Ulcerative colitis (UC) is an inflammatory bowel disease characterized by disruption of the epithelial barrier, and its etiology has long been enigmatic. We here observed a significant depletion of macrophages directly beneath the UC epithelial layer, and hypothesized that this depletion may be caused by a toxic bacteria. By screening fecal bacteria of UC patients, we identified the causative bacteria as Aeromonas spp MTB (macrophage-toxic bacteria), a novel variant of Aeromonas genus. The expressed aerolysin was preferentially toxic towards macrophages, and severs as a primary virulent factor. MTB efficiently colonized mice after pretreatment with DSS and antibiotics, and thereby induced UC-like colitis. Moreover, both aerolysin toxin and fecal MTB respectively distributed in UC colon tissue and stool with high frequency. We thus proposed that MTB infection was causally linked to ulcerative colitis. As aerolysin antibody mitigated the colitis phenotypes, our result also revealed an innovative therapeutic approach for UC.