Severe Ulcerative Colitis Research Articles

Beneficial Effect of Faecal Microbiota Transplantation on Mild, Moderate and Severe Dextran Sodium Sulphate-Induced Ulcerative Colitis in a Pseudo Germ-Free Animal Model.

Transplantation of faecal microbiota (FMT) is generally considered a safe therapeutic procedure with few adverse effects. The main factors that limit the spread of the use of FMT therapy for idiopathic inflammatory bowel disease (IBD) are the necessity of minimising the risk of infection and transfer of another disease. Obtaining the animal model of UC (ulcerative colitis) by exposure to DSS (dextran sodium sulphate) depends on many factors that significantly affect the result. Per os intake of DSS with water is individual for each animal and results in the development of a range of various forms of induced UC. For this reason, the aim of our study was to evaluate the modulation and regenerative effects of FMT on the clinical and histopathological responses and the changes in the bowel microenvironment in pseudo germ-free (PGF) mice of the BALB/c line subjected to chemical induction of mild, moderate and serious forms of UC. The goal was to obtain new data related to the safety and effectiveness of FMT that can contribute to its improved and optimised use. The animals with mild and moderate forms of UC subjected to FMT treatment exhibited lower severity of the disease and markedly lower damage to the colon, including reduced clinical and histological disease index and decreased inflammatory response of colon mucosa. However, FMT treatment failed to achieve the expected therapeutic effect in animals with the serious form of UC activity. The results of our study indicated a potential safety risk involving development of bacteraemia and also translocation of non-pathogenic representatives of bowel microbiota associated with FMT treatment of animals with a diagnosed serious form of UC.

Tofacitinib in Acute Severe Ulcerative Colitis (TACOS): A Randomized Controlled Trial.

Intravenous corticosteroids are the mainstay of treatment of patients hospitalized with acute severe ulcerative colitis (ASUC). However, 30%-40% of the patients are refractory to corticosteroids. We investigated whether addition of tofacitinib to corticosteroids improved the treatment responsiveness in patients with ASUC. This single-center, double-blind, placebo-controlled trial randomized adult patients with ASUC (defined by the Truelove Witts severity criteria) to receive either tofacitinib (10 mg thrice daily) or a matching placebo for 7 days while continuing intravenous corticosteroids (hydrocortisone 100 mg every 6 hours). The primary end point was response to treatment (decline in the Lichtiger index by >3 points and an absolute score <10 for 2 consecutive days without the need for rescue therapy) by day 7. The key secondary outcome was the cumulative probability of requiring initiation of infliximab or undergoing colectomy within 90 days following randomization. All analyses were performed in the intention-to-treat population. A total of 104 patients were randomly assigned to a treatment group (53 to tofacitinib and 51 to placebo). At day 7, response to treatment was achieved in 44/53 (83.01%) patients receiving tofacitinib vs 30/51 (58.82%) patients receiving placebo (odds ratio 3.42, 95% confidence interval 1.37-8.48, P = 0.007). The need for rescue therapy by day 7 was lower in the tofacitinib arm (odds ratio 0.27, 95% confidence interval 0.09-0.78, P = 0.01). The cumulative probability of need for rescue therapy at day 90 was 0.13 in patients who received tofacitinib vs 0.38 in patients receiving placebo (log-rank P = 0.003). Most of the treatment-related adverse effects were mild. One patient, receiving tofacitinib, developed dural venous sinus thrombosis. In patients with ASUC, combination of tofacitinib and corticosteroids improved treatment responsiveness and decreased the need for rescue therapy.

