Journal of Gastroenterology最新文献

Background: Chronic constipation reduces quality of life and imposes a significant economic burden. The introduction of novel agents in Japan has expanded treatment options. This study aimed to establish a cost-effective treatment strategy, considering clinical utility and patient satisfaction.

Methods: Nine treatment strategies were developed, each consisting of three consecutive treatment options selected from five drugs: magnesium oxide (MgO), lubiprostone, linaclotide, elobixibat, and PEG formulation. A Markov state-transition model was used to estimate costs and outcomes. Effectiveness data were derived from a network meta-analysis of spontaneous bowel movements within 24 h (SBM24) using domestic trial data. Expected costs and quality-adjusted life years (QALYs) were calculated from the healthcare payer's perspective.

Results: In the network meta-analysis, lubiprostone had the highest relative risk for SBM24 (2.36), followed by lactulose (1.84) and elobixibat (1.71). Compared to MgO, the lubiprostone-elobixibat-PEG formulation strategy had additional costs of JPY 8,069.5 and a QALY gain of 0.0710, resulting in an incremental cost-effectiveness ratio (ICER) of JPY 113,709/QALY-well below the willingness-to-pay threshold of JPY 5-6 million/QALY. All strategies had ICERs below JPY 200,000/QALY, indicating favorable cost-effectiveness. Sensitivity analyses confirmed that the lubiprostone-elobixibat-PEG formulation strategy remained the most cost-effective, demonstrating its robustness.

Conclusions: The lubiprostone-elobixibat-PEG formulation strategy showed the most favorable cost-effectiveness profile. In addition, novel treatment options, including lubiprostone, linaclotide, elobixibat, and PEG formulation, were found to be cost-effective compared to MgO. Further research is warranted to confirm these findings and support their application in clinical practice.

Background: The Model for End-Stage Liver Disease 3.0 (MELD 3.0) was developed in the United States to improve prioritization for liver transplantation (LT); however, its utility in Japanese patients with liver cirrhosis (LC) and acute decompensation (AD) remains invalidated.

Methods: We retrospectively analyzed 312 patients with LC and first-time AD admitted to our institution between 2012 and 2022. Prognostic accuracy of MELD 3.0 was evaluated at 90 and 180 days after admission by comparison with other predictive models. Prognoses according to cirrhosis etiology and contributing factors were also examined.

Results: MELD 3.0 demonstrated superior prognostic accuracy at day 180 (C-index: 0.770) compared to the original MELD and MELD Na, although its C-index up to day 90 was comparable to that of MELD and MELD Na. A cut-off value of MELD 3.0 > 20.5 predicted LT or liver-related death at day 180. Patients with primary biliary cholangitis (PBC) had poorer outcomes than non-PBC cases through 180 days and remained an independent risk factor in the Cox proportional hazards model incorporating MELD 3.0. A progressive increase in both MELD 3.0 and total bilirubin from day 0 to day 90 after AD was observed specifically in the PBC group, which may have been associated with the poor prognosis at day 180.

Conclusions: MELD 3.0 was effective in predicting 180-day outcomes in Japanese patients with LC and AD. Progressive bilirubin elevation in PBC may be associated with poor prognosis. These findings suggest that early consideration of LT is warranted in patients with PBC.

Background: Ulcerative colitis (UC) presents with diagnostic challenges due to symptom overlap with other gastrointestinal (GI) disorders. Recent studies identify anti-integrin αvβ6 autoantibodies as a promising biomarker for UC. This meta-analysis aims to evaluate the diagnostic accuracy of anti-integrin αvβ6 antibodies in distinguishing UC from healthy individuals and other GI diseases.

Methods: We conducted a systematic literature search of PubMed, Scopus, and Embase up to February, 2025, following PRISMA guidelines. Studies assessing the diagnostic performance of anti-integrin αvβ6 antibodies in UC patients were included. A bivariate random-effects model was used to pool sensitivity and specificity estimates using STATA. Forest plots and SROC curves were generated. Meta-regression and interaction analyses explored the influence of covariates such as control group type, age group, and geographic region on diagnostic performance. Risk of bias was assessed using tool QUADAS-2. Post hoc analyses were conducted to assess the impact of cut-off thresholds and ELISA platforms on the diagnostic performance of anti-integrin αvβ6 antibodies.

