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

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.

In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies.

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.

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 biopsies of patients with cirrhosis indicated similar dysregulation of pathways supporting blood vessels and elevated expression of chemokines.

This study emphasises the critical role of intestinal macrophages in preventing the dissemination of luminal bacteria and highlights the multifaceted breakdown of the intestinal barrier in cirrhosis and the importance of the gut-vascular barrier.