: Colitis is a chronic condition affecting millions worldwide. Purple muscadine wine polyphenols have a unique composition and possible disease-preventive properties. This study aims to determine how dealcoholized muscadine wine (DMW) affects the development of colitis and gut microbiome in IL-10 mice, compared to wild types (WT). : Six-week-old male IL-10 and WT C57BL/6 mice were fed either a DMW-supplemented diet (4.8% /) or a control diet based on AIN-93M for 154 days. Colitis severity was evaluated by disease activity, intestinal permeability, gene expression of cytokines and tight junction proteins in the colon, and inflammatory cytokines in the serum. Fecal samples were collected for gut microbiome profiling via 16S rRNA gene sequencing. : DMW contained predominantly anthocyanins and a significant amount of ellagic acid. IL-10 mice developed mild colitis as indicated by the disease activity index. DMW × gene interactions decreased intestinal permeability, colonic mRNA levels of IL-1β, and serum TNF-α in the IL-10 mice. DMW suppressed the colonic mRNA levels of IL-6, enhanced the gene expression of ZO-1, but did not influence the mRNA level of TNF-α or occludin. While DMW did not alter α-diversity of the gut microbiome, it significantly influenced β-diversity in the WT mice. DMW significantly reduced the relative abundances of in the IL-10 and WT mice. DMW and DMW×gene interaction decreased the relative abundance of only in IL-10 mice. : These results suggested that polyphenols from DMW interacted with genes to moderately alleviate the development of colitis in IL-10 mice and could be a useful dietary strategy for IBD prevention.