Association of Perianal Fistulas with Clinical Features and Prognosis of Crohn's Disease in Korea: Results from the CONNECT Study

Background/Aims: The disease course and factors associated with poor prognosis in Korean patients with Crohn's disease (CD) have not been fully determined. The aim of this study was to explore potential associations between the clinical characteristics and long-term outcomes of CD and perianal fistulas in a Korean population. Methods: The retrospective Crohn's Disease Clinical Network and Cohort (CONNECT) study enrolled patients diagnosed with CD between July 1982 and December 2008 from 32 hospitals. Those followed for ＜12 months were excluded. Clinical outcomes were CD-related surgery and complications, including nonperianal fistulas, strictures, and intra-abdominal abscesses. Results: The mean follow-up period was 8.77 years (range, 1.0 to 25.8 years). A total of 1,193 CD patients were enrolled, of whom 465 (39.0%) experienced perianal fistulas. Perianal fistulizing CD was significantly associated with younger age, male gender, CD diagnosed at primary care clinics, and ileocolonic involvement. Both nonperianal fistulas (p=0.034) and intra-abdominal abscesses (p=0.020) were significantly more common in CD patients with perianal fistulas than in those without perianal fistulas. The rates of complicated strictures and CD-related surgery were similar between the groups. Independently associated factors of nonperianal fistulas were perianal fistulas (p=0.015), female gender (p=0.048), CD diagnosed at referral hospital (p=0.003), and upper gastrointestinal (UGI) involvement (p=0.001). Furthermore, perianal fistulas (p=0.048) and UGI involvement (p=0.012) were independently associated with the risk of intra-abdominal abscesses. Conclusions: Perianal fistulas predicted the development of nonperianal fistulas and intra-abdominal abscesses in Korean CD patients. Therefore, patients with perianal fistulizing CD should be carefully monitored for complicated fistulas or abscesses.ope

Melatonin controls microbiota in colitis by goblet cell differentiation and antimicrobial peptide production through Toll-like receptor 4 signalling

Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD). Although evidence supporting the anti-colitic effects of melatonin have been accumulating, it is not clear how melatonin affects the microbiota. Herein, we investigated the effects of melatonin on the microbiome in colitis and identified involvement of Toll-like receptor (TLR) 4 signalling in the effects. Melatonin improved dextran sulfate sodium (DSS)-induced colitis and reverted microbial dysbiosis in wild-type (WT) mice but not in TLR4 knockout (KO) mice. Induction of goblet cells was observed with melatonin administration, which was accompanied by suppression of Il1b and Il17a and induction of melatonin receptor and Reg3β, an antimicrobial peptide (AMP) against Gram-negative bacteria. In vitro, melatonin treatment of HT-29 intestinal epithelial cells promotes mucin and wound healing and inhibits growth of Escherichia coli. Herein, we showed that melatonin significantly increases goblet cells, Reg3β, and the ratio of Firmicutes to Bacteriodetes by suppressing Gram-negative bacteria through TLR4 signalling. Our study suggests that sensing of bacteria through TLR4 and regulation of bacteria through altered goblet cells and AMPs is involved in the anti-colitic effects of melatonin. Melatonin may have use in therapeutics for IBD.ope

Factors associated with the prescription of probiotics in patients with inflammatory bowel disease: a cross-sectional study

Background: Commensal bacteria play an important role in the pathogenesis of inflammatory bowel disease (IBD) and probiotics have been used as treatment options. We aimed to explore the current use of probiotics and factors associated with their prescription in patients with IBD. Methods: This cross-sectional study was conducted on a single hospital-based cohort. Patients were eligible if they were ≥18 years old, visited the IBD clinic as an outpatient more than twice during the study period, and had a confirmed diagnosis of IBD. Patients were divided into two groups based on the prescription of probiotics. Clinical assessments were compared between the two groups. Results: In total, 217 patients were enrolled in this study. In patients with Crohn disease (CD), moderate or severe abdominal pain; prior use of methotrexate (MTX), iron, thiopurines, or biologics; history of IBD-related surgery; and stool frequency were independently associated with the prescription of probiotics. In patients with ulcerative colitis (UC), moderate or severe abdominal pain, hematochezia, stool frequency, and moderate or severe physician global assessment score were independently associated with the prescription of probiotics. Conclusion: Increased disease activity may be associated with fewer prescriptions of probiotics in patients with IBD. However, physicians prescribed probiotics to control symptoms, such as abdominal pain and increased stool frequency in patients with UC and CD, and hematochezia in patients with UC. Additionally, the use of MTX and iron, and a history of IBD-related surgeries were associated with more frequent probiotic prescriptions in patients with CD.ope

