In vivo experiments showed that, consistent with our previous studies, DCA colorectal instillation at the concentration comparable to HFD obviously induced IL-1β production and aggravated DSS-induced colitis, whereas blockage of S1PR2 signaling or inhibition of cathepsin B effectively protected mice from the exacerbated inflammation superimposed by DCA, as evidenced by much less body weight loss, significantly ameliorated colitis severity, and importantly, pronounced reduction of bioactive IL-1β level in colon tissue. The gene discussed is IL1B; the disease is colitis.