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Isoproterenol Disrupts Intestinal Barriers Activating Gut-Liver-Axis: Effects on Intestinal Mucus and Vascular Barrier as Entry Sites.

Abstract：

BACKGROUND:The gut-liver-axis presents the pathophysiological hallmark for multiple liver diseases and has been proposed to be modulated during stress and shock. Access to the gut-liver-axis needs crossing of the mucus and gut-vascular barrier. The role of β-adrenoreceptor-activation for both barriers has not been defined and is characterized here. METHODS:Splanchnic β-adrenergic stimulation was achieved by chronic intraperitoneal application of isoproterenol via alzet-pump in vivo. The intestinal permeability and gut-vascular barrier function was assessed in ileal loop experiments. The extravasation of predefined sizes of fluorescence isothiocyanate (FITC)-dextran molecules in ileal microcirculation was evaluated by intravital confocal laser endomicroscopy in vivo. Mucus parameters thickness, goblet cell count and mucin-expression were assessed by stereomicroscopy, immunostaining and RNA-sequencing respectively. Ileal lamina propria (LP) as well as mesenteric lymph node mononuclear cells was assessed by FACS. RESULTS:Healthy mice lack translocation of 4 kDa-FITC-dextran from the small intestine to the liver, whereas isoproterenol-treated mice demonstrate pathological translocation (PBT). Mucus layer is reduced in thickness with loss of goblet-cells and mucin-2-staining and -expression in isoproterenol-treated animals under standardized gnotobiotic conditions. Isoproterenol disrupts the gut vascular barrier displaying Ileal extravasation of large-sized 70- and 150 kDa-FITC-dextran. This pathological endothelial permeability and accessibility induced by isoproterenol associates with an augmented expression of plasmalemmal-vesicle-associated-protein-1 in intestinal vessel. Ileal LP after isoproterenol treatment contains more CD11c+-dendritic cells (DC) with increased appearance of CCR7+ DC in mesenteric lymph nodes. CONCLUSIONS:Isoproterenol impairs the intestinal muco-epithelial and endothelial-vascular barrier promoting PBT to the liver. This barrier dysfunction on multiple levels potentially can contribute to liver injury induced by catecholamines during states of increased β-adrenergic drive.

journal_name

Digestion

journal_title

Digestion

authors

Sorribas M,de Gottardi A,Moghadamrad S,Hassan M,Spadoni I,Rescigno M,Wiest R

doi

10.1159/000502112

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

717-729

issue

eissn

0012-2823

issn

1421-9867

pii

000502112

journal_volume

101

pub_type

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Isoproterenol Disrupts Intestinal Barriers Activating Gut-Liver-Axis: Effects on Intestinal Mucus and Vascular Barrier as Entry Sites.