Comparison of accelerated and standard infliximab induction regimens in acute severe ulcerative colitis using propensity score analysis: a retrospective multicenter study in China

Comparison of accelerated and standard infliximab induction regimens in acute severe ulcerative colitis using propensity score analysis: a retrospective multicenter study in China

Cyclosporine A alleviates colitis by inhibiting the formation of neutrophil extracellular traps via the regulating pentose phosphate pathway

BackgroundThe aberrant formation of neutrophil extracellular traps (NETs) has been implicated in ulcerative colitis (UC), a chronic recurrent intestinal inflammation. Cyclosporine A (CsA) is now applied as rescue therapy for acute severe UC. In addition, it has been certained that CsA inhibits the formation of NETs in vitro and the mechanism of which was still vague. The study aimed to explore the mechanism CsA inhibits the NETs formation of colitis in vivo and in vitro.MethodsNETs enrichment in clinical samples was analyzed using databases from Gene Expression Omnibus and verified in our center. Dextran sulfate sodium (DSS)-induced acute colitis mice model was used to investigate the effect of CsA on NETs of colonic tissue expression. To clarify the mechanism, intracellular energy metabolites were examined by Liquid Chromatograph Mass Spectrometer, and reactive oxygen species (ROS) levels were examined by fluorescence intensity in neutrophils treated with CsA after LPS stimulation. The transcriptional level and activity of G6PD of neutrophils were also assessed using qRT-PCR and WST-8. RNA Sequencing was used to detect differentially expressed genes of neutrophils stimulated by LPS with or without CsA. The expression levels of related proteins were detected by western blot.ResultsNETs enrichment was especially elevated in moderate-to-severe UC patients compared to HC. NETs expression in the colon from DSS colitis was decreased after CsA treatment. Compared with neutrophils stimulated by LPS, NETs formation and cellular ROS levels were decreased in LPS + CsA group. Cellular ribulose 5-phosphate and NADPH/NADP + related to the pentose phosphate pathway (PPP) were reduced in LPS + CsA group. In addition, CsA could decrease G6PD activity in neutrophils stimulated with LPS, and the results were further verified by inhibiting G6PD activity. At last, P53 protein was highly expressed in LPS + CsA group compared with the LPS group. Intracellular G6PD activity, ROS level and NETs formation, which were downregulated by CsA, could be reversed by a P53 inhibitor.ConclusionOur results indicated CsA could alleviate the severity of colitis by decreasing the formation of NETs in vivo. In vitro, CsA reduced ROS-dependent NETs release via downregulating PPP and cellular ROS levels by decreasing G6PD activity directly by activating the P53 protein.

Gut microbiota-derived 12-ketolithocholic acid suppresses the IL-17A secretion from colonic group 3 innate lymphoid cells to prevent the acute exacerbation of ulcerative colitis

ABSTRACT Intestinal microbiota dysbiosis and metabolic disruption are well-known as the primary triggers of ulcerative colitis (UC). However, their role in regulating the group 3 innate lymphoid cells (ILC3s), which are essential for intestinal health, remains unexplored during the development of disease severity. Here, our results showed that the microbiota structure of patients with severe UC (SUCs) differed from those with mild UC (MiUCs), moderate UC (MoUCs), and healthy controls (HCs). Microbes producing secondary bile acids (SBAs) and SBAs decreased with the aggravation of UC, and a strong positive correlation existed between them. Next, fecal microbiota transfer was used to reproduce the human-derived microbiota in mice and decipher the microbiota-mediated inflammatory modulation during an increase in disease severity. Mice receiving SUC-derived microbiota exhibited enhancive inflammation, a lowered percentage of ILC3s, and the down-regulated expressions of bile acid receptors, including vitamin D receptor (VDR) and pregnane X receptor (PXR), in the colon. Similar to clinical results, SBA-producing microbes, deoxycholic acids (DCA), and 12-ketolithocholic acids (12-KLCA) were diminished in the intestine of these recipients. Finally, we compared the therapeutic potential of DCA and 12-KLCA in preventing colitis and the regulatory mechanisms mediated by ILC3s. 12-KLCA but not DCA represented a strong anti-inflammatory effect associated with the higher expression of VDR and the lower secretion of IL-17A from colonic ILC3s. Collectively, these findings provide new signatures for monitoring the acute deterioration of UC by targeting gut microbiota and bile acid metabolism and demonstrate the therapeutic and preventive potential of a novel microbiota-derived metabolite, 12-KLCA.

