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Updated: May 31, 2026
Investigating Intestinal Barrier Breakdown in Living Organoids
Published on: March 26, 2020
ABCG2 Upregulation Involving AKT/NF-κB Signaling Contributes to Intestinal Barrier Dysfunction in Inflammatory Bowel
Ping Shi1,2, Juan Deng3, Xiaomei Song4
1Chongqing Key Laboratory of Target-Based Drug Discovery and Research, Chongqing University of Technology, Chongqing, 400054, People's Republic of China.
Background:
Previous investigations demonstrated significant upregulation of ATP-binding cassette subfamily G member 2 (ABCG2) in renal, hepatic, colonic, and intestinal tissues within a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced murine model of Crohn's disease (CD). Nevertheless, the regulatory mechanisms governing ABCG2 expression within inflammatory microenvironments and its consequent impact on intestinal barrier integrity remain incompletely elucidated.
Aims:
This study aimed to elucidate the signaling pathway responsible for ABCG2 upregulation under inflammatory conditions and to investigate the functional role of ABCG2 in intestinal barrier integrity both in vitro and in vivo.
Methods:
Intestinal epithelial barrier integrity was evaluated by measuring transepithelial electrical resistance (TEER), paracellular permeability to fluorescein isothiocyanate (FITC)-dextran, and immunofluorescence/immunoblot analysis of tight junction proteins. Abcg2-/- mice were utilized to evaluate the contribution of ABCG2 to intestinal barrier homeostasis.
Results:
ABCG2 expression was observed to be significantly elevated in lipopolysaccharide (LPS)-stimulated intestinal epithelial cells. This induction coincided with enhanced phosphorylation of AKT and P65. Pharmacological inhibition of AKT (LY294002) or NF-κB (BAY117082) attenuated the LPS-mediated upregulation of ABCG2. Functional assessments revealed that pharmacological inhibition of ABCG2 (using Ko143) or its genetic ablation enhanced intestinal barrier integrity. This was evidenced by increased TEER, reduced permeability to FITC-dextran, and restored expression of key tight junction proteins (ZO-1, occludin, and claudin-1) following LPS challenge. Specifically, Abcg2 knockout improved colon length, preserved mucosal architectural integrity, and diminished inflammatory cell infiltration in both dextran sulfate sodium (DSS)-UC and TNBS-induced CD models.
Conclusions:
ABCG2 reprents a promising therapeutic target for inflammatory bowel disease (IBD), particularly in patient populations exhibiting dysregulated transporter activity or genetic variants influencing drug response.
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