Ulcerative colitis (UC) patients have disturbances in the microbiota-gut-brain axis, and mast cells are important components of this axis. The mast cell-specific receptor Mrgprb2 has effects on host defense against bacterial infection and neurogenic inflammation, which may help mast cells act on the axis. This study analyzed how Mrgprb2 participates in the pathogenesis of UC by affecting the microbiota-gut-brain axis.Mrgprb2 knockout (b2KO) mice and wild-type (WT) mice were fed 2% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days, which was then replaced with normal water for 14 days. This cycle was repeated three times. Feces were collected on Days 21, 42, and 63 for intestinal microbiota analysis, and mice were euthanized on Day 64. Hypothalamus, amygdala and colon tissues were removed and analyzed.Compared with WT mice, B2KO mice exhibited increased weight loss, colon shortening and colonic pathological damage after colitis induction. Analysis of the intestinal microbiota showed that b2KO mice with colitis had a significant decrease in the abundance and diversity, as well as an increase in Allobaculum and a decrease in norank_f__Muribaculaceae and Ileibacterium. In colon tissues, the expression of mucin 2 (MUC2) and junctional adhesion molecule A (JAM-A) in b2KO mice was reduced, and oxidative stress levels were higher. B2KO mice with colitis had higher corticotropin-releasing hormone (CRH), corticotropin-releasing hormone receptor 1 (CRHR1), neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) mRNA levels in hypothalamus tissues and glucocorticoid receptor mRNA levels in the amygdala.In the microbiota-gut-brain axis, Mrgprb2 was involved in regulating the intestinal microbiota composition, intestinal barrier and oxidative stress levels, and was related to stress regulation, which might help to explain the pathogenesis of UC.