6-Bromoindole-3-acetonitrile Attenuates DSS-Induced Colitis by Inhibiting Epithelial Cell Pyroptosis

Area of Science:

• Gastroenterology
• Immunology
• Marine Biotechnology

Background:

• Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) necessitating novel therapeutic strategies beyond conventional anti-inflammatory drugs.
• Pyroptosis, a pro-inflammatory form of programmed cell death, is implicated in epithelial damage observed in UC.
• Single-cell RNA sequencing (scRNA-seq) analysis of a dextran sodium sulfate (DSS)-induced colitis mouse model revealed pyroptosis as a critical factor in disease pathogenesis.

Purpose of the Study:

• To identify novel pyroptosis inhibitors from marine sources for potential UC treatment.
• To evaluate the therapeutic efficacy of the marine-derived compound 6-bromoindole-3-acetonitrile in a preclinical model of UC.
• To elucidate the molecular mechanisms underlying the anti-inflammatory and barrier-protective effects of 6-bromoindole-3-acetonitrile.

Main Methods:

• Analysis of publicly available scRNA-seq data from a DSS-induced colitis mouse model.
• Screening of marine-derived brominated indoles for pyroptosis inhibitory activity.
• In vivo efficacy study of 6-bromoindole-3-acetonitrile in DSS-induced colitis mice, assessing body weight and Disease Activity Index (DAI).
• Quantitative real-time PCR (qRT-PCR) to measure pyroptosis-related gene expression (Nlrp3, Caspase-1).
• Histological analysis to evaluate intestinal barrier integrity, goblet cell regeneration, and tight junction expression.
• Molecular docking simulations to predict binding interactions between 6-bromoindole-3-acetonitrile and myeloperoxidase (MPO).

Main Results:

• 6-bromoindole-3-acetonitrile significantly ameliorated DSS-induced colitis in mice, evidenced by body weight recovery and a substantial reduction in DAI scores (from ~8.5 to <4, p < 0.05).
• The compound suppressed pyroptosis by downregulating mRNA levels of key genes including Nlrp3 and Caspase-1.
• Treatment promoted intestinal barrier restoration through enhanced goblet cell regeneration and strengthened tight junctions.
• Molecular docking revealed stable binding of 6-bromoindole-3-acetonitrile to the active site of MPO, suggesting a potential anti-inflammatory mechanism (binding energy: -18.1 kcal/mol).

Conclusions:

• Marine-derived 6-bromoindole-3-acetonitrile demonstrates significant therapeutic potential for ulcerative colitis by mitigating inflammation and pyroptosis.
• The compound acts by suppressing the pyroptotic pathway and restoring intestinal barrier function.
• Further preclinical validation and clinical studies are warranted to confirm the efficacy and safety of this promising marine-derived therapeutic candidate for IBD.