ZD mice showed persistent colonization for at least 50 days post-infection (pi).<i>S. flexneri</i>-infected mice showed significant weight loss, diarrhea and increased levels of fecal MPO and LCN in both HC and ZD fed mice.<i>S. flexneri</i> preferentially colonized the colon, caused epithelial disruption and inflammatory cell infiltrate, and promoted cytokine production which correlated with weight loss and histopathological changes.Infection with <i>S. flexneri ΔmxiG</i> (critical for type 3 secretion system) did not cause weight loss or diarrhea, and had decreased stool shedding duration and tissue burden.