Colorectal cancer (CRC) is the third most common fatal malignancies worldwide, with 40-50% patients dying from this disease. As its prevalence continues to rise, a comprehensive understanding of the etiology and advances in treatments of CRC are critical to alleviate disease burden and improve survival rate for affected individuals. The intestinal epithelium is a monolayer of cells in the lumen of the gastrointestinal tract that creates a physical and biochemical barrier against commensal and pathogenic microorganisms. Accumulating evidence has demonstrated that intestinal barrier function has profound impact on cancer progression as well as response to chemo- and immuno-therapy. In the present study, three mouse models were utilised to investigate the effects of partial STAT3 ablation on intestinal barrier function. One mouse model harbours a truncated gp130 receptor (gp130DSTAT/+) to reduce gp130-dependent STAT1/3-mediated activation. The second mouse model carries a Doxycycline-inducible Stat3 short-hairpin RNA (shSTAT3) for the reversible silencing of STAT3. Compared to its wild type counterparts, we have identified that both mouse models with partial STAT3 ablation are more prone to chemically-induced colitis, including decreased intestinal barrier function, severe weight loss and histological damage. We further hypothesise that barrier function in these animals are altered due to modification in antimicrobial activity via Reg3-family proteins and expression of tight junction proteins. The findings from this study will determine the clinical importance of the gp130/STAT3 signalling cascade in intestinal epithelial cells, which can be exploited therapeutically to regulate barrier function and response to anti-cancer therapies.