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Selected Publication:
Rainer, F.
Biomarkers of bacterial translocation and their prognostic value in patients with liver cirrhosis
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2024. pp. 106
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- Authors Med Uni Graz:
- Advisor:
- Stadlbauer-Köllner Vanessa
- Stauber Rudolf
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- Abstract:
- Background: In patients with liver cirrhosis, prognosis prediction is of particular importance due to the variable disease course and the need to select and rank end-stage patients for liver transplantation, especially in the context of organ shortage. Most of the well-studied prognostic factors and scores are based on parameters of disease severity and do not take into account representatives of disease activity and progression. Yet, an important role of different components of the gut-liver axis & intestinal barrier on liver disease progression was recently suggested. Therefore, the aim of this scientific work was to investigate the prognostic value of several biomarkers related to bacterial translocation in patients with liver cirrhosis. Methods: Patients in different stages of chronic liver disease (from compensated cirrhosis to acute-on-chronic liver failure) were investigated in terms of patient-specific parameters (e.g., etiology of liver disease, proton pump inhibitor intake), stool microbiome composition (i.e., 16S sequencing of stool samples), morphological alterations of the epithelial barrier (i.e., distal duodenal biopsies and analysis via light and transmission electron microscopy), markers of intestinal inflammation (i.e., fecal calprotectin levels), markers of intestinal permeability (i.e., fecal zonulin levels and the lactulose/mannitol test), markers of bacterial translocation (i.e., serum endotoxin levels), markers of hepatic & systemic inflammation (i.e., macrophage activation markers serum sCD163 & sMR as well as CRP, IL-6, IL-8 & TNF-) and lipid metabolism parameters (i.e., HDL-C and apoA-I). Patients were monitored for occurrence of complications (including infection), transplantation and death. Results: In total, 536 patients were enrolled in 2 cohorts, 256 patients with stable cirrhosis in an Austrian single-center and 280 patients with acute decompensation in a European multicenter cohort. In patients with liver cirrhosis, significant changes were observed at all levels of the intestinal barrier including distinctive alterations in gut microbial composition and intestinal epithelial structure, evidence of intestinal inflammation as well as increased intestinal permeability, bacterial translocation and systemic inflammation. Furthermore, levels of lipid metabolism markers HDL-C and apoA-I were significantly reduced. We found significant associations between PPI use and changes in gut microbiome (in particular increased abundance of Veillonella parvula and Streptococcus salivarius) as well as other aspects of the intestinal barrier, culminating in a higher complication and mortality risk in patients with PPI intake. The increased appearance of V. parvula in stool microbiome (i.e., V. parvula dysbiosis) was linked to intestinal barrier dysfunction, the development of cirrhosis-associated complications, infections and mortality. Macrophage activation parameters sCD163 & sMR have proven their predictive value in liver cirrhosis patients, with better data for sCD163 in terms of survival prediction and for sMR in terms of cirrhosis-associated complication. Furthermore, we identified lipid metabolism parameters HDL-C and apoA-I as robust predictors of disease progression, complications, infections and survival, respectively. Conclusion: We have proven the prognostic value of several biomarkers related to bacterial translocation in patients with liver cirrhosis, most notably V. parvula abundance, sCD163, sMR, HDL-C and apoA-I levels. Some of the solitary parameters demonstrated similar performance in comparison to established composite scores MELD & Child-Pugh, probably due to their qualities as representatives of disease progression.