Bergapten enhances mitophagy to regulate intestinal barrier and Th17/Treg balance in mice with Crohn's disease-like colitis via PPARγ/NF-κB signaling pathway

Ling Xu; Bin Zhao; Haihe Cheng; Gang Li; Yan Sun

doi:10.1007/s00210-024-03113-8

Bergapten enhances mitophagy to regulate intestinal barrier and Th17/Treg balance in mice with Crohn's disease-like colitis via PPARγ/NF-κB signaling pathway

Naunyn Schmiedebergs Arch Pharmacol. 2024 Apr 26. doi: 10.1007/s00210-024-03113-8. Online ahead of print.

Authors

Ling Xu¹, Bin Zhao², Haihe Cheng¹, Gang Li¹, Yan Sun³

Affiliations

¹ Department of Anorectal Surgery, Zhangjiagang Hospital Affiliated to Soochow University, No.68 West Jiyang Road, Zhangjiagang, Suzhou, 215600, Jiangsu, China.
² Department of Gastroenterology, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, 215600, Jiangsu, China.
³ Department of Anorectal Surgery, Zhangjiagang Hospital Affiliated to Soochow University, No.68 West Jiyang Road, Zhangjiagang, Suzhou, 215600, Jiangsu, China. yansunsun@126.com.

PMID: 38664245
DOI: 10.1007/s00210-024-03113-8

Abstract

This study aimed to investigate whether bergapten (BG), a furanocoumarin phytohormone, holds promise for Crohn's disease (CD)-like colitis treatment and to preliminarily explore its potential mechanisms. 2,4,6-Trinitrobenzenesufonic acid (TNBS)-treated mice were applied to establish an in vivo research model, and BG was administered with different concentrations. The status of mice in each group was evaluated by disease activity index (DAI), and the severity was evaluated by pathological sections. The intestinal barrier was assessed by measuring in vivo intestinal permeability, peripheral blood intestinal fatty acid-binding protein (I-FABP) levels, epithelial resistance values, and tight junction protein levels. Markers were then used to assess Th17/Treg levels, mitophagy, and the peroxisome proliferator-activated receptor (PPAR)γ/ nuclear factor kappa B (NF-κB) signaling pathway. BG significantly reduced colon tissue damage in a concentration-dependent manner. DAI scores showed that the loose feces, occult blood, and weight loss of mice in the BG treatment were significantly reduced, and pathological section results revealed reduced inflammatory infiltration and fibrosis. Reduced serum FITC-dextran and I-FABP and increased levels of epithelial resistance and tight junction proteins support that the intestinal barrier was protected upon BG. The proportion of Th17 in mesenteric lymph nodes increased while Treg decreased in the model group. BG treatment effectively reduced the conversion of Treg to Th17. Additionally, BG was found to enhance mitophagy and activate the PPARγ/NF-κB signaling. BG demonstrates promising effects in ameliorating intestinal barrier damage and Th17/Treg imbalance in a murine model of CD-like colitis, while also promoting intracellular mitophagy. The PPARγ/NF-κB signaling pathway may serve as a key mediator of BG's regulatory mechanisms.

Keywords: Crohn’s disease; Inflammatory bowel disease; Intestinal barrier; PPAR; T cell.