Journal of hepatology · 2026
Non-selective β-blockers reduce bacterial translocation by restoring gut barrier function during experimental cirrhosis.
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Castillo Elisa, Felber Marco, Paule Lorena, Juanola Oriol, Wyss Lorena, Wolfisberg Tim, Christensen Sandro, Muñoz Leticia, Miranda Alejandro, Ponce-Alonso Manuel, de Dios Olaya, Campo Rosa Del, Pastor Oscar, Ortega Miguel A, Álvarez-Mon Melchor, Rollenske Tim, Moghadamrad Sheida, de Gottardi Andrea, Ganal-Vonarburg Stephanie, Yilmaz Bahtiyar, Lanza Val F, Felli Eric, Kellmann Philipp, Francés Rubén, Albillos Agustín, Wiest Reiner
Аннотация
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.
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.