Quinazolinone Derivative MR2938 Protects DSS-Induced Barrier Dysfunction in Mice Through Regulating Gut Microbiota.

Abstract

Background/Objectives: Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by colorectal immune infiltration and significant microbiota compositional changes. Gut microbiota homeostasis is necessary to maintain the healthy state of humans. MR2938, a quinazolin-4(3H)-one derivative derived from the marine natural product penipanoid C, alleviated DSS-induced colitis in a dose-dependent manner. Herein, we aimed to investigate the impact of MR2938 on the gut microbiota in dextran sodium sulfate (DSS)-induced colitis in mice and to elucidate the role of the gut microbiota in the therapeutic mechanism of MR2938 for alleviating colitis. Methods: Acute colitis was induced with DSS in mice. Mice were administered with 100 mg/kg or 50 mg/kg of MR2938. Cecal content was also preserved in liquid nitrogen and subsequently analyzed following 16S RNA sequencing. Antibiotic cocktail-induced microbiome depletion was performed to further investigate the relationship between MR2938 and gut microbiota. The inflammatory factor levels were performed by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Alcian blue staining and immunofluorescence were used to estimate the intestinal barrier. Results: The 16S rRNA sequencing revealed microbiota modulation by MR2938. Compared with the model group, the 100 mg/kg MR2938 group was associated with higher abundances of Entercoccus and a lower abundance of Staphylococcus, while the 50 mg/kg MR2938 group was associated with higher abundances of Lactobacillus and a lower abundance of Staphylococcus. The antibiotic-mediated microbiota depletion experiments demonstrated that the gut microbiota primarily contributed to barrier function protection, with little impact on inflammatory factor levels during the MR2938 treatment. Conclusions: These findings suggest that intestinal flora play a crucial role in MR2938's therapeutic mechanism for alleviating colitis.