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.

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.

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.

Low-dose penicillin exposure in early life decreases Th17 and the susceptibility to DSS colitis in mice through gut microbiota modification.

Antibiotic exposure in early life can lead to a significant change of the gut microbiota and may contribute to later onset of inflammatory bowel disease (IBD). However, the relationship between early-life antibiotic treatment and IBD is ambiguous, according to contradicting results of epidemiologic studies. In the present study, we demonstrated that low-dose penicillin pre-treatment had a unique protective effect against mouse colitis induced by dextran sodium sulfate (DSS). Low-dose penicillin also suppressed the expression of pro-inflammatory cytokine IL-17 in various intestinal tissues, and decreased the amount of Th17 cells in small-intestine lamina propria. Neither metronidazole nor enrofloxacin had a similar effect. We further confirmed that low-dose penicillin could cause specific changes of the gut microbiota, especially the eradication of segmented filamentous bacteria (SFB). Mice without SFB inoculation showed no disparity when treated with penicillin or water. Taken together, the results showed that low-dose penicillin can achieve a highly specific manipulation of sensitive bacteria and interfere with development of intestinal immune system in early life. The study may further indicate the possibility of achieving a favorable immune state among a certain group of patients with IBD, or other autoimmune diseases, by fine-tuning the gut microbiota.

Vancomycin pre-treatment impairs tissue healing in experimental colitis: Importance of innate lymphoid cells.

BACKGROUND AND AIMS: The interplay between luminal microbes and innate immunity during colonic epithelial repair has been well noted. At the same time, antibiotic has widely been used during flare-ups of ulcerative colitis. The possible effects of luminal microbiota disruption caused by antibiotics usage on epithelial repairing have been scarcely discussed. Innate lymphoid cells (ILCs) embedded in the lamina propria can be modulated by gut microbes, resulting in altered colonic IL-22/pSTAT3 levels, which is considered a prominent molecular axis in tissue repairing after epithelium damage. This study aimed to investigate whether antibiotics could interfere with ILCs-dependent tissue repair. METHODS: Dextran sodium sulfate (DSS)-induced colitis was established in mice pre-treated with reagent of different antibiotic spectrum. Both morphological and molecular markers of tissue repair after DSS cessation were detected. ILCs population and function status were also recorded. Further attention was paid to the response of dendritic cells after antibiotics treatment, which were claimed to regulate colonic ILC3s in an IL-23 dependent way. RESULTS: Using of vancomycin resulted in delayed tissue repairing after experimental colitis. Both colonic IL-22/pSTAT3 axis and ILC3 population were found decreased in this situation. Vancomycin treatment diminished the upstream IL-23 and producer dendritic cell population. The reduced dendritic cell number may due to inadequate chemokines and colony-stimulating factors supply. CONCLUSION: Presence of vancomycin-sensitive microbiota is required for the maturation of ILC3-activating dendritic cells hence maintain the sufficient IL-22/pSTAT3 level in the colon during tissue healing. Manipulation of colonic microbiota may help achieve colonic mucosal healing post inflammation and injury.