Lycopene improves cisplatin induced hepatointestinal injury in rats by modulating the microbe–gut–liver axis

Cisplatin (CIS) is a commonly used antitumor drug in clinics, but its application is limited due to hepatotoxicity, nephrotoxicity and gastrointestinal toxicity. In recent years, a large number of studies have shown that the imbalance of intestinal flora is one of the important factors in the malignant development of diseases. Therefore, improving organ function by regulating intestinal flora may be an important strategy to prevent the side effects of chemotherapy drugs. Lycopene (LYC) is found in a wide range of red foods and has antioxidant, anti-inflammatory and immune-enhancing effects. So the purpose of this study was to explore its effect on hepatointestinal injury caused by chemotherapy drugs. The results of this study showed that CIS could significantly restore body weight, diet, water intake, and AST, ALT and other physiological and biochemical indexes of rats. HE staining, projective electron microscopy and TUNEL results showed that LYC alleviated morphological and ultrastructural damage of the liver and intestine. Then, ELISA results showed that LYC can reduce cell apoptosis by increasing the antioxidant capacity and reducing inflammatory response. Secondly, 16sRNA and metabolome results showed that LYC enriched beneficial bacteria (Firmicutes and Proteobacteria), reduced harmful bacteria (<i>E. coli</i>, <i>etc</i>.), enhanced metabolic pathway changes such as taurine and hypotaurine metabolism, and alleviated organ damage caused by CIS. Finally, network pharmacology, molecular docking and immunohistochemistry showed that LYC could reduce CIS induced hepatocyte inflammation and apoptosis by activating the PI3K/AKT pathway. In summary, LYC alleviates the toxic side effects of chemotherapy drugs by regulating the PI3K/AKT pathway and the intestinal microbiota-metabolite-liver axis.