Comparing the Efficacy and Safety of Adalimumab and Vedolizumab in Treating Moderate to Severe Crohn's Disease and Ulcerative Colitis.

Numerous patients with inflammatory bowel disease (IBD) do not respond to conventional or biological therapy. Adalimumab (ADA) and vedolizumab (VDZ), according to certain research, may be a useful alternative treatment for these people. The purpose of this study was to assess the effectiveness and safety of using ADA and VDZ to treat moderate to severe IBD: Crohn's disease (CD) and ulcerative colitis (UC). We searched PubMed, Medline, Web of Science, Scopus, the Cochrane Library, Embase, Google Scholar, CINAHL, Clinicaltrials.gov, and WHO trials registry (ICTRP). Randomized controlled trials (RCTs) comparing ADA or VDZ with placebo in participants with active CD or UC were included. The primary outcomes were the clinical response and remission at induction and maintenance phases and mucosal healing. The secondary outcome was the incidence of profound negative events. The research used Comprehensive Meta-Analysis version 3 (Biostat Inc., USA). Eighteen RCTs were incorporated, in which 11 studies described the usefulness and safeness of ADA or VDZ in CD patients, and seven studies investigated the efficacy and safety of ADA or VDZ in UC patients. The meta-analysis revealed that both ADA and VDZ treatments were superior to placebo for producing clinical remission and eliciting clinical response at induction and maintenance phases in individuals with moderately to severely active CD or UC. Interestingly, we found that ADA was superior to VDZ as first-line treatment for patients with CD, but not UC. ADA and VDZ are effective and safe in CD and UC patients. However, RCTs of a larger number of patients are still required for better assessing the safety profile of ADA and VDZ.

S88 Real-Life Experience of Tofacitinib in Colombian Patients With Severe Acute Ulcerative Colitis: An Observational Study

S88 Real-Life Experience of Tofacitinib in Colombian Patients With Severe Acute Ulcerative Colitis: An Observational Study

S87 Use of Tofacitinib as an Alternative in Moderately Severe Ulcerative Colitis in Pediatric Patients Refractory to Tumor Necrosis Factor Inhibitor Therapy

S87 Use of Tofacitinib as an Alternative in Moderately Severe Ulcerative Colitis in Pediatric Patients Refractory to Tumor Necrosis Factor Inhibitor Therapy

S13 Methodological Considerations of Network Meta-Analyses: Improving Evaluation of Comparative Effectiveness and Safety of Advanced Therapies Treating Moderate to Severe Ulcerative Colitis

S13 Methodological Considerations of Network Meta-Analyses: Improving Evaluation of Comparative Effectiveness and Safety of Advanced Therapies Treating Moderate to Severe Ulcerative Colitis

EE177 Cost-Effectiveness Modelling in Moderate to Severe Ulcerative Colitis: Novel Approaches to Capture Variable Induction Periods, Treatment Sequences, and Variable Treatment Cycle Lengths

EE177 Cost-Effectiveness Modelling in Moderate to Severe Ulcerative Colitis: Novel Approaches to Capture Variable Induction Periods, Treatment Sequences, and Variable Treatment Cycle Lengths

S28 Intestinal Ultrasound in Severe Ulcerative Colitis Treated With Intravenous Cyclosporine

S28 Intestinal Ultrasound in Severe Ulcerative Colitis Treated With Intravenous Cyclosporine

S2 Efficacy and Safety of Icanbelimod (CBP-307) in Adults With Moderate to Severe Ulcerative Colitis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial

S2 Efficacy and Safety of Icanbelimod (CBP-307) in Adults With Moderate to Severe Ulcerative Colitis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial

CO83 Disease Burden of Moderate to Severe Ulcerative Colitis in Chinese Patients Under Current Care: A Model Simulation Study

CO83 Disease Burden of Moderate to Severe Ulcerative Colitis in Chinese Patients Under Current Care: A Model Simulation Study

S34 Intestinal Ultrasound to Assess Clinical Response After Induction With Upadacitinib in Acute Severe Ulcerative Colitis

S34 Intestinal Ultrasound to Assess Clinical Response After Induction With Upadacitinib in Acute Severe Ulcerative Colitis

Metabolic stress in patients with acute severe ulcerative colitis - A single-center cohort study

Metabolic stress in patients with acute severe ulcerative colitis - A single-center cohort study

Role of ustekinumab in treatment of ulcerative colitis: a narrative review.