Ternary nanocomposite carriers based on organic clay-lipid vesicles as an effective colon-targeted drug delivery system: preparation and in vitro/in vivo characterization

This study aimed to develop a new colon-targeted drug delivery system via the preparation of ternary nanocomposite carriers based on organic polymer, aminoclay and lipid vesicles. Budesonide (Bud), an anti-inflammatory drug was chosen as a model drug and encapsulated into three different formulations: liposome (Bud-Lip), aminoclay-coated liposome (AC-Bud-Lip), and Eudragit® S100-aminoclay double coated liposome (EAC-Bud-Lip). The formation of the aminoclay-lipid vesicle nanocomposite was confirmed by energy dispersive X-ray spectrum, transmission electron microscopy, and Fourier-transform infrared spectroscopy. All formulations were produced with a high encapsulation efficiency in a narrow size distribution. Drug release from EAC-Bud-Lip was approximately 10% for 2-h incubation at pH 1.2, implying the minimal drug release in acidic gastric condition. At pH 7.4, EAC-Bud-Lip underwent significant size reduction and exhibited drug release profiles similar to that from AC-Bud-Lip, implying the pH-dependent removal of the outer coating layer. Compared to free Bud solution, EAC-Bud-Lip achieved a higher drug uptake in Caco-2 cells and exhibited a stronger inhibition of TNF-α and IL-6 secretion in LPS-stimulated Raw264.7 cells. Furthermore, a bio-distribution study in mice demonstrated that Eudragit® S100-aminoclay dual coating led to a higher colonic distribution with a longer residence time, which correlated well with the delayed systemic drug exposure in rats. Taken together, the present study suggests that the ternary nanocomposite carrier consisting of Eudragit® S100, aminoclay, and lipid vesicle might be useful as an effective colon-targeted drug delivery system.ope

Crohn’s Disease Clinical Network and Cohort (CONNECT) Study: The First Step Toward Nationwide Multicenter Research of Crohn’s Disease in Korea

ope

Comparison of Long-term Outcomes of Infliximab versus Adalimumab in 1,488 Biologic-Naive Korean Patients with Crohn's Disease

Background/aims: Data on the comparative effectiveness of infliximab (IFX) or adalimumab (ADA) in patients with Crohn's disease (CD) are rare, particularly for Asian patients. We compared the key clinical outcomes (surgery, hospitalization, and corticosteroid use) of use of these two drugs in biologic-naive Korean patients with CD. Methods: Using National Health Insurance claims, we collected data on patients who were diagnosed with CD and exposed to IFX or ADA between 2010 and 2016. Results: We included 1,488 new users of biologics (1,000 IFX users and 488 ADA users). Over a median follow-up period of 2.1 years after starting biological therapy, no significant differences were found between IFX and ADA users in the risks for surgery (ADA vs IFX: adjusted hazard ratio [aHR], 1.22; 95% confidence interval [CI], 0.81 to 1.84), hospitalization (aHR, 1.02; 95% CI, 0.81 to 1.28), and corticosteroid use (aHR, 0.82; 95% CI, 0.56 to 1.19). These results were unchanged even when only patients who used biologics for over 6 months were analyzed (aHR [95% CI]: surgery, 1.31 [0.82 to 2.11]; hospitalization, 1.02 [0.80 to 1.30]; corticosteroid use, 0.80 [0.54 to 1.18]). Additionally, these results were unchanged in patients treated with biologics as monotherapy or in combination with immunomodulators. Conclusions: In this nationwide population-based study, no significant difference was found in the long-term effectiveness of IFX and ADA in the real-world setting of biologic-naive Korean patients with CD. In the absence of trials to directly compare IFX and ADA, our study indicates that the selection of one of these two biologics can be determined by patient and/or physician preference.ope

Comparison of Real-World Outcomes of Infliximab versus Adalimumab in Biologic-Naïve Korean Patients with Ulcerative Colitis: A Population-Based Study