Results: Six studies comprising 3887 participants (1904 UC patients) were included in meta-analysis. The pooled sensitivity and specificity of anti-integrin αvβ6 for UC across all comparator groups were 83% (95% CI: 0.70-0.91) and 93% (95% CI: 0.88-0.97), respectively. Diagnostic performance remained consistent across control types for sensitivity but varied significantly for specificity, especially when Crohn's disease was used as a comparator (81%; 95% CI: 0.75-0.86). Multivariate meta-regression identified patient age, geographic region, and control group type as significant modifiers of specificity. Interaction models further confirmed a combined influence of these factors on diagnostic performance. Post hoc analyses revealed that sensitivity remained stable across thresholds (2SD: 0.65, 3SD: 0.87), while specificity varied significantly depending on cut-off values (2SD: 0.89, 3SD: 0.92) and ELISA methodology (0.92 vs. 0.83).

Conclusions: Our meta-analysis demonstrates that anti-integrin αvβ6 antibodies exhibit high diagnostic accuracy for UC, with consistent sensitivity and specificity. Their performance is influenced by patient demographics and study region, suggesting the need for tailored diagnostic criteria in clinical settings.

Background: The prevalence and characteristics of inflammatory bowel disease-associated spondyloarthritis (IBD-SpA) in Japan are unclear. Moreover, methods for screening SpA among IBD patients have not been established.

Methods: This single-center prospective multidisciplinary study included consecutive patients with IBD, which was newly diagnosed within the past 3 years (early IBD). Board-certified rheumatologists examined the patients for disease history and musculoskeletal manifestations, with imaging studies if needed. Questionnaires assessed patient-reported outcomes and Psoriatic Arthritis Screening and Evaluation (PASE) scores.

Results: We identified 85 eligible patients with early IBD, 22 (25.9%) of whom had Crohn's disease, 63 (74.1%) had ulcerative colitis, and 3 (3.5%) had IBD-SpA diagnosed prior to study enrollment. Rheumatologist evaluations identified additional seven SpA cases, resulting in a total of 10 patients (11.8%) with IBD-SpA (1: axial, 9: peripheral). IBD patients without SpA often presented with back pain (52%) and peripheral joint pain (24%), whereas arthritis, cervical and thoracic pain, and inflammatory back pain were more frequent in IBD-SpA. Newly identified IBD-SpA cases tended to have lower-limb arthritis, dactylitis, and enthesitis, compared with previously diagnosed IBD-SpA cases. For patients with active SpA symptoms in the past 6 months, PASE demonstrated that the area under the receiver operating characteristic curve was 0.87 (95% confidence interval: 0.68, 1.00). The optimal cut-off (33 points) had a sensitivity of 0.88 and specificity of 0.88.

Conclusions: This prospective study found rheumatologist evaluation increased SpA diagnosis and 11.8% of Japanese early IBD patients had IBD-SpA. PASE questionnaires may be effective for screening SpA among IBD patients.

Background: Immunoglobulin G4 (IgG4)-related gastrointestinal diseases (IgG4-GID) are becoming increasingly recognized. However, few cases have been reported, and the disease concept is not yet well established. This study aimed to elucidate the clinical features of IgG4-GID.

Methods: This nationwide multicenter retrospective study collected 37 cases of IgG4-GID, which were classified and analyzed based on the pathological findings and the presence or absence of IgG4-related diseases in other organs. The pathological possibility of IgG4-GID was classified as definite, highly likely, probable, or unlikely based on the presence of typical pathological findings, number of IgG4-positive cells, and adequacy of histological evaluation.

Results: Thirteen patients were classified as unlikely to undergo pathological evaluation. Among the remaining 24 cases, 20 had other organ involvement (pathologically definite, n = 8; highly likely, n = 6; probably, n = 6). The four cases without the involvement of other organs were classified as definite. After defining definite and highly likely cases, 18 cases of IgG4-GID were identified. The most commonly affected organs were the stomach (n = 12) and the duodenum (n = 6), with one case involving both. Endoscopic findings most frequently showed ulcers (n  = 7), followed by submucosal tumor (SMT)-like morphology (n  = 6). Treatments included surgery (n  = 8; SMT-like cases), steroids (n  = 2), and proton pump inhibitors or potassium-competitive acid blockers (n  = 3), with all cases showing improvement.

Conclusions: IgG4-GID exhibits characteristic pathological findings and various endoscopic features. Although many patients respond to treatment, some undergo surgery; thus, increased awareness may help avoid unnecessary surgeries.

