Carvacrol attenuates mucosal barrier impairment and tumorigenesis by regulating gut microbiome.

Colitis-associated colorectal cancer (CAC), which stems from inflammatory bowel disease (IBD), exhibits a high mortality rate. Chronic inflammation can drive the development of colorectal cancer via diverse mechanisms; however, proteomic-level studies in this regard are currently scarce. The chemical drugs conventionally employed for treating IBD carry significant side effects, accentuating the exigency for novel therapeutic agents. We focused on carvacrol, a traditional Chinese medicine-derived monoterpene phenol with anti-inflammatory and antioxidant traits, though its role in colitis and CAC was unclear. Employing TMT-based proteomics, we identified the oxidative stress pathway as crucial in CAC, with ALB, ADAM10, and APCDD1 (hub genes) being vital. Using DSS and AOM/DSS mouse models, carvacrol significantly restored colonic length (p < 0.01) and re-established key tight junction proteins like ZO-1. It also downregulated mRNA levels of inflammatory mediators such as iNOS and IL-6. Moreover, 16S rRNA sequencing and fluorescence in situ hybridization (FISH) assays indicated that the potential mechanism might be ascribed to carvacrol's modulation of the abundance of specific microbiota, such as Lactobacillus, Escherichia coli/Shigella, and Lachnoclostridium. In subsequent investigations, we ascertained that carvacrol exerted remarkable efficacy in the AOM/DSS models, as it markedly reduced the number of colonic tumors (p < 0.05) and concurrently suppressed the disease activity index scores (p < 0.05). These results jointly suggest its prospective role in thwarting the progression of colitis-associated colorectal cancer. Collectively, our study substantiates that carvacrol efficiently safeguards the mucosal barrier and curbs tumorigenesis, potentially via the modulation of gut microbiota.