The therapeutic armamentarium for gastroenterologists in treating ulcerative colitis (UC) has been rapidly growing since the introduction of monoclonal antibodies directed against anti-TNFs. Ustekinumab is a monoclonal antibody binding the shared p40 subunit of IL-12and IL-23, and the inhibition of these two cytokines, implicated in host response to microbial pathogens, has demonstrated clinical efficacy in different immune-mediated diseases, including moderate-to-severe UC. This narrative review summarizes the newest clinical evidence regarding the efficacy, effectiveness and safety of ustekinumab in moderate-to-severe UC, including specific situations (pregnancy, breastfeeding, elderly/pediatric populations, extraintestinal manifestations, acute severe UC, pouchitis anddual biological therapy). Finally, positioning is discussed in light of the existing evidence.

Clinical importance of weight gain and associated factors in patients with moderate to severe ulcerative colitis: results from the MOSAIK cohort in Korea

BackgroundMany patients with ulcerative colitis (UC) gain weight after treatment. However, the clinical significance of weight gain in these patients remains unclear. This study aimed to evaluate body weight changes after treatment in patients newly diagnosed with moderate-to-severe UC and their effects on patients’ prognosis.MethodsThe change in weight between diagnosis and 1 year after treatment in 212 patients enrolled in the MOSAIK cohort (mean age, 40 years; males, 60%) was analyzed. Significant weight gain was defined as a weight increase of ≥ 5% from the baseline at 1 year. Factors associated with significant weight gain and the effect of significant weight gain on the risk of major adverse outcomes (clinical relapse, hospitalization, and new use of steroids or biologics) during a follow-up period of 20 months were evaluated.ResultsMean weight gain at 1 year was 1.7 ± 4.2 kg. The proportion of overweight/obese patients increased by 9.0% from 37.9% to 46.9%. Thirty-two percent had significant weight gain; extensive colitis at diagnosis was the only factor associated with significant weight gain (odds ratio 6.5, 95% confidence interval 1.4–31.0, p = 0.006). In multivariable analysis, significant weight gain was not associated with the risk of major adverse outcomes. Weight loss symptoms at diagnosis were associated with an increased risk for new steroid use after 1 year.ConclusionsApproximately one-third of patients with moderate-to-severe UC had significant weight gain after 1 year of treatment. However, significant weight gain was not associated with the patient’s prognosis.

Development and validation of a risk model to predict the progression of ulcerative colitis patients to acute severe disease within one year

ABSTRACT Background and aims Acute severe ulcerative colitis (ASUC) is strongly associated with poor prognosis. We aimed to establish and validate a model predicting ASUC occurrence within 1 year after ulcerative colitis(UC) diagnosis. Methods A cohort of UC patients diagnosed between 2018 and 2020 at Northern Jiangsu People’s Hospital, who were followed up for one year, was used to develop a risk prediction model. An independent cohort from January to December 2021, monitored until December 2022 at the at the First Affiliated Hospital of Nanjing Medical University, was used for external validation. A multivariable logistic regression analysis was conducted to investigate the adjusted association between six risk factors and ASUC. Subsequently, a simplified model was developed by eliminating a relatively insignificant risk factor to create an easy-to-use index. Results The prediction model incorporates five parameters: disease extent, endoscopic appearance, histopathology, baseline response medication, and relapse frequency. It generates a nomogram in the end. The discriminant ability (c-index) was separately calculated as 0.982 and 0.925 in the development and validation cohorts. Conclusions The risk prediction model for developing ASUC within one year demonstrated excellent reliability and validity, which could be a straightforward and clinically valuable tool for predicting ASUC occurrence within 1 year. Clinical trial registration ChiCTR2300071794

Exclusive Enteral Nutrition Mediates Beneficial Gut Microbiome Enrichment in Acute Severe Colitis.

