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 2ʹ-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 2ʹ-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.

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. To investigate the underlying mechanisms of WMW in the treatment of chronic ulcerative colitis (UC) through network pharmacology and experimental validation. 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. 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.

Background. Ulcerative colitis (UC) patients have an increased risk for the development of colorectal cancer (CRC). Our aim was to assess the risk of CRC in UC patients compared with disease extent, disease duration, and geographic variation. Methods. In this systematic review and meta-analysis, we searched PubMed, scientific meetings, and the bibliographies of identified articles, with English language restrictions for studies published from 1988 to 2018, and assessed the risk of CRC in UC patients. Patients with Crohn’s disease, family history of CRC, and colorectal adenomatous polyp (CAP) were excluded from this research. The study was registered with PROSPERO, number CRD42018102213. Findings. We included 58 studies that included 267566 UC patients. Extensive UC and left-sided UC had a higher risk of CRC than proctitis UC. Geography also played a role in UC-associated CRC development. The time of malignant transformation in Asian UC patients started after 10-20 years of this disease duration. North American UC-associated CRC patients significantly increased in more than 30 years of this disease duration. Conclusion. In a systematic review of the literature, we found that disease extent, disease duration, and geography were strong, independent risk factors in UC-associated CRC development.

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.

Colorectal cancer pathogenesis remains incompletely understood. Here, we report that the heterochromatin protein HP1γ is upregulated commonly in human colorectal cancer, where it promotes cell proliferation in vitro and in vivo. Gene-expression and promoter-binding experiments demonstrated that HP1γ directly regulated CDKN1A (p21^Waf1/Cip1) in a manner associated with methylation of histone H3K9 on its promoter. We identified miR-30a as a tumor-suppressive microRNA that targets HP1γ in vitro and in vivo to specifically suppress the growth of colorectal cancer in mouse xenograft models. MiR-30a was widely downregulated in primary human colorectal cancer tissues, where its expression correlated inversely with high levels of HP1γ protein. Our results identify a new miR-30a/HP1γ/p21 regulatory axis controlling colorectal cancer development, which may offer prognostic and therapeutic opportunities. Cancer Res; 75(21); 4593–604. ©2015 AACR.