Background: Overt hepatic encephalopathy (OHE) is a severe complication of liver cirrhosis. However, data on its incidence, prognostic significance, and associated risk factors in patients without OHE at baseline remain limited.

Methods: A multicenter retrospective cohort study was conducted by reviewing records of hospitalized patients with cirrhosis at three institutions in Japan. OHE was defined as West Haven grade ≥ 2 and its incidence during the follow-up was estimated using the cumulative incidence function. Prognostic factors were assessed using Cox proportional hazards regression analysis, with OHE and hepatocellular carcinoma (HCC) development treated as time-dependent covariates. Independent predictors for OHE development were analyzed using fine-gray proportional hazards regression analysis.

Results: Among 652 patients, the median age was 67 years, and 53% were male. The median model for end-stage liver disease (MELD) score was 9. During a median follow-up period of 3.2 years, 136 patients (21%) developed OHE and 183 patients (28%) died. The cumulative incidence of OHE at 1, 3, and 5 years was 8%, 16%, and 20%, respectively. Multivariable analysis demonstrated that OHE development (hazard ratio [HR], 3.07; 95% confidence interval [CI], 1.99-4.75) was a significant independent prognostic factor, regardless of age, sex, liver functional reserve, and HCC development. Furthermore, multivariable analysis identified lower body mass index, higher MELD score, lower albumin levels, and higher ammonia levels as independent predictors for OHE development.

Conclusions: OHE development is common and increases mortality among patients with cirrhosis. Therefore, close monitoring of high-risk populations is warranted for early management of OHE.

Background/objective: Since the 2010s, Japan's national health insurance system has covered key management for chronic pancreatitis (CP), including pancreatic enzyme replacement therapy. These therapies are expected to improve long-term prognosis; however, recent data are lacking. This study aimed to clarify the updated cancer risk and mortality among patients with CP in Japan.

Methods: We conducted a multicenter, retrospective cohort study on 1,110 patients with CP treated at 28 institutions in 2011. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated for comorbidities. Factors associated with the development of malignancy and overall survival were analyzed.

Results: Patients with CP had an elevated SIR of 1.62 (95% confidence interval [CI], 1.43-1.83) for malignancy, with the highest risk observed for pancreatic cancer (SIR = 6.44 [95% CI, 4.64-8.90]). During follow-up, 143 patients (12.9%) died, most frequently from malignancy (47.5%). The SMR was elevated in all patients with CP (SMR = 1.20 [95% CI, 1.01-1.42]) and in those with alcohol-related CP (SMR = 1.49 [95% CI, 1.23-1.81]) but not in those with alcohol-unrelated CP. Pancreatic cancer was identified as the strongest factor associated with overall survival (hazard ratio, 48.92 in multivariate analysis). Overall survival of the patients with pancreatic cancer was significantly longer in those who underwent regular examinations for CP at least every three months (P = 0.011).

Conclusions: Patients with alcohol-related CP have higher mortality than the general population in Japan. Pancreatic cancer remains a crucial prognostic factor in patients with CP. Regular surveillance for pancreatic cancer is important to improve their prognosis.

Background: Gastric intestinal metaplasia (GIM) is a precancerous lesion that elevates gastric cancer risk. Our prior single-cell RNA sequencing (scRNA-seq) analysis implied aberrant lipid metabolism in GIM. We also established a Ddit4-deficient mouse model that developed severe gastric metaplasia lesions upon Helicobacter pylori (H. pylori) infection. This study aims to define the lipid signatures of metaplasia lesions in gastric carcinogenesis.

Methods: We performed lipidomic analysis of gastric tissues from H. pylori-infected Ddit4^-/- and wild-type (WT) mice, and from human GIM and chronic non-atrophic gastritis (CNAG) samples. scRNA-seq data were reanalyzed to identify lipid metabolism-related gene expression during GIM progression. The therapeutic effects of lipid inhibitors sulfosuccinimidyl oleate sodium (SO), TVB3664 and fenofibrate, were evaluated in patient-derived gastric cancer organoids and in a tamoxifen (TAM)-induced gastric metaplasia mouse model. Immunohistochemistry, immunofluorescence, and BODIPY 505/515 staining were also conducted.

