Abstract Background 5-Aminosalicylates (5-ASA) are the key drugs in induction and maintenance therapy in ulcerative colitis (UC). Some UC patients are involved in 5-ASA intolerance after induction of oral 5-ASA compounds. There is no evidence of the prognosis including the risk of colectomy in 5-ASA intolerant UC patients. Methods The aim of this study is to establish the prognosis of 5-ASA intolerant UC patients in a multicenter cohort study. A retrospective review of a prospective multicenter database (2014–2018) of 1,574 UC patients was carried out and a total of 1,286 patients treated with oral 5-ASA compounds were enrolled. We compared the risk of colectomy and biologics induction between patients (i) tolerant to first 5-ASA compound (1079), (ii) intolerant to first 5-ASA compound but tolerant to other 5-ASA compound (107) and (iii) intolerant to 5-ASA compound and withdrawal of 5-ASA (100). Results We identified 1,286 patients with UC, of which 40 patients (3.1%) resulted in colectomy and 247 patients (19%) treated with biologics. Colectomy rate in patients (iii) intolerant to 5-ASA and withdrawal of 5-ASA were higher than (i) tolerant to first 5-ASA and (ii) intolerant to first 5-ASA but tolerant to other 5-ASA (9.0%, 2.7%, 1.9%, respectively). (iii) Patients withdrawal of 5-ASA showed higher risk of colectomy compared with (i) tolerant to first 5-ASA (Hazard ratio (HR) 4.71, 95% Confidence interval (CI): 2.04–10.8). The risk of colectomy among (ii) patients intolerant to first 5-ASA but tolerant to other 5-ASA showed no significant difference compared with (i) tolerant to first 5-ASA (HR 0.76, 95% CI: 0.43–1.35). The biologics induction rate in (iii) patients withdrawal of 5-ASA was significantly higher than (i) tolerant to first 5-ASA and (ii) intolerant to first 5-ASA but tolerant to other 5-ASA (37%, 18%, 16%, respectively). Also (iii) patients withdrawal of 5-ASA showed higher risk of induction with biologics compared with (i) tolerant to first 5-ASA (HR 2.35, 95% CI: 1.50–3.68). Those risk among (ii) patients intolerant to first 5-ASA but tolerant to other 5-ASA showed no significant difference compared with (i) tolerant to first 5-ASA (HR 0.76, 95% CI: 0.43–1.35). Conclusion Patients with UC who had 5-ASA intolerance and withdrew from 5-ASA showed poor prognosis. We should consider trying other 5-ASA compounds even if the patients had intolerance to one 5-ASA compound.

Abstract Background Anti-tumour necrosis factor (TNF)-α agents are the mainstay of the long-term treatments for refractory ulcerative colitis (UC). However, there is no prospective randomised controlled trial evaluating if anti-TNF-α agents can be discontinued in UC patients in remission. Methods Patients with UC maintained in clinical remission with infliximab (IFX) were prospectively enrolled from 23 specialist centres. Patients confirmed to be in (1) clinical remission for > 6 months, (2) steroid-free and (3) Mayo endoscopic subscore (MES) of 0 or 1 were randomised with stratified factors (MES and use of immunomodulators) into two groups (continue or discontinue IFX) in 1:1. The biopsy was taken from the rectum and Nancy histological Index (NI) was centrally scored at randomisation. The primary endpoint was remission rate at week 48 in full analysis set (FAS). Factors associated with remission at Week 48 were evaluated by logistic regression adjusted for the treatment group. Efficacy and safety of retreatment with IFX after relapse were also evaluated. Results A total of 92 patients were included in the FAS and the remission rates at week 48 were 80.4% (95% CI: 66.1–90.6) and 54.3% (95% CI: 39.0–69.1) in IFX-continued and IFX-discontinued groups, respectively (p = 0.008). Although the duration of IFX, use of concomitant immunomodulators, IFX concentration, and MES of 0 at randomisation were not predictive, C-reactive protein and NI were associated with remission at week 48 in FAS (p = 0.039 and 0.019, respectively). Retreatment with IFX lead to remission in 8 out of 12 patients (66.7%) in 8 weeks and was well-tolerated. Conclusion This first prospective multicentre randomised controlled trial confirmed that discontinuation of maintenance IFX resulted in the increased risk of relapse but retreatment was effective in UC. Endoscopic normalisation was not sufficient for the successful discontinuation of IFX.

