Skip to main content

Glial Connexin-43 is a pathogenic mechanism promoting gut inflammation after postsurgical intestinal manipulation with potential relevance to humans.

Cellular and molecular gastroenterology and hepatology

Authors: Samhita Chaudhuri, Reiner Schneider, Dmitrii Pavlov, Alix Zuleta Alarcon, Elvio Mazzotta, Jonathon L McClain, Patrick Leven, Paolo Fadda, Manekeller Steffen, Yunpeng Du, Alan Harzman, Brian D Gulbransen, Sven Wehner, Fievos L Christofi

BACKGROUND & AIMS: Abdominal surgery often precipitates postoperative ileus (POI), a frequent and severe GI motility disorder, through mechanisms that involve intestinal inflammation. Emerging data show that enteric glia acquire a reactive phenotype and that aggravates POI but how glia exert this effect remains unclear. Enteric glia express connexin-43 hemichannels (gCx43), which are implicated in neurological and inflammatory disorders. Thus, we aimed to decipher contributions of glial Cx43 in the pathophysiology of POI.

METHODS: We induced POI in mice using in vivo intestinal manipulation and used glial Cx43cKO (Sox10;Cx43) or RiboTag (Sox10/Rpl22) mice to evaluate Cx43-dependent signaling. Human enteric glial cultures (hEGC) and muscularis externa obtained during intestinal surgery translated findings to patients. Transcriptome analysis, immunofluorescence co-labeling, western blots, and Cx43 hemichannel activation were used for quantitative analysis.

RESULTS: Cx43 is the highest expressed connexin in enteric glia in mice and humans. Up-regulation of Cx43 occurs in various disease models linked to POI, GI surgical trauma, inflammation, immune cell activation, and enteric gliosis. In the mouse POI model, glial Cx43-deletion reduces glial reactivity, pro-inflammatory signals, upregulates host protection genes, regulates immune cell activation and prevents enteric neuropathy. In hEGCs, IL-1β induction opens Cx43 and stimulates release of IL-6 and CCL2. The Cx43 peptide inhibitor, 43Gap26, inhibits glial Cx43 activation, reduces IL-6 release, blocks up-regulation of macrophage activation factors, and immune cell regulation factors. Surgical intestinal trauma in patients up-regulates Cx43 during inflammation and enteric gliosis in mouse POI.

CONCLUSIONS: Glial Cx43 signaling promotes enteric gliosis, and immune cell activation, inflammation, enteric neuropathy in mice with potential translatability to humans after intestinal surgical trauma and mechanical stress in POI. Interventions that block glial Cx43 activation may be protective against POI development.

Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 41722854

Participating cluster members