IL-33-induced signals via membrane-bound ST2 (ST2L) are critical for allergies. However, the physiological role of endogenous soluble ST2 (sST2) remains elusive. Here, we generated sST2-deficient mice with intact ST2L using the CRISPR/Cas9 system. Skin fibroblasts constitutively released sST2 protein at extremely high levels compared to mast cells, which did not reflect the expression levels of sST2 mRNA. This discrepancy can be partly explained by the sST2 protein degradation mediated by mast cell proteases. Accordingly, sST2 deficiency did not affect IL-33- and/or IgE plus antigen-stimulated mast cell activation in vitro. We provided evidence that constitutively high levels of sST2 suppress food allergies in mice by inhibiting IL-33-dependent, both expansion of jejunum mast cells and enhancement of their degranulation. Analysis of bone marrow chimeric mice under steady-state conditions showed that circulating sST2 was derived almost equally from hematopoietic and nonhematopoietic cells. Increased circulating sST2 in food-allergic mice was possibly and partly derived from fibroblasts stimulated by locally released IL-4 and IL-13. In conclusion, endogenous sST2 contributes to the suppression of food allergies.

BACKGROUND:Endoscopic healing is a key therapeutic target for Crohn's disease (CD). However, endoscopy is invasive, and simple, non-invasive biomarkers are needed to assess endoscopic healing. Although leucine-rich alpha-2 glycoprotein (LRG) and fecal calprotectin (FC) are indicators of inflammatory bowel disease activity, few studies have directly compared them for endoscopic disease activity in CD. We aimed to compare the ability of these markers to assess endoscopic remission in CD. METHODS:From October 2022 to December 2023, 100 patients with CD at Nagoya University Hospital were prospectively and consecutively enrolled. Endoscopic activity was assessed using the applied simple endoscopic score for Crohn's disease (aSES-CD), incorporating small bowel lesions. The primary endpoint was the sensitivity of LRG and FC in endoscopic remission (aSES-CD ≤ 3), which was tested using McNemar's exact test. Logistic regression analysis was used to identify factors associated with endoscopic remission. RESULTS:Overall, 84 patients were analyzed (79.8% male; median age 49.5 years). The receiver operating characteristic curve analysis yielded sensitivity/specificity values of 85.9%/90.0% for LRG and 70.3%/85.0% for FC, using cutoff values of 11 µg/mL (LRG) and 100 µg/g (FC) for endoscopic remission. Based on these values, a comparison of sensitivities between LRG and FC showed that LRG had significantly higher sensitivity (P = .013). In multivariate analysis, only LRG was an independent factor for endoscopic remission (odds ratio 3.016; 95% CI, 1.506-6.037). CONCLUSIONS:Compared with FC, LRG shows a higher sensitivity for assessing endoscopic remission. LRG may serve as a useful biomarker for endoscopic activity in CD.

INTRODUCTION:Risankizumab (RZB), an IL-23p19 monoclonal antibody, has demonstrated clinical efficacy in Crohn's disease (CD), yet evidence regarding its effectiveness for deep small-intestinal lesions remains scarce. These lesions are often underdiagnosed due to limited accessibility and subtle clinical presentation. METHODS:We retrospectively analyzed 32 patients with moderate-to-severe CD who underwent total small-intestinal evaluation by double-balloon endoscopy (DBE) both before and 8-14 months after RZB initiation in clinical practice. Endoscopic disease activity was assessed using the modified Simple Endoscopic Score for Crohn's Disease (mSES-CD). Clinical response (Crohn's Disease Activity Index [CDAI]), biomarker changes (C-reactive protein, leucine-rich alpha-2 glycoprotein), and endoscopic outcomes were evaluated. RESULTS:Mean mSES-CD significantly decreased from 14.3 to 8.2 (p < 0.001), indicating substantial mucosal improvement, particularly in the jejunum and deep ileum. Endoscopic remission (mSES-CD <2) was achieved in 13.3% of patients. Clinical remission (CDAI <150) occurred in 80% at week 12 and was sustained in 56% at 1 year. Significant biomarker improvements were observed. No progression of strictures was seen during follow-up. CONCLUSION:This study confirms the therapeutic efficacy of RZB for deep small-intestinal involvement in CD based on comprehensive DBE assessment. The results support the clinical utility of RZB in patients with refractory small-intestinal lesions, highlighting its potential to maintain 1 year disease control when ongoing mucosal inflammation is a concern. These findings underscore the importance of deep enteroscopic evaluation to optimize therapeutic strategies.