Crohn’s disease (CD) is a chronic progressive inflammatory bowel disease. Assessing the severity and extent of the disease is critical to determine appropriate therapeutic strategies in patients with CD. Magnetic resonance (MR) enterography can assess both intestinal walls and extraintestinal structures without radiation exposure and anaesthesia, which makes it appropriate for repeated evaluation in CD patients. We developed novel MR enterocolonography (MREC) for simultaneously evaluating large and small intesntinal lesions of CD. The aim of this study was to establish the efficacy of the simplified 5-point MREC classification for assessing CD activity, comparing to the validated MR score of magnetic resonance index of activity (MaRIA) and endoscopic findings. A total of 120 patients (70 for derivation cohort and 50 for validation cohort) with CD were enrolled and undergone MREC and ileocolonoscopy or balloon-assisted enteroscopy (BAE). MREC results were evaluated for each bowel segment; rectum, sigmoid, descending, transverse, ascending colon, terminal, proximal ileum, and jejunum, by one observer in the derivation phase, and independently by three observers in the validation phase, using the simplified 5-point MREC (sMREC) classification lexicon and MaRIA. Areas under the receiver-operating characteristic curves (AUCs) were obtained to assess the accuracy of discriminating deep ulcers. Inter-observer reproducibility was assessed using weighted Kappa coefficients. The AUCs of sMREC classification were 89.0% in the derivation phase and 88.5, 81.0, and 77.3% for three observers in the validation phase. The AUCs of MREC classification were statistically non-inferior to those of MaRIA (p < 0.001). The cross-validation accuracy was 81.9% in the derivation and 81.5% in the validation phase. sMREC classification showed enough reproducibility. In clinical practice, scoring systems should be simple and provide appropriate levels of accuracy and reproducibility. sMREC classification met these requirements, and was demonstrated to be useful for evaluating CD activity in the large and small intestine.

Mucosal healing (MH) is a target for induction therapy in the management of ulcerative colitis (UC). MH is defined by several endoscopic examinations and correlated with long-term clinical remission. However, the relationship between endoscopic examination and prediction of relapse rate in UC management has not been fully evaluated. We compared three endoscopic scores for the usefulness of relapse prediction after 12 months of endoscopic examination in the MH and non-mucosal healing (non-MH) group in UC. We selected 51 cases of UC who underwent endoscopy at the Tokyo Medical and Dental University hospital from September 2014 to March 2017. Clinical remission was defined as partial Mayo score (pMayo) 2 or less and all other sub-scores were 1 or less. Clinical relapse was defined as introduction of new remission induction therapy. We compared three different endoscopic scores for prediction of relapse risk in UC. MH was defined in each endoscopic scores as Mayo Endoscopy sub-score (MES) 1 or less, Rachmilewitz endoscopic index (EI) 2 or less, and ulcerative colitis Endoscopic Index of Severity (UCEIS) 2 or less, with investigation for cumulative non-relapse rate. Patient background was as follows; average age was 42.9 ± 13.2 years old, 31 males and 20 females, 31 total colitis cases, 15 left-sided colitis cases, and 5 proctitis type cases, 34 clinical remission and 17 clinical non-remission, duration of disease was 9.3 ± 6.8 years. The cumulative non-relapse rate after 12 months of endoscopic examination was not significantly different in between MH group by MES at 75%, and non-MH group by MES at 52.2% (p = 0.071). Similarly, EI showed no significant difference in between MH group 76% and non-MH group 53.8% (p = 0.32). However, UCEIS showed significant difference between MH group 81.8%, and non-MH group 33.3% (p = 0.001). It was suggested that diagnosis of MH by UCEIS might be useful for prediction of cumulative non-relapse rate after 12 months of endoscopic examination.

