Drug therapy and monitoring for inflammatory bowel disease: a multinational questionnaire investigation in Asia.

BACKGROUND/AIMS: The incidence and prevalence of inflammatory bowel disease (IBD) is rising in Asia recently. The study aimed to obtain a comprehensive understanding of the current status of drug therapy and monitoring for IBD in Asia. METHODS: A questionnaire investigation on drug therapy and monitoring for IBD was conducted right before the 6th Annual Meeting of Asian Organization for Crohn's & Colitis. Questionnaires were provided to Asian physicians to fill out via emails between March and May 2018. RESULTS: In total, responses of 166 physicians from 129 medical centers were included for analysis. Among the surveyed regions, the most average number of IBD specialist gastroenterologists and nurses was 4.8 per center in Taiwan and 2.5 per center in Mainland China, respectively. 5-Aminosalicylic acid/sulfasalazine (99.4%) was the most preferred first-line choice for mild-moderate ulcerative colitis (UC), meanwhile corticosteroid (83.7%) was widely applied for severe UC. The first-line medication for Crohn's disease (CD) markedly varied as corticosteroid (68.1%) was the most favored in Mainland China, Japan, and South Korea, followed by infliximab (52.4%) and azathioprine (47.0%). Step-up strategy was preferred in mild-moderate UC (96.4%), while 51.8% of the physicians selected top-down treatment for CD. Only 25.9% and 17.5% of the physicians could test blood concentration of infliximab and antibody to infliximab in their hospitals, respectively. CONCLUSIONS: The current status of drug therapy and monitoring for IBD in Asia possesses commonalities as well as differences. Asian recommendations, IBD specialist teams and practice of therapeutic drug monitoring are required to improve IBD management in Asia.

Interleukin-26 Expression in Inflammatory Bowel Disease and Its Immunoregulatory Effects on Macrophages.

Background and Aim: Interleukin-26 (IL-26) has been implicated in several chronic inflammatory diseases. However, its role in inflammatory bowel disease (IBD) remains to be elucidated. We aimed to investigate IL-26 expression in IBD and its immunoregulatory effects on macrophages. Methods: We assessed IL-26 expression in the intestinal mucosa and blood samples of IBD patients and healthy controls (HC). The associations between the clinical characteristics of IBD and IL-26 expression levels in serum and peripheral blood mononuclear cells (PBMCs) were investigated. In addition, the transcriptional changes in THP-1 macrophages exposed to IL-26 were determined by RNA sequencing and validated with qRT-PCR, ELISA and western blots. Results: Compared with HC, in IBD patients, IL-26 expression levels were elevated in the inflamed intestinal mucosa, and reduced in serum and PBMCs. IL-26 mRNA levels in PBMCs, but not serum IL-26 levels, were inversely correlated with disease activity in IBD. Furthermore, IL-26 mRNA levels in PBMCs were significantly lower in patients with complicated Crohn's disease. A total of 1,303 differentially expressed protein-coding genes were identified between untreated and IL-26-treated macrophages. The up-regulated genes showed enrichment in some inflammatory and immune-related processes and pathways. Additionally, GSEA showed that neutrophil, monocyte, and lymphocyte chemotaxis was significantly enriched in IL-26-treated macrophages. Further validation revealed that IL-26 promotes the secretion of multiple inflammatory cytokines and chemokines and upregulates the expression of adhesion molecules, MMP-8, and MMP-9 while inhibiting MMP-1 in macrophages. Conclusion: Compared with HC, in IBD patients, IL-26 levels were elevated in the inflamed intestinal mucosa, and reduced in the peripheral blood. The transcriptional changes in macrophages exposed to IL-26 suggest that IL-26 may amplify the aberrant immune response in IBD by activating macrophages.

Discovery of new long noncoding RNAs associated with ulcerative colitis with a novel general microarray expression data.

