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.
Maintaining a steady state of mucus barrier is an important potential target for polyphenol to exert its anticolitis activity. This study elucidates the pivotal role of polyphenol rosmaric acid (RA) in regulating the mucus barrier function and alleviating inflammation by identifying its gut microbiota-derived metabolites and evaluating its inhibitory effect on inflammasomes in colitis mice. Results demonstrated that RA treatment promoted the proliferation of goblet cells and restored the level of mucus secretion, especially Muc2. RA reshaped the microbiota of colitis mice, particularly the boost of core probiotics, such as p. Bacteroidaceae, f. Muribaculaceae, g. Muribaculaceae, g. Alistipes, and g. Clostridia_UCG-014. Nontargeted metabonomics and targeted metabonomics confirmed a significant increase in the bile acids and their metabolites (7-sulfocholic acid, stercobilin, chenodeoxycholic acid 3-sulfate, chenodeoxycholic acid sulfate, and ursodeoxycholic acid 3-sulfate), indole metabolites ((R)-2,3-dihydro-3,5-dihydroxy-2-oxo-3-indoleacetic acid, frovatriptan, 3-formyl-6-hydroxyindole, and brassicanal A), and short-chain fatty acids (SCFAs) (acetic acid, butyric acid, isobutyric acid, isovaleric acid, and valeric acid) that contributed to the strengthened mucus barrier function. In addition, being absorbed mainly in the lower digestive tract, RA inhibited the overexpression of inflammasomes (especially NLRP6) that occurred in colitis mice to promote the mucus secretion of goblet cells. These data confirmed that RA, as a promising candidate to enhance gut health, restored colonic mucus secretion in colitis mice by mediating the production of gut microbiota-derived metabolites and the overexpression of inflammasomes. The presented study provides scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols.
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