INTRODUCTION:Mirikizumab (MIR), a selective IL-23p19 inhibitor, has shown efficacy in clinical trials for ulcerative colitis (UC). However, real-world data, especially on long-term outcomes and in treatment-experienced populations, remain limited. METHODS:We conducted a multicenter retrospective cohort study involving 85 patients with moderate-to-severe UC who initiated MIR between July 2023 and December 2024 across 12 Japanese centers. Co-primary endpoints were clinical remission (Simple Clinical Colitis Activity Index [SCCAI] ≤2 and with no rectal bleeding) at weeks 12 and 52. Secondary outcomes included corticosteroid (CS)-free remission, C-reactive protein normalization, treatment persistence, and safety. RESULTS:Clinical remission was achieved in 62.4% at week 12 and 55.3% at week 52. CS-free remission rates were identical to overall remission at both time points. MIR maintained effectiveness regardless of prior exposure to biologics or JAK inhibitors. Early clinical response at week 4 independently predicted week 52 remission, while steroid dependence was a predictor at week 12. Among patients receiving extended induction, 27.3% of initial nonresponders achieved remission by week 24. Treatment was generally well tolerated, with 17.6% experiencing adverse events and 9.4% discontinuing due to these events. No serious infections or hospitalizations occurred. CONCLUSION:MIR demonstrated durable effectiveness and a favorable safety profile over 52 weeks in a real-world UC population, including those with prior treatment failures. These findings support MIR as a viable long-term therapeutic option in routine clinical practice.

ObjectiveUlcerative colitis-associated neoplasia (UCAN) and sporadic neoplasia require different treatment strategies; their differential diagnosis is based on endoscopic findings and biopsy results. However, accurate diagnosis is sometimes difficult. Similarly, it is often challenging to evaluate invasion depth. Recently, their diagnosis has become possible pathologically, following endoscopic UCAN resection. This study investigated whether endoscopic submucosal dissection (ESD) is useful as a treatment or diagnostic (total biopsy) modality for neoplastic lesions within the inflammatory region in patients with ulcerative colitis.MethodsWe retrospectively reviewed the characteristics, accuracy of endoscopic diagnosis, results of ESD, adverse events, and changes in therapeutic strategy after ESD for 27 neoplastic lesions (15 UCANs and 12 sporadic neoplasias) occurring within the inflammatory region of ulcerative colitis in patients at our institution between January 2016 and September 2023.ResultsUCANs had significantly more non-polypoid morphology (P = 0.037) and inflammation around the neoplasia (P = 0.010). The diagnostic accuracy for low-grade dysplasia was higher in sporadic neoplasias than in UCANs. ESD results (en bloc resection/R0 resection) were similar between UCANs (100%/86.7%) and sporadic neoplasias (91.7%/83.3%). The incidence of intraoperative perforation and delayed bleeding was comparable. In eight lesions (29.6%), accurate pathological diagnosis via ESD prompted changes in the pre-ESD treatment strategy. Notably, surgical resection was avoided in three lesions (11.1%), including one UCAN lesion reclassified from high-grade dysplasia to low-grade dysplasia and two sporadic neoplasia lesions initially diagnosed as UCANs.ConclusionESD results of patients with ulcerative colitis were acceptable. ESD may be a useful modality for optimal treatment planning.

