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Background <p>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.</p> Aims <p>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.</p> Methods <p>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. <i>Abcg2</i><sup>−/−</sup> mice were utilized to evaluate the contribution of ABCG2 to intestinal barrier homeostasis.</p> Results <p>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, <i>Abcg2</i> 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.</p> Conclusions <p>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.</p>

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ABCG2 Upregulation Involving AKT/NF-κB Signaling Contributes to Intestinal Barrier Dysfunction in Inflammatory Bowel Disease

  • 期刊论文

  • 发表日期：

    2026年5月29日

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  • Ping Shi,
  • Juan Deng,
  • Xiaomei Song,
  • Lianhua Tang,
  • Hong Guo,
  • Fei Yin

摘要

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.