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.
Wei Zong,Zijing Liu,Haiyan Lan,Jianwei Yang,Yuxuan Xia,Zhongsheng Xu,Li Mai,Jie Wang,Yixi Bao
The polarization of tumor-associated macrophages (TAMs) from M2 to M1 phenotype is an effective strategy for tumor immunotherapy. In this study, a pectic polysaccharide (PEP-1) was isolated from Phyllanthus emblica fruits via hot water extraction, ethanol precipitation, and purified by anion exchange and gel permeation chromatography. PEP-1 was identified as a homogalacturonan (molecular weight, 156.8 kDa) via characterization analysis. The structural attributes of PEP-1 were elucidated through GC–MS and NMR analyses, confirming that its repeating sugar units consist of GalA connected by α-1,4-glycosidic linkage. Functional assays demonstrated that PEP-1, at concentrations of 50, 100, and 200 μg/mL could strongly induce the transformation of M2 macrophages into M1 phenotype in vitro, and the conditioned medium (CM) of M2 pretreated with PEP-1 significantly promoted apoptosis of Hepa1-6 cells. At the cellular level, PEP-1 shifted tumor-promoting M2 macrophages to a tumor-inhibiting M1 phenotype by increasing the phosphorylation of NF-κB and MAPK. Additionally, PEP-1 (200 mg/kg) was capable of reaching the tumor microenvironment (TME), directly binding to TAMs, promoting their polarization towards M1 phenotype, and significantly inhibiting the tumor growth in Hepa1-6 tumor-bearing mice. These findings reveal the structural characteristics of PEP-1 and its potential to treat hepatocellular carcinoma immunotherapy via regulating TAMs.
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