INTRODUCTION:Given the safety concerns associated with the long-term use of Janus kinase (JAK) inhibitors, establishing effective "exit strategies" is crucial for patients with ulcerative colitis (UC). This study investigated the efficacy and safety of switching from tofacitinib (TOF) or upadacitinib (UPA) to the JAK1-selective filgotinib (FIL) in patients maintaining remission. METHODS:We conducted a retrospective, multicenter study involving 13 UC patients who achieved clinical remission with TOF or UPA and subsequently switched to FIL. The primary endpoint was the cumulative non-relapse rate. RESULTS:During a median follow-up of 679 days, symptomatic relapse occurred in 53.8% (7/13) of patients. The 1-year cumulative non-relapse rate was 71.4% for the TOF-switch group and 31.3% for the UPA-switch group. However, many relapses were successfully managed through temporary treatment adjustments, including FIL dose escalation or topical therapy. No serious adverse events were recorded. CONCLUSION:Sequential switching to FIL may represent a practical intermediate maintenance strategy before complete drug withdrawal, balancing disease control with potential safety benefits.

Dysfunctional intestinal fibrosis is an irreversible complication of Crohn’s disease (CD). The complex heterogeneity of intestinal mesenchymal cells makes it difficult to understand the pathogenesis of intestinal fibrosis. Previously, we identified Meflin as a marker of fibroblast subsets. This study aimed to explore the role of Meflin-positive fibroblasts in intestinal fibrogenesis and investigate the potential of pharmacological control of Meflin expression as a treatment for patients with CD. Our results indicated that Meflin expression was upregulated in fibroblasts at the early stage of fibrosis but was downregulated in established fibrosis in both patients with CD and 2 different mouse models, which are the chronic dextran sodium sulfate (DSS) model and an IL-10–deficient model that spontaneously develops intestinal inflammation. Meflin-deficient mice exacerbated intestinal fibrosis with dysregulated expression of noncanonical Wnt ligand WNT5A and its receptor ROR2. Pharmacologically induced Meflin expression through the administration of a synthetic retinoid reversed intestinal fibrosis in the DSS model and suppressed profibrotic protein secretion in fibroblasts isolated from patients with CD. Our findings indicate that Meflin-positive fibroblasts represent a functional subpopulation that suppresses intestinal fibrosis. Augmentation of Meflin expression shows antifibrotic effects and holds promise as a therapeutic approach for intestinal fibrosis in patients with CD.

Fas-associated factor family member 2 (Faf2) is an endoplasmic reticulum (ER)-associated protein implicated in apolipoprotein B (ApoB) metabolism, yet its physiological role in the intestine remains unclear. To investigate this, we generated intestine-specific Faf2 knockout (Faf2-IKO) mice and fed them either a normal diet or a high-fat diet (HFD). Faf2-IKO mice exhibited reduced body weight and adiposity under both conditions, improved glucose tolerance, and protection against HFD-induced hepatic steatosis. In the intestine, Faf2 deficiency was associated with lipid droplet accumulation, intracellular retention of ApoB48, and reduced chylomicron abundance in lacteals, consistent with impaired intestinal lipoprotein handling. Faf2-IKO mice also exhibited elongation of the small intestine and villi after weaning. Despite these changes, Faf2-IKO mice showed elevated postprandial triglyceride and free fatty acid levels during lipid tolerance tests, indicating paradoxical alterations in postprandial lipid responses. Additionally, Faf2 deficiency was associated with ER dilation and increased expression of genes associated with ER-related cellular responses. Furthermore, in the livers of Faf2-IKO mice, genes that govern cholesterol homeostasis and sterol biosynthetic pathways were significantly enriched. Collectively, these findings suggest that intestinal Faf2 deficiency alters chylomicron-associated lipid handling and is associated with protection against obesity and metabolic dysfunction-associated steatotic liver disease in mice.

