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Background: The main aim of the current study was to investigate the potential role of Prox1 in lymphatic function, and analyze Prox1-dependent stimulation of lymphatic function in experimental Crohn's disease (CD).

Methods: Prox1flox/+, Tie2-CreERT2 and IL-10 KO mice were included. Lymphatic vessel density and lymphatic function were analyzed using immunohistochemistry and lymphangiography. The effects of lymphatic function on mesenteric adipose tissue (MAT) and the composition of microbiota were evaluated. Disease activity and enterocolitis inflammation were assessed using a grading system.

Results: For lymphatic vessel, IL-10 KO+Prox1 KO mice showed lower lymphatic vessel density and less functional lymphatic vessels. IL-10 KO+AAV-Prox1 mice showed significantly increased lymphatic vessel density. Delivery of AAV-Prox1 also promoted lymphatic drainage function; Additionally, Prox1-dependent stimulation of lymphatic function reduced hypertrophy of MAT inIL-10 KO mice. Delivery of AAV-Prox1 also modified the composition of microbiota, the proportion of Firmicutes increased and Bacteroidetes decreased in IL-10 KO+AAV-Prox1 mice compared with IL-10 KO mice. An increase in the diversity of gut microbiota in IL-10 KO+ AAV-Prox1 mice was observed; Systemic delivery of AAV-Prox1 ameliorated disease activity index and the severity of gut inflammation in IL-10 KO mice. Without compensatory response of Prox1, IL-10 KO+Prox1 KO mice developed serious inflammation in the colon.

Conclusions: Prox1 played the critical role in lymphatic function. Additionally, Prox1-dependent stimulation of lymphatic function could reduce hypertrophy of MAT, modify the composition of microbiota, and ameliorated gut inflammation. Our findings demonstrated that correction of lymphatic function with Prox1 may lead to improved treatments for CD.

Background: H. pylori-negative gastric cancer (GC) occurs in individuals with specific risk factors. This narrative review will evaluate the role of non-H. pylori gastric microbiota in gastric carcinogenesis and summarize the clinical aspects of non-H. pylori related GC.

Summary: Epstein-Barr virus is the only other infection conclusively proven to be causative of GC. Case-control studies have reported a dysbiotic GC-associated gastric microbiome, with greater abundance of Fusobacterium nucleatum, Streptococcus anginosus, Prevotella and Veillonella. Mice model mechanistic studies have demonstrated the role of non-H. pylori microbiota in gastric carcinogenesis. Current data support their role as promotive factors, with H. pylori infection being the initiating event. In hereditary GC, inherited germline mutations initiate a genetically programmed pathway to gastric carcinogenesis. Autoimmune atrophic gastritis and Ménétrier's disease are associated with increased GC risk. Oxyntic gland adenoma/ gastric adenocarcinoma of fundic gland type and foveolar-type gastric adenoma are distinct histological subtypes of gastric neoplasia. Chronic atrophic gastritis (CAG) and gastric intestinal metaplasia (GIM) persist even after H. pylori eradication, increasing GC risk.

Key messages: There must be greater awareness of H pylori-negative GC as a diagnostic possibility due to the impact on management. There is significant potential for translational application of gastric microbiome as predictive or prognostic biomarkers or even to shape treatment outcomes. Endoscopic surveillance is indicated in the case of extensive CAG or GIM, even after successful H. pylori eradication.

Purpose: Celiac disease is associated with various extraintestinal manifestations, including psychiatric and psychological comorbidities. We evaluated the risk of developing depression and anxiety among patients diagnosed with celiac disease autoimmunity (CDA).

Methods: This retrospective case-control cohort study was conducted using the Clalit Healthcare Services population-based electronic database (~4.5 million individuals). Between January 1, 2008, and December 31, 2022, we identified subjects aged 1-80 years with a positive IgA anti-tissue transglutaminase test and a repeat measurement within 6-36 months. Depression and anxiety were identified over follow-up using ICD-9 diagnostic codes or by documented regular use of antidepressants or anxiolytics.

Results: We identified 3,797 patients with CDA, and the cohort was matched in a 1:3 ratio with 11,387 healthy controls having a negative anti-tTG2 serology. Over a median 60 months follow up duration, 5.9% of CDA patients developed depression or anxiety, compared to 1.7% of the control group (HR 2.89, 95% CI 2.2-3.8, p < 0.001), and 67% of anxiety and depression cases among CDA patients were developed during childhood. On multivariate analysis, very high baseline anti-tTG2 level (>10 X ULN), older age at diagnosis, and female sex were independently associated with the risk of developing anxiety and depression among CDA patients (HR 1.82, 1.03, and 1.38, p-values 0.029, 0.018 and 0.038, respectively).

Conclusions: CDA appears to increase the risk for anxiety and depression, particularly with very high baseline anti-tTG2 levels, advanced age at diagnosis and in females.