Ulcerative colitis (UC) causes chronic inflammation and ulceration which is continuously located from rectum to colon. Recently, it has been recommended that mucosal healing is therapeutic goal of UC, however, the pathogenesis of colonic epithelial cells in UC remains unknown. The comparison of the mucosal tissues between UC patients and healthy control is not efficient to identify a fundamental difference because the difference of genetic background and inflammatory modification are not able to exclude. We therefore aimed to generate colonic organoids from both lesion and non-lesion parts of same patients by primary culture system to unify the genetic background and to avoid inflammatory modification of colonic cells. The comparison of these organoids might clarify lesion-specific pathogenesis of epithelial cells in UC. Colonic organoids were generated from both lesion (rectum) and non-lesion (ascending colon) parts of surgically resected tissue in same patients with UC. Both organoids were cultured for a month to remove the effect of inflammation in tissue before the resection. Cell proliferation were assessed by MTS assay. Phenotypic gene expression was assessed by RT-PCR. Oxidative stress of organoid is measured by using CellROX®. Candidate genes specifically expressed in the organoids derived from lesion part were selected by microarray analysis. The expression of candidate genes was confirmed by RT-PCR using lesion and non-lesion parts of surgical specimens resected from 10 patients with UC. We have established both colonic organoids generated from lesion and non-lesion parts of same UC patient. There is no significant difference of phenotypes such as stem cell and differentiation markers between these organoids. However, cell proliferation of organoids from lesion part was significantly slower than that from non-lesion part in spite of same culture condition. Moreover, oxidative stress of the organoids from lesion part is higher, suggesting that the pathogenesis of UC lesion might be maintained in the organoids from lesion part. Microarray analysis identified 22 genes upregulated in the organoids from lesion part more than 10 times compared with the organoids from non-lesion part. 16 genes downregulated in the organoids from lesion part less than one-tenth were also shown. The expression of some genes was also preserved in surgical specimens resected from 10 patients with UC. Comparison between organoids from lesion and non-lesion part of same patient might reveal the fundamental pathogenesis in intestinal epithelial cells of UC. The identification of lesion specific genes might also be useful for the elucidation of molecular mechanism and therapeutic target for mucosal healing in UC.

The patients with ulcerative colitis (UC) are at increased risk of developing colitis-associated cancer, suggesting that the effect of long-term inflammation might be important for colonic epithelial cell transformation. The transformation by long-term inflammation has however not been elucidated. We therefore have established in vitro chronic inflammation model by using mice colonic organoids (J Crohns Colitis, 2017). We then could find that colonic organoids were transformed into excessive NF-κB signal resulting in gradual induction of DUOXA2, indicating the mimic of UC. We further aimed to establish in vitro human model for UC using human primary colon organoid because human model might be more useful to assess the molecular mechanism of pathogenesis and therapeutic target for UC than in vitro mice model. This study was approved by the Ethics Committee. Human colonic organoids were generated from non-inflamed colon. The expression of cytokine receptors in the organoid was assessed by RT-PCR. The mixture of cytokines (TNF-α, IL-1β, Poly(I:C), and flagellin) were added into the medium for 12 weeks. The expression of NF-κB target genes IL-8, DUOXA2 was assessed by RT-PCR. CellROX® was used for the detection reactive oxygen species (ROS). Microarray analysis was performed after 5 weeks of inflammatory stimulation. Gene Set Enrichment Analysis (GSEA) was also performed for the comparison between organoids and colonic biopsies from active UC patients (data were acquired from GEO: GDS4365) The stimulation with each reagent showed the significant induction of IL-8 in colonic organoids. Strongest induction of IL-8 was shown by the treatment with mixture of all reagents. The expression of DUOXA2 gene was gradually increased by the continuous stimulation, suggesting that NF-κB signalling might be accumulated by the stimulating time. ROS were also induced by stimulation with cytokines. Microarray analysis showed significant induction of inflammatory signalling-related genes after 5 weeks of cytokines stimulation. We found that the highest induced gene was Claudin-18, which has been reported to be increased in UC patients. GSEA analysis showed the similarities of upregulated genes in between inflamed human organoids and mice organoids treated with inflammation for 60 weeks. Moreover, GSEA analysis showed the similarities of upregulated genes in between inflamed human organoids and biopsies from active UC patients, suggesting that the organoids might acquire UC like phenotype. Persistent inflammation into the human organoid might mimic disease history of UC. Establishment of in vitro human model for UC might be useful for developing effective therapy targeted mucosal healing and carcinogenesis.

Recent advances in the treatment of inflammatory bowel diseases has raised its therapeutic goal up to completely repairing the damaged intestinal tissue and achieve "mucosal healing". To improve and further facilitate the tissue repair process in inflammatory bowel disease patients, stem cell based therapy using mesenchymal stem cells is under development. Also, transplantation of ex-vivo cultured intestinal stem cells is another regenerative therapy that may become an alternative choice to treat refractory ulcers in inflammatory bowel disease patients. Therefore, the present review summarizes the present achievement as well as future prospects of stem cell based therapy in inflammatory bowel disease.