Since even subtle mucosal changes may be depicted using virtual endoscopy created by the three-dimensional reconstruction of MDCT images, we developed a novel diagnostic imaging system that integrates and displays virtual enteroscopy, curved planar reconstruction, and a virtual unfolded view, the width of which changes with increases/decreases in the inner luminal diameter. The system is also equipped with artificial intelligence that superimposes and displays depressed areas, generates an automatic small bowel centerline that connects fragmented small bowel regions, and performs electronic cleansing. We retrospectively evaluated the diagnostic performance of this system for small bowel lesions in Crohn's disease, which were divided into two groups: endoscopically-observable and endoscopically-unobservable. Lesion detection rates for stenoses, longitudinal ulcers with a cobblestone appearance, and scars were excellent in both groups. This system, when used in combination with endoscopy, shows slight mucosal changes in areas in which an endoscope cannot reach due to strictures, thereby extending the range of observation of the small bowel. This system is a useful diagnostic modality that has the capacity to assess mucosal healing and provide extraluminal information.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used for the treatment of type 2 diabetes mellitus. Recently, their association with drug-induced bullous pemphigoid (BP) has attracted increasing attention. In this report, we present a case of an 84-year-old woman who developed BP after COVID-19 infection while taking a DPP-4 inhibitor. The temporal relationship between drug administration, viral infection, and onset of autoimmune disease indicates a possible interaction between COVID-19-induced immune dysregulation and DPP-4 inhibition. The coexistence of these factors may increase the risk of developing BP in older patients with diabetes, which warrants careful monitoring.

Objective: Clinical value of screening colonoscopy (SC) has been widely accepted; however, its clinical utility remains controversial in patients who undergo laparoscopic cholecystectomy (LC). The aim of this study was to evaluate the clinical value of medical care costs for SC before LC. Subject and Methods: Of the 509 patients who underwent LC, 335 underwent preoperative SC before LC. The electronic medical records were retrospectively reviewed, and the technical fees of SC and endoscopic and/or surgical resection for colorectal neoplasia (CRN) were analyzed. Results: In the 335 patients with SC before LC, the rate of CRN requiring resection, including advanced adenoma and adenocarcinoma, was 13.1%. The detected rate of CRN requiring resection in the age-groups of <45, 44–55, 55–65, 65–75, ≥75 years was 5.3%, 3.8%, 9.8%, 17.4%, and 22.9%, respectively. Of the 174 patients without SC before LC, 4 patients were diagnosed with resectable colorectal carcinomas after LC. The total technical fees of SC and/or treatment of CRNs among the 335 patients with SC before LC and surgical procedures among the 4 patients with resectable colorectal carcinoma were United States dollar (USD) 84,700 and USD 32,000 USD, respectively. Regarding the technical fee per person, the former group (USD 250) had much economic advantage compared to the latter group (USD 8,000). Conclusion: Scheduling LC is recognized as an important chance to undergo SC. For the patients aged ≥55 years, colonoscopy is no longer a screening option but a clinical necessity due to the high detected rates of CRN requiring resection.

BACKGROUND AND AIMS:The newly developed self-assembling peptide (SAP) is expected to exert hemostatic effects on the gastrointestinal tract and promote ulcer healing. However, its efficacy in preventing postprocedural hemorrhage after colorectal endoscopic submucosal dissection (ESD) remains uncertain. This study aimed to determine whether SAP could reduce hematochezia, including delayed bleeding (DB), and prevent its occurrence after colorectal ESD. METHODS:This multicenter retrospective study included 1597 patients with 1654 colorectal ESD-related lesions treated between January 2017 and July 2024. Initially, 1419 lesions were analyzed and categorized into non-SAP and SAP groups. Subsequently, the differences between lesions with and without postprocedural hematochezia and DB were explored. Factors associated with hematochezia and DB were examined using univariate and multivariate logistic regression analyses. RESULTS:A total of 719 and 700 lesions were assigned to the non-SAP and SAP groups, respectively. The use of SAP was associated with a significant reduction in hematochezia. In addition, SAP significantly reduced DB. SAP was identified as a significant factor in the prevention of hematochezia and DB after colorectal ESD. CONCLUSIONS:The application of SAP significantly reduced the occurrence of hematochezia and DB after colorectal ESD. Furthermore, SAP was a significant factor associated with the reduction of hematochezia and DB. Therefore, SAP may be appropriate for the prevention of post-ESD bleeding in the colon.

