Brevilin A reverses colitis of inflammatory bowel disease via modulation of TNF-α signaling and microbiome dysregulation.

backgroundBrevilin A (Br) has shown potential in modulating inflammatory bowel disease (IBD). Our study aims to explore its mechanism of anti-inflammatory action.

methodsColitis was induced in C57BL/6 mice with dextran sulfate sodium (DSS), followed by treatment with or without Br(20 mg/kg). Fecal microbiota and metabolites were profiled by metagenomic sequencing and liquid chromatography-mass spectrometry (LC-MS), respectively. Furthermore, to delineate the essential role of the gut microbiota, we employed antibiotic-treated (microbiota-depleted) mice in our investigation of Br's mechanism of action.

resultsBr significantly alleviated DSS-induced colitis and modulated the gut microbiota profile. Specifically, Br enriched beneficial bacteria such as Lactobacillus, while suppressing pathogenic bacteria including Escherichia coli and Clostridium perfringens. Metabolomic analysis revealed that Br significantly altered bacterial metabolites, including 7-Oxolithocholic Acid, Kudinoside A, Veratrine, and Soyasaponin. These metabolites were linked to key pathways such as GPCR signaling, DNA damage response, aminoacyl-tRNA biosynthesis, riboflavin metabolism, and central carbon metabolism in cancer. Transcriptomic profiling indicated that Br inhibited the TNF-α signaling pathway, and this inhibition was confirmed as TNF-α overexpression reversed its anti-inflammatory effects. Furthermore, the therapeutic effects of Br were partially recapitulated in microbiota-depleted mice through fecal microbiota transplantation from Br-treated donors.

conclusionBr's ability to regulate gut microbiota and metabolites, improve gut barrier function, and eliminate inflammation by inhibiting TNF-α highlights its potential as a novel therapeutic medicine for IBD. Future research should focus on further exploring its mechanisms and clinical applications.