Introduction: Reliable closure of mucosal/full-thickness defects after endoscopic treatment is crucial to prevent complications. Although various techniques have been clinically introduced, a direct comparison of these techniques has not been conducted. Thus, the present ex vivo study aimed to evaluate the closure strength of these methods.

Methods: Using a porcine stomach, 4 × 2.5-cm mucosal and full-thickness defects were prepared. Each closure was performed for three specimens. For the mucosal defects, the following methods were performed in the mucosal (Group M) and muscular-mediated mucosal (Group MM) closures: simple clipping (Clip-M), loop-assisted closure (Loop-M), line-assisted closure (Line-M), and endoscopic hand suturing (EHS-M); Clip-MM, Line-MM, and EHS-MM. For the full-thickness defects, a single-layered closure (Group F) was performed by loop-assisted closure (Loop-F), line-assisted clip closure (Line-F), and EHS (EHS-F). The maximum tension (N) was measured using a mechanical traction device by mechanically pulling both ends of the specimen.

Results: In the closure of mucosal defects, among the techniques in Group M, EHS-M (11.32 ± 2.1 N) demonstrated the highest strength as compared to the other three methods. For Group MM, EHS-MM (13.1 ± 5.3 N) showed the highest strength, significantly outperforming Clip-MM (p = 0.03). Among the full-thickness defect closure methods, EHS-F (9.5 ± 0.73 N) had the significantly highest strength among the three methods.

Conclusions: Our ex vivo data showed that EHS has superior closure strength in both mucosal and full-thickness defects. Surgery-oriented endoscopic closure appears a reliable method for artificially created intraluminal defects.

Introduction: Traditional risk stratification heavily relies on expert judgment and manually established thresholds. This study aims to automatically identify subtypes in the patients of T1-stage colorectal cancer with distinct clinicopathologic characteristics and recurrence risk profiles, using machine learning.

Methods: We analyzed data from 3,367 patients (mean follow-up, 1281 days) with T1 colorectal cancer who underwent surgical resection between 2009 and 2016 across 27 high-volume core Japanese institutions. Patients were split into derivation and test datasets (4:1 ratio). Hierarchical clustering was employed to identify recurrence subtypes in the derivation dataset. Machine learning classifiers were developed and validated on the test dataset. Co-occurrence and Bayesian network analyses aided interpretation.

Results: Three distinct subtypes were identified: two high-risk (subtypes 1 and 2) and one low-risk (subtype 3). Subtype 1 was predominantly associated with polypoid morphology (94.8%), whereas subtype 2 was characterized by flat morphology (89.4%). Subtype 2 showed a relatively consistent presence across most factors, with comparable levels of lymphatic invasion, vascular invasion and tumor budding. Subtype 3 shared similarities with subtype 1 in polypoid morphology (76.5%) but differed in other factors. These findings showed similar trend on the test dataset. Subtype-specific risk factors included lymphovascular invasion and nodal metastasis in both high-risk subtypes, while rectal location was unique to subtype 1 and polypoid morphology and large size were specific to subtype 2.

Conclusions: This machine learning approach identified three distinct recurrence subtypes of T1 colorectal cancer, each with unique characteristics and risk profiles, indicating the potential value of subtype-specific clinical strategies.

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.

Background: Artificial intelligence (AI) applications in endoscopy, particularly computer-aided detection (CADe), have shown consistent benefit in randomized controlled trials (RCTs), with improvements in adenoma detection rate (ADR) and reductions in adenoma miss rate (AMR). Despite these findings, adoption of CADe in routine colonoscopy remains controversial, with international guidelines issuing divergent recommendations.

Summary: Evidence from RCTs demonstrates that CADe increases ADR, predominantly through detection of diminutive adenomas, while its effect on advanced adenomas is limited. Real-world implementation studies show comparatively diminished benefits, likely explained by factors which are difficult to measure, such as the absence of Hawthorne effect in real-world practice, the quality of mucosal exposure and decision-making regarding diminutive polyps. Cost-effectiveness analyses generally favour CADe even with varying assumptions across healthcare systems, although these are based on the high degree of improvement in ADR seen in RCTs with CADe. Potential harms include increased polypectomy of non-neoplastic lesions, higher lifetime colonoscopy burden, and the risk of deskilling among endoscopists. Concerns remain about bridging the gap between trial efficacy and real-world effectiveness, optimizing surveillance intervals, and mitigating deskilling and human-AI interaction issues.

Key messages: (1) CADe improves ADR in RCTs, but real-world effectiveness is inconsistent and often lacklustre. (2) Gains in ADR are largely derived from diminutive adenomas, and less with advanced adenomas, with uncertain impact on clinically significant outcomes such as colorectal cancer incidence and mortality. (3) Cost-effectiveness analyses are generally favourable, but dependent on assumptions about ADR improvement, CADe cost, and surveillance policies. (4) Deskilling and altered endoscopist behaviour represent important considerations that require further study. (5) Future integration of CADe with computer-aided diagnosis (CADx) and quality-assurance (CAQ) tools may maximize clinical benefit and cost-effectiveness, but evidence gaps must be addressed before widespread implementation.

