Polysaccharide from <i>Gynostemma pentaphyllum</i> Makino Modulates the Oxidative Stress Response under an Acute Hypobaric Hypoxia Environment by Enhancing the Relative Abundance of Anti-inflammatory Gut Microbiota

<i>Gynostemma pentaphylla</i> Makino, a plant renowned for its dual medicinal and culinary properties, is rich in high-quality phytochemicals with significant therapeutic potential. Polysaccharides represent one of their key bioactive components. This study investigated the mechanism of polysaccharide from <i>Gynostemma pentaphyllum</i> Makino (GPMP) in counteracting high-altitude hypoxic stress. Experiment 1 demonstrated that GPMP significantly enhanced hypoxia tolerance and antifatigue capacity in mice (<i>p</i> < 0.05). Experiment 2 established a simulated 6300 m hypobaric hypoxia model, revealing that GPMP intervention (300 mg/kg) ameliorated oxidative stress damage: MDA levels decreased by 44.53%, SOD and GSH-Px activities restored to 73.91% and 91.87% of normal levels, respectively, anti-inflammatory factors IL-10 and TGF-β increased with a 1.33-fold elevation in Bcl-2/Bax ratio, while pro-inflammatory factors IL-1β and TNF-α decreased by 30.06-32.04%. GPMP concurrently improved intestinal barrier integrity (the V/C ratio increased to 1.74-fold of model control) and modulated gut microbiota, reducing the F/B ratio by 3.25-fold while enriching anti-inflammatory and SCFA-producing genera like<i>Odoribacter</i> and <i>Ruminiclostridium_5</i>, with total cecal SCFA and butyrate elevated by 62.14% and 50.77%, respectively. Mechanistic studies indicated GPMP activates the "microbiota-SCFA-gut barrier" axis through GPR41 and GPR109A activation/HDAC inhibition, regulating the Nrf2 pathway to mitigate oxidative stress, providing theoretical foundations for developing high-altitude functional foods.