The Deficiency of Chymase Mast Cell Protease 4 Exacerbates Dextran Sulfate Sodium Salt -Induced Colitis in Mice and Is associated with Altered Microbiota and Metabolome Profiles

Dashuang Mo¹Xiaoyuan Kuang¹Ge Shan¹Magnus Åbrink²Jin-ping Li³can yang⁴Yuexi Wang¹Tao Shen¹Weiwei Yu⁵Zhiqiang Li^1,3*

• ¹Guizhou Medical University, Guiyang, China
• ²Swedish University of Agricultural Sciences, Uppsala, Uppsala, Sweden
• ³Uppsala University, Uppsala, Uppsala, Sweden
• ⁴Tongren Municipal People’s Hospital, Guizhou, China
• ⁵Nanjing Drum Tower Hospital, Nanjing, Jiangsu Province, China

Ulcerative colitis (UC) is a chronic gastrointestinal disease characterized by symptoms of abdominal pain and diarrhea. Chymase is a serine protease released by the mast cells and is highly expressed in patients with UC. However, its role in disease pathogenesis remains poorly understood. In mice, mast cell protease-4 (MCP-4) is considered as the functional homolog of human chymase, sharing similar enzymatic activity and biological roles. To investigate the role of mMCP-4 in UC, we applied the dextran sulfate sodium salt (DSS) to induce colitis model using Mcpt-4-deficient (Mcpt-4∆Cre) along with littermate control (Mcpt-4fl/fl) mice. The results show that the Mcpt-4-deficiency exacerbated colitis, as reflected by the significantly greater weight loss, higher histological scores, elevated levels of myeloperoxidase and most of determined cytokines. Furthermore, the Mcpt-4∆Cre colitis mice displayed a distinct shift in colonic microbiota composition, notably with significantly increased abundance of bacteria (Akkermansia and Turicibacter), associated with potentially worsened inflammation in colitis models. In addition, metabolomic profiling revealed alterations in colonic metabolites involved in key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including NF-kappa B signaling, Th1 and Th2 cell differentiation. These findings reveal that the mouse chymase MCPT-4 plays important roles in maintaining the intestinal homeostasis during colitis, potentially through regulation of colonic cytokines, microbial and metabolic networks.