Introduction: Esophageal achalasia is a rare motility disorder, and esophagogastroduodenoscopy (EGD) alone has limited diagnostic accuracy, often leading to delayed diagnosis. High-resolution manometry remains the diagnostic gold standard, but its availability in primary care is limited. Therefore, more accessible diagnostic methods are needed. Given the widespread use of chest X-ray, we investigated whether it reveals distinctive features in achalasia patients.

Methods: In this retrospective cohort study, 215 patients with esophageal achalasia treated between 2015 and 2024 were analyzed. Diagnostic yields of EGD, esophagography, and computed tomography (CT) were evaluated among patients who underwent these examinations in primary care facilities. Chest X-rays were systematically reviewed for paratracheal radiolucency, and a novel radiographic sign - the paratracheal air stripe sign (PASS) - was defined as a paratracheal radiolucent area with a minimum width of ≥5 mm and length of ≥20 mm. To assess specificity, an additional analysis was performed in 210 patients with esophageal cancer as a non-achalasia control cohort.

Results: Diagnostic yields in primary care were 41.1% for EGD, 88.4% for esophagography, and 34.8% for CT. PASS was present in 67.0% of achalasia cases and more frequent in patients with type I achalasia, sigmoid-type morphology, and advanced esophageal dilation. Among patients undiagnosed by EGD, 63.9% exhibited PASS. In the non-achalasia control cohort, PASS was observed in 18.0% of cases, predominantly in patients with structural esophageal changes such as tortuosity or dilatation.

Conclusion: PASS represents a novel and clinically useful chest X-ray feature associated with esophageal achalasia. Its relatively high prevalence, even among cases missed by EGD, and low occurrence in non-achalasia patients suggest that routine assessment of PASS in chest X-rays may aid early detection and timely referral for definitive diagnosis, particularly in primary care settings.

Background and aim: The efficacy of electroacupuncture (EA) treatment in alleviating visceral hypersensitivity with irritable bowel syndrome (IBS) has been established. Abnormal bile acid metabolism and farnesoid X receptor (FXR) expression are recognized as potential contributors to visceral hypersensitivity in IBS. This study as a preclinical study of the IBS visceral hypersensitivity, explored the potential of EA to reduce visceral hypersensitivity in rats with IBS by improving bile acid metabolism and FXR expression. Methods：Heterotypic intermittent stress (HIS) for 9 days was used to induce visceral hypersensitivity in constipation-predominant irritable bowel syndrome (IBS-C). EA/Sham EA bilateral ST36 and LR3 acupoints began on the 5th day of HIS. Electromyography of the abdominal external oblique muscle and calcitonin gene-related peptide were used to assess colonic hypersensitivity. Colonoscopy and histopathological examination were used to evaluate pathological changes in the colon. Bile acid composition was analyzed using high performance liquid chromatography-mass spectrometry (HPLC-MS/MS), while FXR expression in colon tissue was quantified through immunofluorescence and Western blot.

Results: HIS induced visceral hypersensitivity in IBS-C rats. EA not only regulated bile acid levels in the feces of IBS-C rats, but it also had a downregulatory effect on the overexpression of FXR in the colon tissue of rats with IBS-C. The therapeutic effects were better than those of the sham EA. EA treatment alleviated visceral hypersensitivity in the colon of IBS-C rats.

Conclusion: Our data suggested that EA normalised colonic bile-acid signaling and FXR protein expression in an IBS-C rat model, offering a mechanistic hypothesis for future clinical evaluation.

Background: Emerging evidence highlights the gut microbiota as a key contributor to the pathophysiology of irritable bowel syndrome (IBS), acting through complex interactions with intestinal motility, immune function, epithelial barrier integrity, and the gut-brain axis. This narrative review summarizes current knowledge regarding the roles of the gut microbiota and their metabolites in IBS.

Summary: We discuss alterations in the gut microbiota in IBS, with particular emphasis on changes in short-chain fatty acid production, bile acid metabolism, serotonin signaling, and gas handling. Special attention is given to microbial metabolites as mediators of visceral hypersensitivity, intestinal permeability, and neuromodulation within the microbiota-gut-brain axis. Major alterations in the gut microbiota of IBS are characterized by a reduction in Bacteroidetes, Bifidobacteria, and Faecalibacterium, accompanied by an increase in Firmicutes. We explain the importance of butyrate metabolism in colonic epithelial cells for maintaining the anaerobic environment of the gut. In addition, we review the impact of diet-microbiota interactions, including FODMAP restriction, resistant starch intake, and protein fermentation, on symptom generation and microbial stability.

Key message: Although accumulating evidence supports a link between gut dysbiosis and IBS, establishing causal relationships remains challenging due to disease heterogeneity and dietary influences. Future large-scale, well-phenotyped, multi-omics studies integrating microbiota, metabolomic, and host factors are required to elucidate underlying mechanisms and to guide personalized therapeutic strategies for IBS.