Results: Lipidomic profiling revealed a marked increase in triglyceride (TG) levels in Ddit4^-/- mice with gastric metaplasia. Similarly, human GIM tissues showed elevated TG content compared to CNAG. BODIPY staining confirmed lipid droplet (LD) accumulation in GIM. GSEA analysis of scRNA-seq data indicated upregulation of TG metabolism and synthesis pathways in GIM. Key genes involved in TG synthesis (DGAT1, MOGAT2, MOGAT3) and fatty acid (FA) transport (FABP1, FABP2, SLC27A4) were significantly elevated in GIM. Notably, DGAT1 protein levels were substantially upregulated in human GIM tissues relative to CNAG controls. In contrast, certain membrane lipids like lysophosphatidylcholine (LPC) subclasses were reduced in GIM. FA transport inhibitor SO and synthesis inhibitor TVB3664 suppressed gastric cancer organoid growth. In mice, TVB3664 and fenofibrate alleviated gastric pathology including inflammation and metaplasia.

Conclusions: Our study reveals a distinct lipid signature in gastric metaplasia characterized by TG and LD accumulation, providing novel therapeutic insights into targeting lipid metabolism to prevent GIM malignant transformation and reduce cancer risk.

Background: Obesity is a known risk factor for colorectal cancer (CRC), but its impact on prognosis and tumor biology remains unclear. This study aimed to identify molecular biomarkers that reflect obesity-associated tumor characteristics and stratify patient outcomes.

Methods: We conducted a multi-step analysis integrating transcriptomic data, clinical validation, and spatial profiling. Candidate genes were first screened in the TCGA-COADREAD dataset based on expression trends across normal, healthy-weight CRC, and obese CRC samples. Prognostically relevant genes were then validated in an independent cohort using immunohistochemistry (IHC). Finally, spatial transcriptomic analysis using GeoMx DSP was performed to elucidate the tumor microenvironment associated with the top candidate.

Results: Among six shortlisted genes, NNT showed a significant association with overall survival specifically in obese patients and was validated at the protein level by IHC. High NNT expression was independent of TNM stage and associated with improved prognosis. Spatial transcriptomic profiling revealed that NNT-high tumors were enriched for antioxidant, apoptotic, and metabolic programs, while oncogenic and proliferative pathways were suppressed. These patterns suggest that NNT contributes to a redox-balanced and metabolically adaptive tumor state.

Conclusions: Through integrative molecular and spatial analyses, NNT was identified as a potential prognostic biomarker in obesity-associated CRC. This study highlights the importance of combining clinical data with spatial transcriptomics to uncover context-specific tumor biology.

Background: High-alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) can cause metabolic dysfunction-associated steatotic liver disease (MASLD) through sustained alcohol overflow in the microenvironment. As a probiotic, Bifidobacterium bifidum (B. bifidum) exhibits unique anti-inflammatory properties; however, whether and how it alleviate MASLD induced by HiAlc Kpn requires further investigation.

Methods: MASLD mouse model was constructed by gavage administration with HiAlc Kpn W14 to assess the therapeutic effect of B. bifidum CIP-01 in vivo. Cell infection models, metabolomics sequencing, and in vitro antibacterial assays were integrated to systematically elucidate the mechanism by which B. bifidum CIP-01 mitigates HiAlc Kpn W14-induced cell damage.

Results: B. bifidum CIP-01 was able to ameliorate MASLD induced by HiAlc Kpn through a multi-target mechanism. Compared to pair-fed mice, HiAlc Kpn W14 disrupted gut barrier and promoted inflammatory cytokines release. While, supplementation with B. bifidum CIP-01 reversed these effects by a) restoring intestinal integrity via upregulating tight junction proteins (ZO-1/Occludin) and mucin protein MUC-2, reducing reactive oxidative stress (ROS) and apoptosis in colonic cells, and b) rescuing hepatic cytochrome P450 2E1 (CYP2E1)-driven oxidative injury (ROS/Caspase-3) while promoting mitochondrial β-oxidation, as well as c) directly suppressing HiAlc Kpn proliferation and biofilm formation. Metabolomics and 16S rRNA of fecal samples analyses revealed B. bifidum CIP-01-mediated metabolic regulation: depletion of toxic branched-chain amino acids (BCAAs) intermediates and restoration of energy homeostasis and antioxidant defense alongside increased short-chain fatty acids (SCFAs)-associated pathways.

Conclusion: Our findings highlight B. bifidum CIP-01 as a novel therapeutic candidate for HiAlc Kpn-induced MASLD, operating through a triad of pathogen suppression, gut-liver axis repair, and metabolic regulation.