Exclusive enteral nutrition (EEN) supplementation of the standard of care (SOC) augments steroid responsiveness in patients with acute severe ulcerative colitis (ASUC). EEN is known to alter gut microbial composition. The present study investigates EEN-driven gut microbial alterations in patients with ASUC and examines their correlations with clinical parameters. Stool samples from patients with ASUC (n = 44) who received either EEN-supplemented SOC (EEN group; n = 20) or SOC alone (SOC group; n = 24) for 7 days were collected at baseline (day 0) and postintervention (day 7). Microbiome analysis was carried out using 16S ribosomal RNA gene sequencing followed by data processing using QIIME2 and R packages. Seven-day EEN-conjugated corticosteroid therapy in patients with ASUC enhanced the abundances of beneficial bacterial genera Faecalibacterium and Veillonella and reduced the abundance of Sphingomonas (generalized linear model fitted with Lasso regularization with robustness of 100%), while no such improvements in gut microbiota were observed in the SOC group. The EEN-associated taxa correlated with the patient's clinical parameters (serum albumin and C-reactive protein levels). Unlike the SOC group, which retained its preintervention core microbiota, EEN contributed Faecalibacterium prausnitzii, a beneficial gut bacterial taxon, to the gut microbial core. EEN responders showed enhancement of Ligilactobacillus and Veillonella and reduction in Prevotella and Granulicatella. Analysis of baseline gut microbiota showed relative enhancement of certain microbial genera being associated with corticosteroid response and baseline clinical parameters and that this signature could conceivably be used as a predictive tool. Augmentation of clinical response by EEN-conjugated corticosteroid therapy is accompanied by beneficial gut microbial changes in patients with ASUC.

ENTERPRET: A Randomized Controlled Trial of Vedolizumab Dose Optimization in Patients With Ulcerative Colitis Who Have Early Nonresponse

BACKGROUND & AIMSPatients with ulcerative colitis (UC) may experience nonresponse to biologics, possibly due to low drug exposure. This trial assessed the efficacy of dose optimization in patients with UC who have early nonresponse to vedolizumab and high drug clearance. METHODSENTERPRET was a phase 4, open-label, randomized controlled trial that included patients with moderate to severe UC who had high drug clearance at week 5 (serum concentration <50 μg/mL) and nonresponse to standard vedolizumab treatment at week 6. At week 6, eligible patients were randomized 1:1 to receive standard dosing (300 mg every 8 weeks) or dose-optimized vedolizumab (600 mg at week 6, then 300 mg every 4 weeks; or 600 mg at week 6, then 600 mg every 4 weeks [based on week 5 serum concentration]). The primary end point was endoscopic improvement at week 30. RESULTSOf 278 enrolled patients, 132 (47.5%) had a clinical response at week 6. From week 6, 108 patients received standard (n = 53) or dose-optimized vedolizumab (n = 55); among patients with nonresponse at week 6, 86.5% had high drug clearance. At week 30, 10 patients (18.9%) who received standard vedolizumab had endoscopic improvement versus 8 patients (14.5%) who received dose-optimized vedolizumab. Five patients (9.4%) who received standard vedolizumab had clinical remission at week 30 versus 5 patients (9.1%) who received dose-optimized vedolizumab; clinical response was observed in 17 (32.1%) and 17 patients (30.9%), respectively. Safety event rates were similar among treatment groups. CONCLUSIONSIn patients with early nonresponse and high drug clearance, vedolizumab dose optimization is probably not required. A proportion of patients benefited from continued treatment irrespective of the dose received. ClinicalTrials.gov Number: NCT03029143.