BACKGROUND:IgE is a key molecule that plays a role in allergic disorders. Compared to other subtypes of immunoglobulins, IgE has a unique immunoglobulin-like domain, Cε2, which is implicated in stabilizing the complex of IgE and its high-affinity receptor, FcεRI. However, whether human IgE Cε2 domain can be targeted as a functional domain by antibody therapeutics remains elusive. OBJECTIVE:We aimed to investigate competitive and dissociating effects of fragment antigen-binding (Fab) fragments targeting Cε2 on IgE-receptor interactions. METHODS:Fab libraries against human IgE Cε2-4 were generated by rabbit immunization and subsequent phage display screening. The sublibrary against Cε2 portion was subjected to competition and removal screening on IgE-FcεRI interactions. The binding sites of 3 potent Fab clones were determined by mutational analysis. The competition and removal activities against human FcεRI and CD23 on cell surface, and consequences on anaphylactic reactions were assessed in vitro and in vivo. RESULTS:Anti-Cε2 Fab clones exhibited various disruptive activities on preformed IgE-FcεRI complexes, which were correlated with the competing activities. Selected potent Fab clones exhibited removal activities on IgEs of IgE-presensitized mast cells, leading to suppression of antigen-induced immediate reactions in vitro and in vivo. However, the competing and disruptive activities on IgE-CD23 complex varied among these clones. The core responsible epitopes were found in close proximity to the fifth β-sheet and helix regions in Cε2. CONCLUSION:These results highlight the crucial role of human Cε2 in stabilizing IgE-receptor complexes and its potential as a target for anti-IgE therapeutics.

Understanding the complex interplay between intestinal microbiomes and ampullary tumors is crucial for distinguishing between adenomas and carcinomas, especially when considering the role of Fusobacterium. We characterized the microbiome associated with ampullary tumors using samples collected from the tumor surface (tumor samples, TSs) and surrounding normal duodenal mucosa (normal samples, NSs) via brush rubbing. In total, samples from 17 patients, divided into an adenoma group (n = 11) and a carcinoma group (n = 6), were analyzed. The Shannon α-diversity index was significantly higher in the carcinoma group compared with the adenoma group, indicating a more diverse bacterial community in the carcinoma environment. The TSs of the carcinoma group exhibited enrichment of Fusobacterium, Leptotrichia, Methylorubrum, and Micrococcus. The relative abundance of Fusobacterium increased as the tumor progressed. The NSs of the carcinoma group showed a higher presence of Fusobacterium, Porphyromonas, Granulicatella, Rikenellaceae RC9 gut group, and Solobacterium, whereas Bergeyella was more prevalent in the adenoma group. These results suggest that ampullary carcinomas exhibit a characteristic microbiome compared to adenomas. Fusobacterium is enriched in the tumor and surrounding normal duodenal mucosa, increases in abundance as the tumor progresses, and may be associated with ampullary tumors.

Introduction: the PillCamTM patency capsule is useful to prevent capsule endoscope retention; however, visual confirmation of patency capsule excretion is challenging for many patients. Objective: we investigated the factors related to the patency capsule remaining in the colon after 33 hours and the factors hindering the visual confirmation of its excretion. Methods: we retrospectively analyzed 498 patients with intestinal patency who underwent patency capsule examination. Patients were categorized into the "excretion group" and "colon group," depending on whether the capsule was excreted or remained in the colon after 33 hours, respectively. Patients were further classified into self-confirmed and non-self-confirmed groups within the excretion group. Univariate and multivariate logistic regression analyses were used to analyze the factors associated with the colon and non-self-confirmed groups. Results: overall, 49 % of patients visually confirmed capsule excretion within 33 hours, whereas 51 % did not and required radiological examination. Among those without capsule excretion, 34 % of patients had a detectable capsule in the colon, whereas 16 % had no detectable capsule. In the excretion group, 75 % and 25 % of patients were self-confirmed and non-self-confirmed, respectively. Female sex, inpatient status, constipation, and capsule in the colon during the previous examination were independent factors associated with the colon group. Male sex and younger age were the independent factors associated with the non-self-confirmed group. Conclusions: our findings highlight the need for new approaches to facilitate patency capsule excretion to avoid radiation exposure, especially in females, inpatients, those with constipation, and those with capsule remaining in the colon from the previous examination.