Mice deficient in the megakaryoblastic leukaemia 1 (Mkl1) gene experience less severe dextran sulphate sodium (DSS)-induced colitis, implying that Mkl1 plays a pathological role in inflammatory bowel disease (IBD). However, the contribution of Mkl1 to the development of colitis remains to be elucidated. The expression of Mkl1 is higher in the colonic lamina propria macrophages (LPMac) of DSS-treated mice than in those of control mice. Therefore, we established a transgenic mouse line that overexpresses human MKL1 (MKL1-Tg) specifically in cells of the monocyte/macrophage lineage, in order to investigate the potential role of macrophage MKL1 in the pathogenesis of colitis. MKL1-Tg mice displayed spontaneous colon shortening and rectal prolapse. Flow cytometric and quantitative RT-PCR analyses revealed that, in MKL1-Tg mice compared to littermate controls, the population of LPMac was decreased and had an altered inflammatory phenotype indicative of impaired anti-inflammatory properties, whereas bone marrow-derived macrophages from MKL1-Tg mice skewed towards M1 polarisation. In addition, MKL1-Tg mice had higher susceptibility to DSS-induced colitis than their littermate controls. These observations indicated that MKL1 crucially contributes to the development of colitis via the regulation of the function of macrophages, suggesting that it may be a potential therapeutic target for the prevention of IBD.

Following the success of anti-TNF antibody reagents, the development of new therapies for inflammatory bowel disease is mainly based on molecular targeted drugs. Among them, the effectiveness of therapeutic agents targeting lymphocyte migration and proinflammatory cytokines has been successful. The anti-a4β7 integrin antibody, vedolizumab, has already been used in the treatment of both ulcerative colitis and Crohn's disease in Europe and the United States. The anti-interleukin 12/23 p40 subunit, ustekinumab, was recently approved for use in the treatment of Crohn's disease in the United States. Other than those drugs, various molecular targeted drugs are currently under development. Despite the emergence of these new therapeutic agents, it is most important to appropriately use basic therapeutic drugs in the treatment of inflammatory bowel disease.

Background: Calprotectin is a calcium-binding protein that is abundantly contained in the cytoplasm of neutrophils and monocytes. It is secreted at the site of inflammation. Fecal calprotectin is a fecal biomarker used for the assessment of intestinal inflammation in patients with inflammatory bowel disease; however, the accuracy of fecal calprotectin in the evaluation of small bowel inflammation in patients with Crohn's disease (CD) is unclear. This study aimed to assess the diagnostic accuracy of fecal calprotectin to detect intestinal inflammation evaluated with small bowel balloon-assisted endoscopy (BAE) in patients with CD. Methods: This was a cross-sectional observational study involving a total of 54 patients who underwent BAE between June 2015 and October 2016 at our institution. Endoscopic severity was evaluated with modified simple endoscopic score for CD (mSES-CD), which evaluated the ileum and jejunum in addition to the terminal ileum, colon, and rectum. The severity of inflammation in each segment was evaluated with the same endoscopic parameters (0–3 for ulcer size, ulcerated/affected surface, and stenosis) as the original SES-CD. The total score of each segment was taken as the final score. Mucosal healing was defined as an mSES-CD score of 3 or less. Fecal calprotectin level was determined with EliA Calprotectin 2. Results: Among the 54 patients, 44 patients (83.0%) were male, 13 patients (24.1%) had past history of bowel resection, and 22 patients (41.5%) were treated with anti-TNF α reagents. Fecal calprotectin levels were significantly correlated with mSES-CD scores (r=0.589). In the receiver-operator curve analysis, the cut-off value of fecal calprotectin level was determined as 250 μg/g for mucosal healing. The sensitivity and specificity at this cut-off value to detect mucosal healing were 92.3% and 83.3% respectively. This cut-off value was also evaluated in 31 patients who had no large-bowel disease. The sensitivity and specificity to detect mucosal healing were 90.9% and 75.0% respectively in this subgroup. Conclusions: The levels of fecal calprotectin were correlated with the endoscopic activity assessed with BAE.

Background: Balloon-assisted enteroscopy is a useful modality for the evaluation of the small intestinal lesions in patients with Crohn's disease (CD). Not infrequently, deep insertion of the enteroscope carries difficulty due adhesion, stricture, or other causes. Deep insertion is required especial