Resveratrol Derivatives Alleviate Colorectal Adenoma via Gut Microbiota-Mediated ADA-Ado-A2AR Pathway in Apc Min/+ Mice

Derivatives of the natural polyphenol resveratrol, particularly MR-4 (a methoxylated derivative with potent chemopreventive effects in liver, colorectal, and ovarian cancer models), show stronger antiproliferative properties in human colorectal cancer (CRC) cells and are more bioavailable than resveratrol. However, the role and mechanism of MR-4 against colorectal adenoma (CRA), the most common precancerous lesion of CRC, remain elusive. The current study investigates the impact of MR-4 on the interactions between CRA-associated gut microbiota, metabolites, and microbial enzymes by performing metagenome and metabolome analyses. MR-4 intervention significantly decreases the number of adenomas, ameliorates gut barrier disruption, and inhibits inflammation and related oncogenic pathways. Notably, the anti-adenoma effects of MR-4 are reduced in ApcMin/+mice with gut microbiota depletion. Furthermore, MR-4 reduces gut dysbiosis and reinstates beneficial bacteria, including Roseburia intestinalis (R. intestinalis). In addition, metabolomics analysis reveals significant alterations in purine metabolism during CRA progression in ApcMin/+ mice, which are notably inhibited by MR-4, especially for adenosine (Ado). Multi-omics analysis shows that MR-4 modulates R. intestinalis, to upregulate Ado deaminase (ADA), thereby reducing Ado accumulation and A2AR signaling, which in turn decreases VEGF expression in CRA, highlighting a novel mechanism where MR-4 reduces tumor angiogenesis by restoring gut microbiota and purine metabolism, with R. intestinalis–ADA-Ado-A2AR signaling as potential targets. This study reveals gut microbiota-dependent mechanisms of a structurally optimized food compound, advancing strategies for dietary polyphenol-based CRA prevention.