Non-selective β-blockers reduce bacterial translocation by restoring gut barrier function during experimental cirrhosis.

BACKGROUND & AIMS: Intestinal barriers limiting gut-to-liver translocation of bacteria/l products are disrupted in cirrhosis. Cirrhosis is characterised by sustained β-adrenergic overactivity, which may contribute to barrier dysfunction but, its impact on the gut-liver-axis remains unclear. We investigated whether β-adrenergic signalling drives barrier disruption in experimental cirrhosis being amenable for treatment by non-selective beta blockers such as propranolol.

METHODS

Cirrhosis was induced in rats (CCl4, BDL) and mice (BDL), followed by propranolol or vehicle treatment. Chronic β-adrenergic stimulation was modelled by isoproterenol in mice, and VE-cadherin gain-of-function mice were used for mechanistic experiments. Barrier integrity and bacterial translocation were assessed by gut-to-liver FITC-dextran translocation, FITC-albumin endomicroscopy, hepatic 16S rDNA, faecal albumin, junctional immunofluorescence. Ileal transcriptomics, microbiota profiling, primary intestinal endothelial cells and human ileal organoids were used.

RESULTS

Propranolol reduced hepatic 16S rDNA load and gut-to-liver translocation of FITC-dextran but not viable bacteria in both cirrhosis models. It restored muco-epithelial integrity, increasing mucus thickness, goblet cell number and epithelial tight junction proteins. Propranolol improved gut-vascular barrier dysfunction, reducing PV1 expression and normalising pathological FITC-albumin extravasation in BDL mice, with model-dependent modulation of VE-cadherin and claudin-5. Without liver injury, isoproterenol recapitulated intestinal barrier disruption and gut-to-liver translocation in absence of microbiota changes but being attenuated by propranolol. VE-cadherin GOF mice were protected from β-adrenergic-induced barrier disruption and showed reduced gut-to-liver translocation after BDL. Ileal transcriptomic alterations were partially reversed in pathways related to barrier function, inflammation and adrenergic signalling.

CONCLUSIONS

Sustained β-adrenergic hyperstimulation disrupts the multi-layer intestinal barrier, promoting pathological bacterial translocation in cirrhosis. Propranolol restores barrier integrity through mechanisms involving endothelial VE-cadherin stabilisation, at least partly independent of microbiota changes and haemodynamic effects.