Wogonin improves colitis by activating the AhR pathway to regulate the plasticity of ILC3/ILC1.

BACKGROUND: Intestinal barrier dysfunction caused by the disrupted balance of group 3 innate lymphoid cells (ILC3)/group 1 innate lymphoid cells (ILC1) is a significant feature in the pathogenesis of inflammatory bowel disease (IBD). Activation of aryl hydrocarbon receptor (AhR) signaling contributes to the maintenance of ILC3/ILC1 balance. Wogonin, a natural flavonoid from Scutellaria baicalensis Georgi, can repair intestinal mucosal damage of IBD. However, it remains unclear if wogonin can exert a therapeutic effect by activating the AhR pathway to regulate the plasticity of ILC3/ILC1. PURPOSE: In this study, we investigated the immunomodulatory effects of wogonin on IBD and its potential mechanisms in vitro and in vivo. STUDY DESIGN AND METHODS: Chronic colitis was induced by four cycles of 2 % DSS treatment in mice. 20 mg kg-1/day wogonin was administrated by oral gavage and mice were treated intraperitoneally with 10 mg kg-1/2 days CH223191 to block the AhR pathway. Colon tissues were processed for histopathological examination and evaluation of the epithelial barrier function by immunohistochemistry. The activation of the AhR pathway and the plasticity of ILC3/ILC1 were determined by western blot and flow cytometry. Then, we also detected the intestinal microflora and their metabolites by 16 s sequencing and non-targeted Metabolomics analysis. Furthermore, an in vitro culture system consisting of MNK3 cells and NCM460 cells, and a CETSA assay were performed to confirm the molecular mechanism. RESULTS: Wogonin ameliorated histological severity of the colon, decreased the secretion of inflammatory factors, and increased tight junction proteins in colitis mice. These effects are associated with the tendency of conversion from ILC3 to ILC1 prevented by wogonin, which was offset by AhR antagonist CH223191. In addition, wogonin exerted the curative effect by altering gut microbiota to produce metabolites such as Kynurenic acid, and 1H-Indole-3-carboxaldehyde as AhR endogenous ligands. In vitro data further verified that wogonin as an exogenous ligand directly binds to the structural domain of AhR by CETSA. Also, the supernatant of MNK-3 cells stimulated with wogonin enhanced expression of Occludin and Claudin1 in NCM460 cells induced by LPS. CONCLUSION: Cumulatively, our study illustrated that wogonin improved the outcomes of DSS-induced chronic colitis via regulating the plasticity of ILC3/ILC1. Its specific mechanism is to binding to AhR directly, and to activate the AhR pathway indirectly by altering the tryptophan metabolisms of gut microbiota.

Ursolic acid improves the bacterial community mapping of the intestinal tract in liver fibrosis mice.

Liver fibrosis often appears in chronic liver disease, with extracellular matrix (ECM) deposition as the main feature. Due to the presence of the liver-gut axis, the destruction of intestinal homeostasis is often accompanied by the development of liver fibrosis. The inconsistent ecological environment of different intestinal sites may lead to differences in the microbiota. The traditional Chinese medicine ursolic acid (UA) has been proven to protect the liver from fibrosis. We investigated the changes in the microbiota of different parts of the intestine during liver fibrosis and the effect of UA on these changes based on high-throughput sequencing technology. Sequencing results suggest that the diversity and abundance of intestinal microbiota decline and the composition of the microbiota is disordered, the potentially beneficial Firmicutes bacteria are reduced, and the pathways for functional prediction are changed in the ilea and anal faeces of liver fibrosis mice compared with normal mice. However, in UA-treated liver fibrosis mice, these disorders improved. It is worth noting that the bacterial changes in the ilea and anal faeces are not consistent. In conclusion, in liver fibrosis, the microbiota of different parts of the intestines have different degrees of disorder, and UA can improve this disorder. This may be a potential mechanism for UA to achieve anti-fibrosis. This study provides theoretical guidance for the UA targeting of intestinal microbiota for the treatment of liver fibrosis.

Antibiotic resistance and CYP2C19 polymorphisms affect the efficacy of concomitant therapies for Helicobacter pylori infection: an open-label, randomized, single-centre clinical trial.

OBJECTIVES: We evaluate the efficacy of concomitant therapy for Helicobacter pylori infection and the associated factors that influence it in China, where it has not previously been investigated. METHODS: In this prospective study, 374 consecutive patients with H. pylori infection were randomly assigned to 10 day regimens of concomitant therapy with different proton pump inhibitors: esomeprazole (20 mg)/omeprazole (20 mg), amoxicillin (1000 mg), clarithromycin (500 mg) and metronidazole (400 mg). All drugs were administered twice daily. A [(13)C]urea breath test was performed at least 4 weeks after the completion of treatment. Gene polymorphisms and antimicrobial susceptibility were determined. RESULTS: A total of 374 patients with active, uncomplicated duodenal ulcer disease were enrolled in the study (187 cases in each group). The overall eradication rate resulting from concomitant therapy was 90.7% (PP) and 86.1% (ITT) and the eradication rate was significantly higher in the group that received an esomeprazole-based regimen compared with the group that received an omeprazole-based regimen [95.4% versus 86.0%, respectively, P = 0.003 (PP) and 89.8% versus 82.4%, P = 0.036 (ITT), respectively]. Moreover, the omeprazole-based regimen was an independent risk factor for treatment failure (P = 0.039), as were CYP2C19 extensive metabolizer (P = 0.005), clarithromycin (P = 0.000) and metronidazole resistance (P = 0.000). In addition, CYP2C19 polymorphisms and antibiotic resistance had a synergistic effect on eradication rates. The majority of side effects were mild and none was serious. CONCLUSIONS: The 10 day concomitant therapy yielded an eradication rate of nearly 90%. Antibiotic resistance, CYP2C19 polymorphisms and their interactions were closely associated with regimen efficacy.