Toxicology and applied pharmacology · 2025
Paeoniflorin attenuates ASA-induced enteropathy in simulated high-altitude hypoxia in rats by regulating intestinal inflammation, intestinal barrier, and intestinal flora.
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Tuerxuntayi Ailifeire, Shi Wenhui, Shi Tian, Abudukelimu Kudelaiti, Gao Beiyao, Abulaiti Paziliya, Nuermaimaiti Kailibinuer, Rehemutula Najimangu, Xue Shenglong, Xing Yingying, Liu Weidong, Liu Zhuoshuyi, Liu Jiangwei, Gao Feng
Аннотация
PURPOSE: This study aimed to investigate whether high-altitude hypoxia exacerbates non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury and to evaluate the protective effects of Paeoniflorin (PF).
METHODS: Male Sprague-Dawley rats were orally administered 300 mg/kg aspirin (ASA) to induce NSAID enteropathy, followed by 3 weeks of 5500 m high-altitude hypoxia exposure. Rats were divided into normoxic control (Con), hypoxic control (Hcon), hypoxic ASA model (HAsa), and PF treatment groups (25/50/100 mg/kg/day, LPF/MPF/HPF). The body weight changes, oxidative stress markers (MPO, SOD), inflammatory factors (IL-1β, TNF-α, IL-10), intestinal histology, tight junction proteins (ZO-1, Occludin), TLR4/NF-κB pathway activation, and gut microbiota composition (16S rRNA sequencing) were evaluated.
RESULTS: The HAsa group exhibited the most severe intestinal damage, characterized by significant villus injury and inflammatory cell infiltration (P < 0.05). Mechanistically, this damage was driven by TLR4/NF-κB pathway activation, accompanied by significantly increased pro-inflammatory cytokines (IL-1β, TNF-α) and decreased anti-inflammatory cytokine IL-10 (P < 0.05). Oxidative stress was concurrently heightened, as evidenced by significantly elevated MPO levels and reduced SOD activity (P < 0.05). Consequently, the expression of tight junction proteins (ZO-1, Occludin) was significantly downregulated (P < 0.05), indicating compromised intestinal barrier function. Furthermore, 16S rRNA sequencing revealed gut microbiota dysbiosis, characterized by a decline in beneficial bacteria like Lactobacillus and Bifidobacterium and an expansion of harmful genera like Romboutsia and Turicibacter (P < 0.05). PF intervention dose-dependently reversed these alterations by effectively suppressing the TLR4/NF-κB pathway (P < 0.05), ameliorating inflammation and oxidative stress, and restoring mucosal barrier integrity. Concurrently, PF supplementation reshaped the gut microbiota, thereby normalizing the balance between beneficial and pathogenic bacteria (P < 0.05).
CONCLUSION: High-altitude hypoxia synergistically exacerbates NSAID-induced intestinal injury. PF protects against this injury primarily via modulating the TLR4/NF-κB pathway, highlighting its therapeutic potential for high-altitude populations on NSAIDs.
METHODS: Male Sprague-Dawley rats were orally administered 300 mg/kg aspirin (ASA) to induce NSAID enteropathy, followed by 3 weeks of 5500 m high-altitude hypoxia exposure. Rats were divided into normoxic control (Con), hypoxic control (Hcon), hypoxic ASA model (HAsa), and PF treatment groups (25/50/100 mg/kg/day, LPF/MPF/HPF). The body weight changes, oxidative stress markers (MPO, SOD), inflammatory factors (IL-1β, TNF-α, IL-10), intestinal histology, tight junction proteins (ZO-1, Occludin), TLR4/NF-κB pathway activation, and gut microbiota composition (16S rRNA sequencing) were evaluated.
RESULTS: The HAsa group exhibited the most severe intestinal damage, characterized by significant villus injury and inflammatory cell infiltration (P < 0.05). Mechanistically, this damage was driven by TLR4/NF-κB pathway activation, accompanied by significantly increased pro-inflammatory cytokines (IL-1β, TNF-α) and decreased anti-inflammatory cytokine IL-10 (P < 0.05). Oxidative stress was concurrently heightened, as evidenced by significantly elevated MPO levels and reduced SOD activity (P < 0.05). Consequently, the expression of tight junction proteins (ZO-1, Occludin) was significantly downregulated (P < 0.05), indicating compromised intestinal barrier function. Furthermore, 16S rRNA sequencing revealed gut microbiota dysbiosis, characterized by a decline in beneficial bacteria like Lactobacillus and Bifidobacterium and an expansion of harmful genera like Romboutsia and Turicibacter (P < 0.05). PF intervention dose-dependently reversed these alterations by effectively suppressing the TLR4/NF-κB pathway (P < 0.05), ameliorating inflammation and oxidative stress, and restoring mucosal barrier integrity. Concurrently, PF supplementation reshaped the gut microbiota, thereby normalizing the balance between beneficial and pathogenic bacteria (P < 0.05).
CONCLUSION: High-altitude hypoxia synergistically exacerbates NSAID-induced intestinal injury. PF protects against this injury primarily via modulating the TLR4/NF-κB pathway, highlighting its therapeutic potential for high-altitude populations on NSAIDs.