Context-Dependent Epithelial and Immune Programs Shape Intestinal Resilience or Vulnerability Following Prior Colitis

Area of Science:

• Gastroenterology
• Immunology
• Microbiology

Background:

• Prior intestinal inflammation can alter immune and epithelial responses to subsequent injury.
• Infectious and sterile colitis share features like barrier disruption and cytokine secretion.
• The influence of initial inflammatory events on subsequent disease outcomes is not fully understood.

Purpose of the Study:

• To investigate if the type of initial colitis (infectious vs. sterile) affects protection or susceptibility to secondary intestinal insult.
• To define how prior infectious versus sterile colitis shapes secondary disease progression.

Main Methods:

• Reciprocal mouse models of Citrobacter rodentium (CR) infection and dextran sodium sulphate (DSS)-induced colitis were employed.
• Assessed barrier integrity, immune cell populations, cytokine production, and susceptibility to wild-type and CR mutants.
• Evaluated the role of type III secretion system effectors and IL-17A signaling.

Main Results:

• Mice recovered from CR infection were protected against DSS colitis, showing reduced pathology and preserved epithelial architecture.
• Protection after CR infection was linked to sustained IL-17A signaling and required type III secretion system effectors.
• Mice recovered from DSS colitis had persistent barrier defects and were more susceptible to CR infection, even with minimal epithelial damage.

Conclusions:

• The nature of primary colitis establishes distinct, persistent epithelial and immune programs.
• Infectious colitis promotes a protective mucosal state, with IL-17A as a key contributor.
• Sterile colitis results in epithelial barrier dysfunction, increasing susceptibility to subsequent infections, highlighting the impact of inflammatory history on intestinal resilience.