Intestinal blood vessel-associated macrophages and gut-vascular barrier dysfunction in cirrhosis

作者：Lena Smets, Maria Francesca Viola, Markus Boesch, Jana Raman, Lukas Van Melkebeke, Max Nobis, Emilio Flint, Nika Pajk, Paola Brescia, Alessandra Silvestri, Rita Feio‐Azevedo, Elodie Modave, Lander De Herdt, Annalisa Sanga, Oltin T. Pop, Olivier Govaere, Jef Verbeek, Alexandre Denadai‐Souza, David Cassiman, Niels Vandamme, Bram Boeckx, Diether Lambrechts, María Rescigno, Christine Bernsmeier, Elizabeth A. V. Jones, Jan G. Hengstler, Ahmed Ghallab, Colinda L. G. J. Scheele, Frederik Nevens, Hannelie Korf, Guy E. Boeckxstaens, Van der Merwe · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2025-335745 · 被引用次数：12 · 研究领域：Liver Disease and Transplantation、Organ Transplantation Techniques and Outcomes、Liver physiology and pathology

BACKGROUND: Bacterial translocation in cirrhosis can trigger infection and hepatic decompensation, leading to systemic inflammation, organ failure and increased mortality. These infections often originate from the gastrointestinal tract after bacteria breach the intestinal barrier and disseminate to systemic sites. OBJECTIVE: In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies. DESIGN: We developed a murine model of cirrhosis through chronic administration of carbon tetrachloride for up to 20 weeks. We investigated both the intestinal epithelial and vascular compartments and performed single-cell transcriptomic profiling of myeloid cells isolated from cirrhotic mice and from individuals with compensated and decompensated cirrhosis. RESULTS: Our findings indicate that bacterial translocation in cirrhosis is the result of failure at multiple checkpoints, including aberrant epithelial cell death, vascular barrier damage and dysfunction of gut-vascular macrophages. In a preclinical model of cirrhosis, macrophages exhibited increased levels of monocyte-attracting chemokines, reduced bacterial clearance and impaired interactions with blood vessels. Importantly, depleting vascular-lining macrophages resulted in bacterial translocation to systemic sites, even in the absence of experimental liver disease. Transcriptional profiling of macrophages from duodenal biops...