Wumei Wan attenuates angiogenesis and inflammation by modulating RAGE signaling pathway in IBD: Network pharmacology analysis and experimental evidence.

BACKGROUND: Wumei Wan (WMW) has been used to address digestive disorder for centuries in traditional Chinese medicine. Previous studies have demonstrated its anti-colitis efficacy, but the underlying mechanism of its action remains to be further clarified. PURPOSE: To investigate the underlying mechanisms of WMW in the treatment of chronic ulcerative colitis (UC) through network pharmacology and experimental validation. METHODS: Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform were used to identify the ingredients and potential targets of WMW. The microarray gene data GSE75214 datasets from GEO database was used to define UC-associated targets. Cytoscape3.7.2 was employed to construct the protein-protein interaction (PPI) network and compounds-disease targets network. GO enrichment analysis and KEGG pathway analysis were performed by R software for functional annotation. UPLC-TOF-MS/MS method was used to quantitatively analyze the active ingredients of WMW. For experimental validation, three cycles of 2% dextran sulfate sodium salt (DSS) were used to construct chronic colitis model. The hub targets and signal pathway were detected by qPCR, ELISA, western blotting , immunohistochemical and immunofluorescence. RESULTS: Through network analysis, 104 active ingredients were obtained from WMW, and 47 of these ingredients had potential targets for UC. A total of 41 potential targets of WMW and 13 hub targets were identified. KEGG analysis showed that WMW involved in advanced glycation end products-receptor of advanced glycation end products (AGE-RAGE) signaling pathway. Taxifolin, rutaecarpine, kaempferol, quercetin, and luteolin of WMW were the more highly predictive components related to the AGE-RAGE signaling pathway. In vivo validation, WMW improved DSS-induced colitis, reduced the expression of inflammatory cytokines and chemokines. Notably, it significantly decreased the mRNA expression of Spp1, Serpine1, Mmp2, Mmp9, Ptgs2, Nos2, Kdr and Icam1, which were associated with angiogenesis. In addition, we confirmed WMW inhibited RAGE expression and diminished DSS-induced epithelial barrier alterations CONCLUSION: Our results initially demonstrated the effective components and the strong anti-angiogenic activity of WMW in experimental chronic colitis. Sufficient evidence of the satisfactory anti-colitis action of WMW was verified in this study, suggesting its potential as a quite prospective agent for the therapy of UC.

Akkermansia muciniphila Protects Against Psychological Disorder-Induced Gut Microbiota-Mediated Colonic Mucosal Barrier Damage and Aggravation of Colitis.

Psychological disorders are associated with increased risk of severe inflammatory bowel disease (IBD) by causing gut microbiota dysbiosis and colonic mucosal barrier damage. However, the interaction between chronic restraint stress (CRS), gut microbiota composition, and colonic mucus remains unclear. We demonstrated that mice under CRS conditions exhibited alterations in microbiota composition, disruption of colonic mucus, and aggravation of colitis. In addition, the abundance of Akkermansia muciniphila was significantly decreased in mice under CRS and UC patients with depression, and positively associated with the expression of MUC2. After antibiotic treatment, the recipient mice colonized with CRS microbiota showed barrier defects and severe colitis. Administration of Akkermansia muciniphila was found to restore colonic mucus and modify the gut microbiota. We confirm that CRS-mediated gut microbiota dysbiosis results in colonic mucosal barrier damage and aggravation of colitis. Our results suggest that A. muciniphila is expected to be a potential probiotic to protect and treat colonic mucus that is involved in IBD with psychological disorders.

Depression and anxiety in patients with active ulcerative colitis: crosstalk of gut microbiota, metabolomics and proteomics.

Patients with ulcerative colitis (UC) have a high prevalence of mental disorders, such as depression and anxiety. Gut microbiota imbalance and disturbed metabolism have been suggested to play an important role in either UC or mental disorders. However, little is known about their detailed multi-omics characteristics in patients with UC and depression/anxiety. In this prospective observational study, 240 Chinese patients were enrolled, including 129 patients with active UC (69 in Phase 1 and 60 in Phase 2; divided into depression/non-depression or anxiety/non-anxiety groups), 49 patients with depression and anxiety (non-UC), and 62 healthy people. The gut microbiota of all subjects was analyzed using 16S rRNA sequencing. The serum metabolome and proteome of patients with UC in Phase 2 were analyzed using liquid chromatography/mass spectrometry. Associations between multi-omics were evaluated by correlation analysis. The prophylactic effect of candidate metabolites on the depressive-like behavior of mice with colitis was investigated. In total, 58% of patients with active UC had depression, while 50% had anxiety. Compared to patients with UC without depression/anxiety, patients with UC and depression/anxiety had lower fecal microbial community richness and diversity, with more Lactobacillales, Sellimonas, Streptococcus, and Enterococcus but less Prevotella_9 and Lachnospira. Most metabolites (e.g., glycochenodeoxycholate) were increased in the serum, while few metabolites, including 2'-deoxy-D-ribose and L-pipecolic acid, were decreased, accompanied by a general reduction in immunoglobulin proteins. These related bacteria, metabolites, and proteins were highly connected. A prophylactic administration of 2'-deoxy-D-ribose and L-pipecolic acid significantly reduced the depressive-like behaviors in mice with colitis and alleviated the inflammatory cytokine levels in their colon, blood and brain. This study has identified a comprehensive multi-omics network related to depression and anxiety in active UC. It is composed of a certain set of gut microbiota, metabolites, and proteins, which are potential targets for clinical intervention for patients with UC and depression/anxiety.

