Dysregulated signal transducer and activator of transcription 3 drives intestinal permeability and may contribute to acute-on-chronic liver failure

BACKGROUND: Enhanced intestinal epithelial permeability contributes to disease progression in advanced liver disease. Patients with acute-on-chronic liver failure (ACLF) frequently exhibit gut barrier dysfunction. However, mechanisms underlying the transition from cirrhosis to ACLF remain incompletely understood. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of epithelial homeostasis, yet its role in intestinal barrier integrity during ACLF has not been explored.
AIM: To investigate whether imbalanced intestinal STAT3 expression drives gut barrier dysfunction during liver disease advancement, particularly during progression to ACLF, we analyzed its effects on tight junction architecture, lipid composition, and epithelial morphology.
METHODS: Morphology of intestinal tissues from mouse models of steatosis, cirrhosis, and ACLF was analyzed by hematoxylin and eosin staining while STAT3 expression and activation were determined by immunohistochemistry. Messenger RNA levels of Stat3, Stat1, and tight junction components [zonula occludens-1 (Tjp1), occludin (Ocln), claudin (Cldn) 1, Cldn2, and Cldn3] from intestinal mouse tissues were analyzed by reverse transcription-quantitative polymerase chain reaction. Additionally, stably differential STAT3-expressing epithelial Caco-2 or T84 monolayers were generated to assess barrier integrity using transepithelial electrical resistance measurements. Protein expression of STAT3, STAT1, zonula occludens-1, OCLN, claudin (CLDN) 1, CLDN2, and CLDN3 was determined by western blotting. Lipid composition was analyzed by lipidomics, and epithelial morphology was assessed through immunofluorescence and electron microscopy.
RESULTS: Liver disease progression was associated with pronounced intestinal morphological alterations accompanied by a marked increase in STAT3 expression during the transition from cirrhosis to ACLF. In vitro, elevated STAT3 levels induced tight junction remodeling, increased epithelial permeability, and significantly altered lipid composition. Lipidomic profiling revealed remodeling of major phospholipid, ether lipid, sphingolipid, lysophospholipid, and triglyceride classes, indicating disturbed epithelial membrane lipid homeostasis. These effects were paralleled by pronounced STAT3-dependent structural changes in epithelial monolayers.
CONCLUSION: Accumulation of unphosphorylated STAT3 may serve as a potential biomarker of gut barrier destabilization during the transition from cirrhosis to ACLF.