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Scope: This study investigates the modulatory effects of Lonicera caerulea L. polyphenols (LCPs) on the intestinal environment and lipopolysaccharide (LPS)-induced liver injury via the nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (HO-1)/NQO1 and mitogen-activated protein kinase (MAPK) pathways in a rat model of oxidative stress damage (OSD). Methods and results: To examine the prebiotic properties of LCP, a model of high-fat-diet-induced OSD is established using Sprague Dawley rats. In the colon, treatment with LCP for 8 weeks ameliorates enhanced intestinal permeability (glucagon-like peptide-2 content and occludin protein increase, whereas claudin-2 protein decreases), intestinal inflammation (levels of pro-inflammatory cytokines, such as tumor necrosis factor-, interleukin-6, cyclooxygenase-2, and nuclear factor kappa-B p65 (NF-B p65), decrease), and intestinal OSD (through regulation of the Nrf2/HO-1/NQO1 pathway). Moreover, LCP alleviates LPS-induced liver injury by suppressing the nuclear translocation of NF-B p65 and activation of the MAPK signaling pathway. Additionally, Bacilli, Lactobacillales, Lactobacillaceae, Lactobacillus, Akkermansia, Actinobacteria, Proteobacteria, Rothia, and Blautia are found to be the key intestinal microbial taxa related to intestinal OSD and LPS-induced liver injury in rats. Conclusion: LCP treatment potentially modulates the intestinal environment and alleviates liver injury by suppressing oxidative-stress-related pathways and altering the composition of the intestinal microbiota.