Eurotium cristatum-Fermented White Tea Ameliorates DSS-Induced Colitis by Multi-Scale

<i>Eurotium cristatum</i>-Fermented White Tea (FWT) significantly alters white tea (WT) composition, increasing caffeine while decreasing polyphenols and amino acids. FWT effectively ameliorated dextran sulfate sodium (DSS)-induced murine colitis symptoms (reducing weight loss, colon shortening). Mechanistically, FWT suppressed TLR4/Myd88/NF-κB signaling and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) while upregulating tight junction proteins (ZO-1, occludin, claudin-1), MUC2, and E-cadherin. Single-cell/spatial transcriptomics revealed that FWT treatments augment enterocyte, goblet cell, and stem cell populations, optimize goblet function, restructure stem cell differentiation, and induce epithelial REG3B (antimicrobial) and LYPD8 (motility inhibitor), plus immunomodulator GM42418 lncRNA across cell types, repairing the barrier. FWT intervention was also associated with an increase in beneficial bacteria (<i>Akkermansia</i>, <i>Lactobacillus</i>, <i>Bifidobacterium</i>), restoration of microbiota balance, and elevated levels of short-chain fatty acids (SCFAs) and was associated with alterations in caffeine-related metabolite profiles. Collectively, these multi-scale changes correlate with the alleviation of UC, suggesting an integrated mechanism involving mucosal barrier repair, immune-stromal modulation, microbiota-metabolism regulation, and cellular reprogramming.