Black tea ethanol soluble fraction restores intestinal homeostasis by modulating PI3K/AKT signaling and gut microbiota.

While black tea's oxidized polyphenols hold potential for gut health, the specific protective mechanisms of its ethanol-soluble fraction (BES), particularly regarding host-microbiota interactions, remain poorly defined. This study elucidated the dual mechanisms through which BES ameliorates dextran sulfate sodium (DSS)-induced colitis in mice. By integrating network pharmacology, molecular docking/dynamics simulations, RT-qPCR, and Western blot analysis, we identified the PI3K/AKT signaling axis as a potential host target. Our findings suggest that key flavonoid constituents stably bind to critical nodes, potentially downregulating the expression and activation of pathway components. Concurrently, 16S rRNA sequencing and metabolomics revealed that BES reshaped gut microbiota by suppressing Akkermansia and enriching SCFA producers such as Lactobacillus, restoring fecal SCFA levels. Fecal microbiota transplantation confirmed that BES-modulated microbiota alone transferred protection. Thus, BES acts concertedly through direct PI3K/AKT inhibition and indirect microbiota-SCFA modulation, providing a mechanistic basis for targeted use of black tea fractions in intestinal inflammation.