Phyllanthus emblica L. polyphenols alleviate ulcerative colitis in mice by modulating the interplay between intestinal barrier integrity, ER stress, and gut microbiota

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is becoming increasingly prevalent worldwide. It has a complex, multifactorial pathogenesis and limited therapeutic efficacy. Emerging evidence indicates that Phyllanthus emblica polyphenols (PEP) exert protective effects against UC. However, its precise molecular mechanisms have yet to be fully elucidated. In this study, 71 polyphenolic compounds were identified from PEP using UPLC-Q-Exactive Orbitrap/MS, including 8 flavonoids, 27 phenolic acids, and 2 lignans. The symptoms of UC in mice were significantly reduced by PEP when induced with dextran sulfate sodium (DSS). Histological and biochemical analyses revealed that PEP ameliorated mucosal damage, restored goblet cell numbers, and enhanced the expression of tight junction (TJ) proteins, indicating improved intestinal barrier integrity. This restoration of barrier function was associated with the attenuation of endoplasmic reticulum (ER) stress, evidenced by the downregulation of the ATF4/eIF2α/CHOP signaling pathway, and a concurrent reduction in intestinal epithelial cell apoptosis involving the modulation of the Bax/Bcl-2 balance and Caspase 3 expression. In parallel, gut microbiota analysis showed that PEP restored microbial community structure, increasing the relative abundance in a higher Firmicutes/Bacteroidetes ratio. Furthermore, PEP enhanced short-chain fatty acid (SCFA) production, particularly acetic, propionic, isobutyric, and isovaleric acids, which were positively correlated with beneficial bacterial taxa. Collectively, these findings demonstrate that PEP exerts therapeutic effects against UC by modulating the interplay between intestinal barrier integrity, ER stress, the apoptotic pathway, and the gut microbiota-SCFA metabolism axis.