Colitis Induces Sex-Specific Intestinal Transcriptomic Responses in Mice

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Colorectal cancer (CRC) exhibits significant sex differences in incidence and onset.
• Inflammatory bowel disease (IBD) increases CRC risk, with men facing a 60% higher risk than women.

Purpose of the Study:

• To investigate sex differences in colitis-associated CRC (CAC) using a mouse model.
• To identify transcriptomic sex differences in non-tumor colon tissue during CAC development.

Main Methods:

• Chemically induced CAC mouse model using azoxymethane (AOM) and dextran sodium sulfate (DSS).
• RNA-sequencing of colon samples from male and female mice at 9 and 15 weeks.
• Analysis of transcriptomic responses and sex-specific gene expression patterns.

Main Results:

• Both sexes showed significant transcriptomic responses to AOM/DSS, involving inflammation and cell proliferation pathways.
• Males exhibited a stronger overall response, with male-specific genes linked to NFκB signaling and circadian rhythm.
• Female-specific gene regulations were associated with the glucocorticoid receptor (Gr/Nr3c1), while male-specific ones targeted Stat3.
• At 15 weeks, T cell proliferation and demethylase regulation showed the most prominent sex differences, predominantly immune-related.

Conclusions:

• Chemically induced colitis and CAC reveal distinct sex differences in CRC initiation and progression.
• Transcriptomic profiling highlights sex-specific immune and inflammatory responses contributing to CRC development.