Hydroxytyrosol (HT), a polyphenol derived from olive oil, was examined against dextran sulfate sodium (DSS)-induced colitis to study its potential in preventing colitis and the underlying mechanisms involved. The low dose and high dose of HT used in mice were 10 and 50 mg/kg, respectively. Research findings have shown that HT is effective in preventing colitis by alleviating the signs of colitis. HT intervention significantly reduces colitis markers such as myeloperoxidase (MPO) and proinflammatory cytokine (IL-6, IL-1β, and TNF-α). Also, mice treated with a high dose of HT showed increased secretion of antioxidant enzymes (heme oxygenase-1 (HO) and anti-inflammatory cytokine (IL-10) by 2.32- and 2.28-fold, respectively, in comparison to the DSS-treated group. Modulation effects of HT on the antioxidant signal pathway (NRF2) and the inflammatory pathway (NF-κB) were confirmed. Meanwhile, HT promoted the regeneration of the intestinal barrier and maintained intestinal functional homeostasis by boosting the regeneration of goblet cells and the expression of mucin protein (Muc2) and tight junction (TJ) proteins (claudin-1, occludin, and Zonula Occludens-1). Moreover, HT intervention obviously transformed the gut microbiota, leading to a lower abundance of inflammation-related microbes (e.g., Bacteroidaceae and Desulfovibrionaceae) and a higher level of short-chain fatty acids (SCFAs) producing bacteria (e.g., Lachnospiraceae, Muribaculaceae, ASF356, and Colidextribacter). Scientific evidence for the beneficial effect of the “Mediterranean diet” (MD) on intestinal health was achieved by elucidating the alleviation mechanism of hydroxytyrosol on colitis.

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