Cellular Crosstalk at the Gut-Liver Interface in Liver Cirrhosis: Epithelial Barrier Failure, Bacterial Translocation and Immune Activation as a Bidirectional Network.
- 11st Department of Internal Medicine and Infectious Diseases, Faculty of Medicine, School of Health Sciences, University of Ioannina, University Campus, 45110 Ioannina, Greece.
- 2Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece.
Abstract
The gut-liver axis is central to the systemic complications of liver cirrhosis, but it is usually described as a linear cascade in which barrier failure releases microbial products that activate a downstream immune response. This review proposes instead a four-compartment framework, in which the epithelial/barrier, innate immune, adaptive effector, and stromal-endothelial compartments-the last including the gut-vascular barrier-are treated as reciprocally interacting nodes, and pathological bacterial translocation is treated as both an input to and an output of the network rather than as its endpoint. Applying this framework across the stages of cirrhosis, we examine how tight-junction disassembly, mucus-layer thinning, Paneth-cell dysfunction and reduced secretory IgA, together with dysbiosis and small-intestinal bacterial overgrowth, permit translocation; how translocated bacteria and pathogen-associated molecular patterns activate all four compartments; and how the resulting cytokine circuits further degrade the barrier, generating feed-forward loops that underlie cirrhosis-associated immune dysfunction and chronic systemic inflammation. We relate these circuits to spontaneous bacterial peritonitis, hepatic encephalopathy, aggravated portal hypertension, and acute-on-chronic liver failure, distinguishing throughout between mechanisms demonstrated in humans and those inferred from animal or in vitro models. We identified evidence through structured searches of PubMed/MEDLINE, Embase, and Web of Science, and report it according to the SANRA checklist. Framed as a network, biomarkers become compartment-specific reporters, and barrier-, microbiome-, and immune-directed therapies become interventions at defined nodes and edges-a view that clarifies both their rationale and the current limits of the evidence.
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BibTeX
@article{nitsotolis2026cellular,
title = {{Cellular Crosstalk at the Gut-Liver Interface in Liver Cirrhosis: Epithelial Barrier Failure, Bacterial Translocation and Immune Activation as a Bidirectional Network.}},
author = {Thomas N Nitsotolis and Stelios F Assimakopoulos and Eleftheria Mastoridou and Nikolaos-Gavriel Kolios and Dimitrios Biros and Eleni-Dimitra Oikonomidi and Maria Lagadinou and Alexia Papalexandrou and Haralampos Milionis and Eirini Christaki and Georgios Kalambokis},
journal = {Cells},
year = {2026},
month = sep,
doi = {10.3390/cells15191739},
url = {https://europepmc.org/article/MED/42882437},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cellular Crosstalk at the Gut-Liver Interface in Liver Cirrhosis: Epithelial Barrier Failure, Bacterial Translocation and Immune Activation as a Bidirectional Network.
AU - Thomas N Nitsotolis
AU - Stelios F Assimakopoulos
AU - Eleftheria Mastoridou
AU - Nikolaos-Gavriel Kolios
AU - Dimitrios Biros
AU - Eleni-Dimitra Oikonomidi
AU - Maria Lagadinou
AU - Alexia Papalexandrou
AU - Haralampos Milionis
AU - Eirini Christaki
AU - Georgios Kalambokis
PY - 2026
DA - 2026/09/23
JO - Cells
DO - 10.3390/cells15191739
UR - https://europepmc.org/article/MED/42882437
AB - The gut-liver axis is central to the systemic complications of liver cirrhosis, but it is usually described as a linear cascade in which barrier failure releases microbial products that activate a downstream immune response. This review proposes instead a four-compartment framework, in which the epithelial/barrier, innate immune, adaptive effector, and stromal-endothelial compartments-the last including the gut-vascular barrier-are treated as reciprocally interacting nodes, and pathological bacterial translocation is treated as both an input to and an output of the network rather than as its endpoint. Applying this framework across the stages of cirrhosis, we examine how tight-junction disassembly, mucus-layer thinning, Paneth-cell dysfunction and reduced secretory IgA, together with dysbiosis and small-intestinal bacterial overgrowth, permit translocation; how translocated bacteria and pathogen-associated molecular patterns activate all four compartments; and how the resulting cytokine circuits further degrade the barrier, generating feed-forward loops that underlie cirrhosis-associated immune dysfunction and chronic systemic inflammation. We relate these circuits to spontaneous bacterial peritonitis, hepatic encephalopathy, aggravated portal hypertension, and acute-on-chronic liver failure, distinguishing throughout between mechanisms demonstrated in humans and those inferred from animal or in vitro models. We identified evidence through structured searches of PubMed/MEDLINE, Embase, and Web of Science, and report it according to the SANRA checklist. Framed as a network, biomarkers become compartment-specific reporters, and barrier-, microbiome-, and immune-directed therapies become interventions at defined nodes and edges-a view that clarifies both their rationale and the current limits of the evidence.
SN - 2073-4409
ER -