Abstract
BACKGROUND AND PURPOSE Diosmetin exhibits a series of therapeutic
efficacy but little is known of its effects on colitis. EXPERIMENTAL
APPROACH In this study, two mouse models of DSS (the concentration of
3% and 5%)-induced colitis and Caco2 and IEC-6 cells were employed.
The 16S amplicon sequencing was used to assess Gut microbiota changes by
diosmetin. Various physical signs of mice (body weight, colon length and
DAI score), proinflammatory cytokines and antioxidant enzymes were
tested. KEY RESULTS The results showed that diosmetin can markedly
decrease the disease activity index and microscopic colon tissue damage,
increase the expression of tight junction protein (Occludin, Claudin-1
and Zo-1) and reduce the secretion of proinflammatory cytokines. And
diosmetin also significantly inhibited colon oxidative damage through
adjusting the levels of intracellular ROS, mitochondrial ROS, GSH-Px,
SOD, MDA and GSH in vitro and in vivo. Furthermore, it was found that
diosmetin can modulate the abundance of Bacteroidetes, Actinobacteria,
Cyanobacteria and Firmicutes, which were reported to be the crucial
bacteria related to inflammatory bowel disease (IBD). Also, diosmetin
significantly increased the expression of Nrf2 and HO-1 and reduced the
ratio of acetylated NF-κB and NF-κB by activating the circ-Sirt1/Sirt1
axis, thereby inhibiting oxidative stress and inflammation. CONCLUSIONS
AND IMPLICATIONS Our results have linked colitis to the circ-Sirt1/Sirt1
signaling pathway, which is regulated by diosmetin. It implies that
diosmetin may be a novel candidate to alleviate DSS-induced colitis or a
lead compound for future optimization and modification.