A next-generation probiotic: Akkermansia muciniphila ameliorates chronic stress-induced depressive-like behavior in mice by regulating gut microbiota and metabolites.

Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for 3 weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson's correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression-related molecular (corticosterone, dopamine, and BDNF). Moreover, AKK altered chronic stress-induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson's correlation coefficient analysis revealed that AKK predominantly upregulated ß-alanyl-3-methyl-L-histidine and edaravone to relieve depression. Furthermore, ß-alanyl-3-methyl-L-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress-induced depressive symptoms in mice by regulating gut microbiota and metabolites. KEY POINTS: • AKK reduces depressive-like behaviors induced by chronic stress. • AKK regulates the gut microbial structure and metabolomics of serum under the chronic stress. • Antidepressant effect of AKK correlates with the increase of ß-alanyl-3-methyl-l-histidine and edaravone.

Total Flavone of Abelmoschus manihot Ameliorates Stress-Induced Microbial Alterations Drive Intestinal Barrier Injury in DSS Colitis.

PURPOSE: Total flavone of Abelmoschus manihot (TFA), the effective constituents extracted from Flos Abelmoschus Manihot, has been reported to inhibit inflammation. However, the effect of TFA on ulcerative colitis (UC) progression in patients with depression is unknown. The purpose of our research was to explore the anti-UC effects of TFA in the context of depression in mice with UC by regulating the gut microbiota to drive the intestinal barrier. METHODS: In this study, chronic stress (CS) and dextran sodium sulfate (DSS) were used to induce depression and UC, respectively, in C57BL/6J mice. Fecal microbiota transplantation (FMT) was used to evaluate how treating mice modeling UC and depression with TFA effected their gut microbiota. RESULTS: Our results showed that TFA effectively improved UC aggravated by CS. In addition, TFA treatment improved the depression-like phenotype, the disturbed gut microbiota, and the intestinal barrier function in CS mice. It is worth noting that FMT from the CS mice to the receptor group further aggravated the damage of the intestinal barrier and the disturbance of the gut microbiota in the recipient DSS mice, thus further aggravating UC, however, treatment of the intervention of TFA in the CS fecal microbiota transplant with TFA also played its therapeutic outcome. CONCLUSION: Taken together, our results show that CS disrupts the gut microbiota, triggers intestinal barrier injury and aggravates DSS colitis, while TFA is a promising drug for the treatment of UC in patients with depression.

Pharmacological inhibition of IRAK1 attenuates colitis-induced tumorigenesis in mice by inhibiting the inflammatory response and epithelial-mesenchymal transition.

Colorectal cancer (CRC) is the third most common type of cancer. Here, we studied the inhibitory effect of IRAK1 and IRAK4 as a preventive strategy using a colitis-induced tumorigenesis mouse model. CRC clinical data were obtained from the Gene Expression Omnibus (GEO). An experimental inflammation-dependent CRC model was induced by treatment with azoxymethane (AOM) and then dextran sodium sulfate (DSS) in C57BL/6 mice. Mice were administered an IRAK1/4 inhibitor by intraperitoneal injection at 3 mg/kg twice each week for 9 weeks. The IRAK1/4 inhibitor attenuated histological changes and prevented tumor growth. Tumor-associated proteins, including p65 and Ki-67, were downregulated by the IRAK1/4 inhibitor in AOM/DSS-treated mice. Additionally, IRAK1/4 inhibitor administration effectively decreased the expression of inflammatory cytokines. Furthermore, we observed that IRAK1/4 inhibitor treatment attenuated colitis-induced tumorigenesis by inhibiting epithelial-mesenchymal transition. These observations indicate that inhibition of IRAK1 and IRAK4 may suppress experimental colitis-induced tumorigenesis by inhibiting inflammatory responses and epithelial-mesenchymal transition.

A critical review on the relationship of herbal medicine, Akkermansia muciniphila, and human health.

There are trillions and trillions of microorganisms in the human gut, and these microorganisms and their metabolites are closely related to human health. Recent studies have found that the abundance of Akkermansia muciniphila is decreased in many diseases. Supplementation of A. muciniphila is used to treat many diseases, suggesting it as a probiotic. Herbal medicines are considered as valuable asset of traditional Chinese medicine. Recent studies have revealed traditional Chinese medicine as a potential prebiotic agent for the treatment of many diseases. Hence, in this review, we aimed to provide a plausible mechanistic basis for the interactions between herbal medicines and A. muciniphila, and therapeutic benefits on this interaction in various illnesses.