PURPOSE: Data on the comparative effectiveness of infliximab (IFX) or adalimumab (ADA) in patients with ulcerative colitis (UC) are extremely limited, especially in the Asian population. We compared clinically important outcomes [colectomy, UC-related emergency room (ER) visits, UC-related hospitalizations, and need for corticosteroids] for these two biologics in biologic-naïve Korean patients with UC. MATERIALS AND METHODS: Using National Health Insurance claims, we collected data on patients who were diagnosed with UC and exposed to IFX or ADA between 2010 and 2016. RESULTS: A total of 862 new users of biologics were included, of whom 630 were treated with IFX and 232 were treated with ADA. Over a median follow-up of 1.8 years after starting biologic therapy, there were no significant differences in the risk of colectomy [adjusted hazard ratio (aHR), 1.87; 95% confidence interval (CI), 0.30-11.63], ER visits (aHR, 1.58; 95% CI, 0.79-3.16), hospitalizations (aHR, 0.83; 95% CI, 0.59-1.17), and corticosteroid use (aHR, 1.16; 95% CI, 0.76-1.78) between IFX and ADA users. These results were stable even when only patients who used biologics for ≥6 months were analyzed. Additionally, these results were unchanged in patients treated with biologic monotherapy or combination therapy with immunomodulators. CONCLUSION: In this nationwide population-based study, there was no significant difference in the risk of colectomy, ER visits, hospitalizations, and corticosteroid use between IFX and ADA users. Our findings indicate that IFX and ADA have comparable effectiveness in biologic-naïve Korean patients with UC.ope

Lactobacillus plantarum CBT LP3 ameliorates colitis via modulating T cells in mice

Lactobacillus plantarum has been identified as a probiotic bacterium owing to its role in immune regulation and maintenance of intestinal permeability. Here, we investigated the anti-colitic effects and mechanism of L. plantarum CBT LP3 (LP3). This in vivo study was performed using dextran sodium sulfate (DSS) to induce colitis in mice. Mice were randomly divided into three groups: a control supplied with normal drinking water, a DSS-treated group followed by oral administration of vehicle, and a DSS-treated group gavaged with LP3 daily for 7 days following DSS administration. An analysis of macrophages and T cell subsets harvesting from peritonium cavity cells and splenocytes was performed using a flow cytometric assay. Gene expression and cytokine profiles were measured using quantitative reverse transcriptase polymerase chain reaction. The administration of LP3 significantly attenuated disease activity and histolopathology compared to control. LP3 had anti-inflammatory effects, with increased induction of regulatory T cells and type 2 helper T cells in splenocytes and restoration of goblet cells accompanied by suppression of proinflammatory cytokine expressions. These findings suggest that L. plantarum CBT LP3 can be used as a potent immunomodulator, which has significant implications for IBD treatment.ope

Is fasting beneficial for hospitalized patients with inflammatory bowel diseases?

BACKGROUND/AIMS: Patients with inflammatory bowel disease (IBD) are usually hospitalized because of aggravated gastrointestinal symptoms. Many clinicians empirically advise these patients to fast once they are admitted. However, there has been no evidence that maintaining a complete bowel rest improves the disease course. Therefore, we aimed to investigate the effects of fasting on disease course in admitted patients with IBD or intestinal Behçet's disease. METHODS: A total of 222 patients with IBD or intestinal Behçet's disease, who were admitted for disease-related symptoms, were retrospectively analyzed. We divided them into 2 groups: fasting group (allowed to take sips of water but no food at the time of admission) and dietary group (received liquid, soft, or general diet). RESULTS: On admission, 124 patients (55.9%) started fasting and 98 patients (44.1%) started diet immediately. Among patients hospitalized through the emergency room, a significantly higher proportion underwent fasting (63.7% vs. 21.4%, P<0.001); however, 96.0% of the patients experienced dietary changes. Corticosteroid use (P<0.001; hazard ratio, 2.445; 95% confidence interval, 1.506-3.969) was significantly associated with a reduction in the disease activity score, although there was no significant difference between the fasting group and the dietary group in disease activity reduction (P=0.111) on multivariate analysis. CONCLUSIONS: In terms of disease activity reduction, there was no significant difference between the fasting and dietary groups in admitted patients with IBD, suggesting that imprudent fasting is not helpful in improving the disease course. Therefore, peroral diet should not be avoided unless not tolerated by the patient.ope

A transepithelial pathway delivers succinate to macrophages, thus perpetuating their pro-inflammatory metabolic state

The gut metabolite composition determined by the microbiota has paramount impact on gastrointestinal physiology. However, the role that bacterial metabolites play in communicating with host cells during inflammatory diseases is poorly understood. Here, we aim to identify the microbiota-determined output of the pro-inflammatory metabolite, succinate, and to elucidate the pathways that control transepithelial succinate absorption and subsequent succinate delivery to macrophages. We show a significant increase of succinate uptake into pro-inflammatory macrophages, which is controlled by Na+-dependent succinate transporters in macrophages and epithelial cells. Furthermore, we find that fecal and serum succinate concentrations were markedly augmented in inflammatory bowel diseases (IBDs) and corresponded to changes in succinate-metabolizing gut bacteria. Together, our results describe a succinate production and transport pathway that controls the absorption of succinate generated by distinct gut bacteria and its delivery into macrophages. In IBD, this mechanism fails to protect against the succinate surge, which may result in chronic inflammation.ope