This series evaluates mirikizumab efficacy in 10 ulcerative colitis patients previously treated with ustekinumab. Seven achieved corticosteroid-free remission, highlighting potential benefits despite limited data for such cases. No adverse events were reported, warranting further investigation.

Background:Crohn's disease (CD) is a chronic inflammatory bowel disease. Monitoring the disease activity and providing appropriate treatment are essential for improving long-term prognosis. Endoscopy remains the gold standard for assessing disease activity; however, it is invasive and costly. Recently, we identified gelsolin as a promising serum biomarker for endoscopic disease activity in ulcerative colitis. Objective:To investigate serum gelsolin levels as a potential biomarker for mucosal activity in the small bowel and colon of patients with CD. Furthermore, we aimed to compare the performance of gelsolin with that of C-reactive protein (CRP) in detecting mucosal activity. Design:A retrospective observational study at a single tertiary care center. Methods:Serum gelsolin and CRP were measured in 82 patients with CD and 16 healthy controls. Endoscopic disease activity was assessed using the Applied Simple Endoscopic Score for CD (aSES-CD). We conducted receiver operating characteristic curves and correlation analyses. In addition, subgroup analyses were performed to evaluate differences in the biomarker performance between ileal and ileocolonic types of CD. Results:Serum gelsolin levels were significantly lower in patients with CD than in healthy controls (p < 0.001). Gelsolin levels were negatively correlated with aSES-CD, particularly in patients with the ileocolonic-type CD, and showed a stronger correlation with endoscopic activity than CRP. The area under the curve for gelsolin was 0.8377, with a cutoff of 13 µg/mL, yielding 75% and 83% sensitivity and specificity, respectively. Conclusion:Serum gelsolin is a prospective noninvasive biomarker that outperforms CRP in detecting endoscopic disease activity in patients with ileocolonic-type CD.

INTRODUCTION:Recently, the detection of superficial non-ampullary duodenal epithelial tumors (SNADETs) including adenomas and superficial duodenal carcinomas has increased. Various endoscopic treatment methods have also been reported for SNADETs, but there are few reports on the natural history. The aim of this study was to analyze factors related to tumor growth and determine the characteristics of SNADETs which need early therapeutic intervention. METHODS:A single-center, retrospective study was performed on the medical records of 309 patients with SNADETs who underwent endoscopic or surgical resection between January 2010 and May 2021. Of these, 41 patients who were followed up for more than 1 year by endoscopy were analyzed. The primary outcome was an analysis of the tumor growth speed. Secondary outcomes were the relationship between the tumor growth speed and mucin phenotype, tumor size and findings of magnifying endoscopy with narrow-band imaging (M-NBI). RESULTS:The observation period was 24 months (13-182). Tumor growth speed was 1.1 mm/year (0-21.6). Tumor diameter ≥10 mm at first detection (p = 0.004; odds ratio 19.5 [2.03-186.96]) and mixed type by M-NBI (p = 0.036; odds ratio 9.69 [1.05-89.88]) were identified as risk factors of tumors growing at a rate of ≥3 mm/year. There was no statistically significant difference in the speed of tumor growth between the different mucin immunohistochemical phenotypes. CONCLUSION:Initial tumor size and findings of M-NBI are useful to predict tumor growth and consider early intervention.