Liquiritigenin ameliorates DSS-induced ulcerative colitis by improving intestinal barrier function, reducing endoplasmic reticulum stress and modulating gut microbiota

Inflammatory bowel disease remains a high recurrence rate and broad populations all over the world. Liquiritigenin isolated from licorice possess anti-inflammatory and antioxidative activities, suggesting its potential of treating ulcerative colitis (UC). In this study, we explored the effect of oral liquiritigenin on the DSS-induced mice colitis and underlying mechanisms in the aspect of gut microbiome and intestinal barrier dysfunction. The results showed liquiritigenin had protective effects against DSS-induced mice colitis, including attenuating weight loss, disease activity index score elevation, colon length shortening and histological lesions. In addition, the treatment with liquiritigenin significantly reduced the plasma cytokine levels, TNF-α, IL-1β and IL-6 levels as well as the expression of iNOS and COX-2 compared to control group. Liquiritigenin supplementation also led to a restoration of oxidative homeostasis, as indicated by a decrease of myeloperoxidase (MPO) and malondialdehyde (MDA) levels and an increase in reduced glutathione (GSH) and total Superoxide Dismutase (T-SOD) activities in the colitis mice. In regulation of mice gut microbiota, liquiritigenin augmented probiotics abundance (e.g., Akkermansia), decreased harmful bacteria (e.g., Turicibacter), and restored Firmicutes/Bacteroidetes balance. Furthermore, the mRNA levels of tight junction (TJ), including ZO-1, occludin, and claudin-1 were downregulated in colitis mice, whereas these changes were reversed by liquiritigenin. As indicated by TEM images and Endoplasmic reticulum stress (ERs) marker genes expression like GRP78, IRE1α, ATF6 and PERK that mice with colitis treated by oral liquiritigenin trended to attenuate ER stress. Collectively, the ameliorating role of liquiritigenin in gut inflammation can be attributed to intestinal barrier modulation, gut microbiome regulation, and ER stress alleviation. These findings provide a new perspective for developing liquiritigenin as a promising functional compound of food origin for preventing and mitigating UC.