For the past 20 years, numerous murine models of colitis have been developed to study human Inflammatory Bowel Disease (IBD) mechanistically. However, these neither reflect the heterogeneous symptoms observed in the IBD-affected population nor can be used to test the efficacy of clinical drugs which show no cross-reactivity with murine targets. In an attempt to overcome these problems, we have successfully developed a colitis mouse model that relies on DSS-induced NCG-M mice reconstituted with human hematopoietic stem cells (HSCs) from healthy individuals. We also observed a significant pharmacodynamic effect of Mesalazine and a small molecular inhibitor in this colitis model.