UC is a chronic, nonspecific disease and characterized by a chronic relapsing intestinal inflammation, which puts a person at a higher risk of developing bowel cancer, while the causes of UC are unknown. Recently, with the development of microarray technology, more and more studies are focusing on the potential roles of long noncoding RNAs (lncRNAs) in the pathogenesis of diseases. The purpose of this study is to devise a method, based on cDNA microarray probe genomics data, to computationally determine the potential function of evolutionary conserved lncRNAs in ulcerative colitis (UC). We analysed a total of 12,593 microarray probes present in the Ensembl, OMIM, UniGene, and Gene Ontology databases. We found that lncRNA n385775 was significantly higher (P < 0.001) in patients with active UC, while n336281 (P = 0.017), n341081 (P = 0.041), and n387236 (P = 0.006) were significantly lower. Then, we validated our findings by measuring the expression of lncRNAs in colon tissue samples from patients affected by UC. Moreover, we validated the expression pattern of the lncRNAs in two cell lines, Caco2/bbe and T84, treated with TNF-α. In Caco2/bbe cells, lncRNA n385775 was significantly upregulated after TNF-α treatment (P = 0.002). This study reports a novel method to re- annotate the transcriptome expression profile from existing cDNA microarray data as a potential approach to investigate the function of lncRNAs in UC.

Multi-factor mediated functional modules identify novel classification of ulcerative colitis and functional gene panel.

Ulcerative colitis is a chronic, idiopathic, and inflammatory disease of the rectal and colonic mucosa, the behavior of which is of heterogeneity in individuals. Here, we explored the multifactor-mediated functional modules associated with ulcerative colitis classification in the whole genome. Datasets downloaded from the GEO database were used to identify differentially expressed genes between ulcerative colitis patients and healthy individuals initially, followed by acquisition of the remaining ulcerative colitis -related genes from the OMIM and STRING databases. The results identified 914 ulcerative colitis-related genes, of which 60 were differentially expressed genes obtained from GEO datasets. Through weighted co-expression network analysis of ulcerative colitis-related genes, four modules were obtained, three of which were related to ulcerative colitis. Following interactions between microRNA, long noncoding RNA, transcription factors, and module hub genes were predicted and used to construct ulcerative colitis multifactor networks. Additionally, we performed consensus clustering of the ulcerative colitis samples. The results revealed that ulcerative colitis could be divided into four subtypes, with six hub genes identified as potential biomarkers for classification. These findings offer novel insights into ulcerative colitis and a basis for disease classification of ulcerative colitis.

Identification of Common Differentially Expressed Genes and Potential Therapeutic Targets in Ulcerative Colitis and Rheumatoid Arthritis.

Ulcerative colitis (UC) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases (IMIDs) with similar symptoms and common genomics. However, the relationship between UC and RA has not been investigated thoroughly. Therefore, this study aimed to establish the differentially expressed genes (DEGs) and potential therapeutic targets in UC and RA. Three microarray datasets (GSE38713, GSE1919, and GSE12251) were selected from the Gene Expression Omnibus (GEO) database for analysis. We used R software to identify the DEGs and performed enrichment analyses. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape software were used to construct the protein-protein interaction (PPI) network and identify the hub genes. A regulatory network based on the constructed PPI was generated using StarBase and PROMO databases. We identified a total of 1542 and 261 DEGs in UC and RA. There were 169 common DEGs identified in both UC and RA, including 63 upregulated genes (DEGs1) and nine downregulated genes (DEGs2). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of DEGs1 and DEGs2 in the PPI network revealed that the genes enriched were involved in immunity. A total of 45 hub genes were selected based on high scores of correlation; three hub genes (SRGN, PLEK, and FCGR3B) were found to be upregulated in UC and RA, and downregulated in UC patients with response to infliximab treatment. The identification of novel DEGs and hub genes in the current study contributes to a novel perception for latent functional mechanisms and presents potential prognostic indicators and therapeutic targets in UC and RA.

