphological changes, flow cytometry confirmed mitochondrial and plasma membrane damage.\nThe known paraptosis inhibitor acinomycin D efficiently blocked bacterial-induced cell death.\nIn agreement with the measured induction of the \u039440p53 isoform, the induction of cell death was significantly delayed by a CRISPR\/Cas9-mediated p53 knockout. <\/p>\n\n

Summary<\/strong><\/td><\/tr>
In liver cirrhosis with acute decompensation (AD), the risk of developing acute-on-chronic liver failure (ACLF) is increased.\nIn the study by Dechaumet et al.\nshowed that metabolic signatures from the blood, but also from urine and faeces, differentiate between AD patients with and without ACLF.\nThe data obtained from the blood compartment appears to provide the best stratification performance. <\/td><\/tr>
In patients with liver cirrhosis, bacterial translocation occurs due to impaired epithelial integrity.\nThe cellular responses to bacterial stress are regulated by specific p53 isoforms.\nThe study by Ernst et al.\nshows that the p53 status exerts a decisive influence on susceptibility to paraptosis.\nTargeted induction or stabilization of specific p53 isoforms could therefore represent a therapeutic option for the treatment of spontaneous bacterial peritonitis. <\/td><\/tr>
to [2,3]<\/em><\/td><\/tr><\/tbody><\/table><\/figure>\n\n

Congress: EASL Congress 2024<\/em><\/p>\n\n

Literature:<\/p>\n\n

    \n
  1. H\u00fcbener P, Braun G, Fuhrmann V: Med Klin Intensivmed Notfmed 2018; 113(8): 649-657.<\/li>\n\n\n\n
  2. Dechaumet S, et al: Multi-compartment metabolomics for stratifying cirrhotic patients with acute decompensation, WED-083, EASL Congress, Milan, June 5-8, 2024.<\/li>\n\n\n\n
  3. Ernst M, et al: Liver cirrhosis and epithelial damage – The gut-liver axis in spontaneous bacterial peritonitis and its modulation by p53, WED-106, EASL Congress, Milan, June 5-8, 2024.<\/li>\n\n\n\n
  4. Moreau R, et al: J Hepatol 2020; 72: 688-701.<\/li>\n\n\n\n
  5. Haderer, M. et al: Gut 2022; 71: 580-592. <\/li>\n\n\n\n
  6. Rayes N: Experimental and clinical investigation of the influence of pre- and probiotics on bacterial translocation and postoperative infections after abdominal surgery, Habilitationsschrift, 2004, https:\/\/core.ac.uk,<\/a>(last accessed 27.08.2024) <\/li>\n\n\n\n
  7. Weilbacher A: The role of p53 status for the sensitivity of tumors to different p53 activators, Dissertation, 2017, https:\/\/elib.uni-stuttgart.de,<\/a>(last accessed 27.08.2024) .<\/a><\/li>\n\n\n\n
  8. “New designer proteins make isoforms non-invasively visible”, Helmholtz Munich, 04.06.2021. <\/li>\n\n\n\n
  9. Truong, D-JJ, et al: Non-Invasive and High Throughput Interrogation of Exon-Specific Isoform Expression. Nature Cell Biology 2021, doi:10.1038\/s41556-021-00678-x<\/li>\n\n\n\n
  10. Raja G, et al.: Recent Advances of Microbiome-Associated Metabolomics Profiling in Liver Disease: Principles, Mechanisms, and Applications. International Journal of Molecular Sciences 2021; 22(3): 1160. www.mdpi.com\/1422-0067\/22\/3\/1160#<\/a>, (letzter Abruf 27.08.2024)\u00a0<\/li>\n\n\n\n
  11. “Spontaneous Bacterial Peritonitis (SBP),” Danielle Tholey, MD, www.msdmanuals.com\/de,<\/a>(last accessed 8\/27\/2024).<\/li>\n<\/ol>\n\n

    <\/p>\n\n

    HAUSARZT PRAXIS 2024; 19(9): 38-39 (published on 18.9.24, ahead of print)<\/em><\/p>\n","protected":false},"excerpt":{"rendered":"

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