Licorice-Yuanhua Herbal Pair Induces Ileum Injuries Through Weakening Epithelial and Mucous Barrier Functions: Saponins, Flavonoids, and Di-Terpenes All Involved

Abstract

In traditional Chinese Medicine (TCM), the licorice-yuanhua herbal pair is one of the most representative incompatible herbal pairs recorded in the "eighteen incompatible herbal pairs" theory. Previous studies of our research group have demonstrated several gutrelated side-effects induced by the licorice-yuanhua herbal pair. In this study, we investigated whether and why this incompatible herbal pair could induce gut tissue damage. After licorice-yuanhua treatment, the duodenum, ileum, and colon and serum biomarkers of mice were examined by pathological staining, Western blot, and ELISA assays. The IEC-6 cells and LS174T cells were treated with licorice saponins, yuanhua flavonoids, and di-terpenes; iTRAQ-labeled proteomic technology was then used to explore their synergistic effects on mucosa cells, followed by verification of ZO-1 and MUC-2 protein expressions. The results showed that the licorice-yuanhua herbal pair induced ileum tissue injuries, including epithelial integrity loss, inflammation, and edema. These injuries were verified to be related to epithelial and mucous barrier weakening, such as downregulated ileum ZO-1 and MUC-2 protein expressions. Proteomic analysis also suggested that glycyrrhizic acid and genkwanin synergistically influence tight junction pathways in LS174T cells. Furthermore, licorice saponins, yuanhua flavonoids, and diterpenes dose/structure-dependently downregulate ZO-1 and MUC-2 protein expressions in mucosa cells. Our study provides different insights into the incompatibility mechanisms and material basis of the licorice-yuanhua herbal pair, especially that besides toxic di-terpenes, licorice saponins and yuanhua flavonoids,

Yuanhuacin and Related Anti-Inflammatory and Anticancer Daphnane Diterpenes from Genkwa Flos—An Overview

“…In particular, the herb yuanhua cannot be combined with Glycyrrhizae radix (licorice), another common traditional Chinese herbal medicine. The licorice-yuanhua herbal pair is incompatible due to major gastro-intestinal side effects [ 104 , 105 ]. The combination of these two plants causes colonic H 2 S metabolism disturbance [ 106 ].…”

Herbal medicine and gut microbiota: exploring untapped therapeutic potential in neurodegenerative disease management

“…These beneficial microbes can outcompete pathogenic bacteria, enhance gut mucosal immunity, and contribute to the production of short-chain fatty acids (SCFAs), which strengthen the gut barrier (Cheng et al 2023 ; Wang et al 2023a ). Herbal medicine can enhance gut barrier function by upregulating the expression of tight junction proteins, such as occludin and claudins, and downregulating the levels of proinflammatory cytokines that disrupt the gut barrier, such as TNF-α and IL-1β (Yu et al 2020 ; Liu et al 2022a ). These proteins are critical components of the tight junctions that seal the space between epithelial cells, preventing the leakage of luminal contents into the underlying tissue.…”

Polysaccharide from Edible Alga Enteromorpha clathrata Improves Ulcerative Colitis in Association with Increased Abundance of Parabacteroides spp. in the Gut Microbiota of Dextran Sulfate Sodium-Fed Mice

“…H&E staining and Alcian blue staining of the colon tissues were performed as previously described [13,22,23]. The symptom score and histopathological colon score analyses were performed as described elsewhere [13,24,25].…”