Hydroxytyrosol attenuates diquat-induced oxidative stress by activating Nrf2 pathway and modulating colonic microbiota in mice

Oxidative stress is characterized by a state where oxidation exceeds the antioxidant defenses due to the imbalance between them. Severe oxidative stress can damage major cellular macromolecules (DNA, protein, and lipid) and thus cause various pathological diseases, including cancer and age-related and metabolic diseases in humans [1], [2], [3], [4], [5]. Additionally, our previous studies also found that oxidative stress has detrimental effects on the growth performance and intestinal health in farm animals [6], [7], [8], [9]. Intestine is essential for maintaining host health since it is the main site for nutrition absorption and the first defense to protect against pathogenic invasions. Previous studies have shown that small intestine is highly susceptible to oxidative stress [6, 10]. It has been well established that oxidative stress can damage intestinal morphology by decreasing villus height and increasing crypt depth [11].

Hydroxytyrosol (HT) is one of the major polyphenols present in olive fruits, leaves, and oil. HT has attracted high interest due to its wide range of beneficial properties [12]. It has been reported that HT has powerful antioxidative, anti-inflammatory, anti-cancer, and cardioprotective effects [13]. In human intestinal Caco-2 cells, HT alleviated oxidative stress by inhibiting the production of malondialdehyde (MDA) and enhancing the activities of antioxidant enzymes, including glutathione peroxidase (GSH-Px) [14]. In murine peritoneal macrophages, HT treatment attenuated LPS-induced oxidative stress by upregulating the protein expressions of NF-E2-related factor 2 (Nrf2) and Heme Oxygenase-1 (HO-1) [15]. Similarly, HT treatment could enhance antioxidant capacity by increasing the activities of superoxide dismutase (SOD) and catalase (CAT) and decreasing the MDA levels in mouse serum and rat brain and liver [16], [17], [18]. Additionally, HT, like other polyphenols, has the ability of modulating gut microbiota [19, 20]. It has been well established that oxidative stress is associated with gut microbiota [21]. On the one hand, it has been reported that gut microbiota is associated with the development of oxidative stress via directly influencing the production of ROS from mitochondria [22]. Additionally, microbial metabolites, such as glutathione and butyrate, can act as antioxidants to suppress oxidative stress [23]. On the other hand, oxidative stress can induce alterations in gut microbiota [24].

Although HT has demonstrated antioxidant effects, information on how HT alleviates intestinal oxidative stress and the role of gut microbiota in HT-enhanced antioxidant capacity is still not well recognized. Diquat (DQ) is used extensively to induce oxidative stress in animals [6, 25]. We, therefore, investigated the antioxidant activity of HT administration using DQ-challenged mice models and explored the mechanism.

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