Dysregulated Microbiota-Driven Gasdermin D Activation Promotes Colitis Development by Mediating IL-18 Release

Area of Science:

• Microbiology
• Immunology
• Gastroenterology

Background:

• Gut microbiota homeostasis is vital for host health.
• Gut microbiota dysregulation is linked to inflammatory diseases like colitis.
• The precise molecular mechanisms of microbiota-driven colitis remain unclear.

Purpose of the Study:

• To investigate the role of gasdermin D (GSDMD) in colitis pathogenesis.
• To elucidate the molecular mechanisms by which gut microbiota contributes to colitis.
• To identify potential therapeutic targets for colitis.

Main Methods:

• Utilized a dextran sulfate sodium (DSS)-induced colitis mouse model.
• Compared colitis severity in wild-type and Gsdmd-deficient mice.
• Analyzed GSDMD expression in intestinal epithelial cells (IECs) and infiltrating immune cells.
• Investigated the role of commensal Escherichia coli (E. coli) in GSDMD activation.
• Measured interleukin-18 (IL-18) release and goblet cell loss.

Main Results:

• GSDMD activation was observed during acute colitis.
• Gsdmd-deficient mice exhibited reduced colitis severity compared to wild-type mice.
• GSDMD expression in IECs, not immune cells, was crucial for colitis progression.
• Dysregulated commensal E. coli overgrowth mediated GSDMD activation.
• Activated GSDMD promoted IL-18 release, leading to goblet cell loss and colitis.

Conclusions:

• GSDMD plays a critical role in promoting colitis development by mediating IL-18 release.
• Gut microbiota, specifically E. coli overgrowth, can drive colitis pathogenesis via GSDMD activation.
• This study reveals a molecular mechanism linking microbiota dysregulation, GSDMD activation, and colitis.