Metabolic Regulation of Group 3 Innate Lymphoid Cells and Their Role in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is characterized by chronic and relapsing inflammatory disorder of the intestine. IBD is associated with complex pathogenesis, and considerable data suggest that innate lymphoid cells contribute to the development and progression of the condition. Group 3 innate lymphoid cells (ILC3s) not only play a protective role in maintaining intestinal homeostasis and gut barrier function, but also a pathogenic role in intestinal inflammation. ILC3s can sense environmental and host-derived signals and combine these cues to modulate cell expansion, migration and function, and transmit information to the broader immune system. Herein, we review current knowledge of how ILC3s can be regulated by dietary nutrients, microbiota and their metabolites, as well as other metabolites. In addition, we describe the phenotypic and functional alterations of ILC3s in IBD and discuss the therapeutic potential of ILC3s in the treatment of IBD.

Development of a susceptibility gene based novel predictive model for the diagnosis of ulcerative colitis using random forest and artificial neural network.

Ulcerative colitis is a type of inflammatory bowel disease characterized by chronic and recurrent nonspecific inflammation of the intestinal tract. To find susceptibility genes and develop a novel predictive model of ulcerative colitis, two sets of cases and a control group containing the ulcerative colitis gene expression profile (training set GSE109142 and validation set GSE92415) were downloaded and used to identify differentially expressed genes. A total of 781 upregulated and 127 downregulated differentially expressed genes were identified in GSE109142. The random forest algorithm was introduced to determine 1 downregulated and 29 upregulated differentially expressed genes contributing highest to ulcerative colitis occurrence. Expression data of these 30 genes were transformed into gene expression scores, and an artificial neural network model was developed to calculate differentially expressed genes weights to ulcerative colitis. We established a universal molecular prognostic score (mPS) based on the expression data of the 30 genes and verified the mPS system with GSE92415. Prediction results agreed with that of an independent data set (ROC-AUC=0.9506/PR-AUC=0.9747). Our research creates a reliable predictive model for the diagnosis of ulcerative colitis, and provides an alternative marker panel for further research in disease early screening.

Transcribed ultraconserved region (T-UCR) uc.261 expression is closely correlated with disease activity and intestinal permeability in Crohn's disease.

OBJECTIVES: Transcribed ultraconserved region (T-UCR) uc.261 is reported to participate in intestinal mucosa barrier damage in Crohn's disease (CD). The aim of this study was to determine the association with disease activity and intestinal permeability. METHODS: Uc.261 level in colon mucosa and Harvey-Bradshaw Index (HBI) were evaluated in 20 active CD patients. Uc.261 expression and transepithelial electrical resistance (TEER) were determined in Caco2 and T84 cells treated with tumor necrosis factor alpha (TNF-α), respectively. Body weight, disease activity index (DAI), colon length, histological index (HI), intestinal permeability to FITC-dextran, uc.261, and tight junction proteins (TJPs) levels were evaluated in BALB/C mice treated with saline enema, trinitrobenzene sulfonic acid (TNBS)/ethanol enema, and anti-TNF-α monoclonal antibody injection, respectively. RESULTS: Uc.261 expression was overexpressed in CD patients, TNF-α treated cells, and colitis mice. Uc.261 expression was positively correlated with HBI (r = 0.582, p = 0.007) in CD patients, and positively correlated with TNF-α concentration and negatively correlated TEER in Caco2 and T84 cells (all p < 0.05). Furthermore, uc.261 was positively correlated with DAI (r = 0.824, p = 0.008), HI (r = 0.672, p = 0.021), and intestinal permeability (r = 0.636, p = 0.012), while negatively correlated with body weight (r = -0.574, p = 0.035), colon length (r = -0.866, p = 0.017), and TJP expression (all p < 0.05) in colitis mice. CONCLUSIONS: Uc.261 expression was closely correlated with disease activity and intestinal permeability in CD. Anti-TNF-α treatment may play its role through suppressing uc.261 expression in colitis mice.