Pinocembrin alleviates ulcerative colitis in mice via regulating gut microbiota, suppressing TLR4/MD2/NF-κB pathway and promoting intestinal barrier

Abstract

Pinocembrin, a plant-derived flavonoid, has a variety of pharmacological activities, including anti-infection, anti-cancer, anti-inflammation, cardiovascular protection, etc. However, the mechanism of pinocembrin on the anti-colitis efficacy remains elusive and needs further investigation. Here, we reported that pinocembrin eased the severity of dextran sulfate sodium (DSS)-induced colitis in mice by suppressing the abnormal activation of toll-like receptor 4 (TLR4) / nuclear factor-kappa B (NF-κB) signal pathway in vivo. In addition, the gut microbiota was disordered in DSS colitis mice, which was associated with a significant decrease in microbiota diversity and a great shift in bacteria profiles; however, pinocembrin treatment improved the imbalance of gut microbiota and made it similar to that in normal mice. On the other hand, in vitro, pinocembrin down-regulated the TLR4/NF-κB signaling cascades in lipopolysaccharide (LPS)-stimulated macrophages. At the upstream level, pinocembrin competitively inhibited the binding of LPS to myeloid differentiation protein 2 (MD2), thereby blocking the formation of receptor multimer TLR4/MD2·LPS. Furthermore, pinocembrin dose-dependently promoted the expression of tight junction proteins (ZO-1, Claudin-1, Occludin and JAM-A) in Caco-2 cells. In conclusion, our work presented evidence that pinocembrin attenuated DSS-induced colitis in mouse, at least in part, via regulating intestinal microbiota, inhibiting the over-activation of TLR4/MD2/NF-κB signaling pathway, and improving the barriers of intestine.

Acacetin Ameliorates Experimental Colitis in Mice via Inhibiting Macrophage Inflammatory Response and Regulating the Composition of Gut Microbiota

“…Moreover, significant alterations were observed in DSS-treated mice, as levels of Firmicutes were reduced at the phylum level and those of Escherichia-Shigella were increased at the genus level; however, acacetin alleviated these changes. Notably, this results are quite consistent with our previously studied natural compounds, including obacunone and pinocembrin ( Luo et al, 2020 ; Yue et al, 2020 ). There are also some researches indicate that Escherichia-Shigella are positively correlated with high expression of inflammatory cytokines, and many studies have shown its adverse effects in IBD ( Zeissig et al, 2019 ).…”

Sinapic Acid Alleviated Inflammation-Induced Intestinal Epithelial Barrier Dysfunction in Lipopolysaccharide- (LPS-) Treated Caco-2 Cells

“…TLR4, one of the best characterized pattern recognition receptors, is activated by LPS, leading to the activation of NF-κB and subsequently inducing the production of proinflammatory mediators. Recently, many studies have indicated that NF-κB is a key factor in inflammatory gene expression [37][38][39]. Under normal conditions, NF-κB binds with IκB to form an inactivation complex.…”

6,7,4′-Trihydroxyflavanone Protects against Dextran Sulfate Sodium-Induced Colitis by Regulating the Activity of T Cells and Colon Cells In Vivo

“…It has been investigated that diplacone and mimulone protect rats from DSS-induced colitis through increments in antioxidant activity and modulation of metalloproteinase activity [ 20 ]. A recent report has evaluated the protective effect of pinocembrin on colitis, whereby it suppresses gut microbiota and toll like receptor 4/myeloid differentiation factor 2/NF-κB pathway but enhances the intestinal barrier by upregulating the expression of tight junction proteins [ 21 ]. Since the literature reports on the potent bioactivities of flavanone family on the attenuation of colitis, further studies should look at whether THF has an antioxidant activity, modulates metalloproteinase activity or increases intestinal barrier function in colonic inflammation conditions.…”