Journal of Gastroenterology最新文献

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.

The role of endoscopic submucosal dissection (ESD) in treating superficial non-ampullary duodenal epithelial tumors (SNADETs) remains controversial. This study aimed to evaluate the role of ESD for SNADETs by lesion size. A systematic review and meta-analysis were conducted to compare outcomes between ESD and endoscopic mucosal resection (EMR). For duplicate publications, the study with the largest sample was included. Key outcomes included rates of en bloc resection, intraoperative perforation, and delayed adverse events (AEs) (bleeding, perforation). Data were analyzed according to lesion size categories (< 20 mm and ≥ 20 mm). Corresponding authors were contacted for data clarification when necessary. Fifteen retrospective observational studies met the inclusion criteria. For lesions < 20 mm, there was no significant difference in the en bloc resection rates between both groups (OR: 1.12 [95% CI 0.50-2.51]); however, the intraoperative perforation (OR: 9.74 [95% CI 5.07-18.69]) and delayed AEs rates (OR: 4.21 [95% CI 2.54-6.98]) were significantly higher for the ESD group. For lesions ≥ 20 mm, ESD was associated with a significantly higher en bloc resection rate (OR: 6.17 [95% CI 3.52-10.80]) and intraoperative perforation rate (OR: 5.33 [95% CI 2.23-12.76]), whereas the rate of delayed AEs was not significantly different from that of EMR (OR: 1.34 [95% CI 0.58-3.11]). For SNADETs ≥ 20 mm, ESD demonstrates a higher en bloc resection rate while maintaining a comparable rate of delayed AEs compared to EMR. These findings suggest that ESD may be considered a potential treatment option for large SNADETs, with careful patient selection and risk assessment.

Background and aims: Inflammatory cell infiltration in the liver is a hallmark of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the pathological events that trigger the infiltration of inflammatory cells to mediate MAFLD pathogenesis remains poorly understood. This study aims to investigate the function and mechanism of Hic-5 on hepatic inflammation of MAFLD.

Methods: MAFLD animal models were fed a methionine- and choline-deficient (MCD) diet in Hic-5 knockout mice. Liver tissues were analyzed by immunohistochemical staining, immunofluorescence and flow cytometry, with a particular focus on the impact on the immune microenvironment.

Results: Hic-5 deficiency alleviates the severity of MAFLD, particularly the inflammation response. Gain- and loss-of-function experiments revealed that Hic-5 deficiency results in decreased neutrophil proliferation and increased apoptosis, as well as impaired migration. Conversely, Hic-5 overexpression had the opposite effects. This study confirmed that METTL3-mediated methylation of m⁶A stabilizes Hic-5 mRNA and promotes its expression, which in turn regulates the infiltration of neutrophils by the CXCL1-CXCR2 axis.

Conclusions: The study reveals the role of Hic-5 in regulating neutrophils and indicates that it may be a potential therapeutic target for MAFLD.

Background: Autoimmune gastritis (AIG) is a chronic atrophic gastritis that affects the gastric corpus, leading to achlorhydria, hypergastrinemia, and a precursor of neuroendocrine tumors (NETs). This study aimed to elucidate the underlying mechanisms of gastric NET formation in AIG by analyzing gastric mucosa-associated microbiota and host tissue-derived metabolite profiles.

Methods: A total of 19 patients diagnosed with AIG and 12 controls uninfected with Helicobacter pylori underwent gastric mucosal biopsies for microbiome analysis using next-generation sequencing with primers targeting the V3-V4 region of the 16S rRNA gene, and metabolome analysis using capillary electrophoresis time-of-flight mass spectrometry.

Results: Microbiome analysis revealed significantly reduced α-diversity indices in patients with AIG when compared with the control group. β-Diversity analysis showed distinct microbial compositions among the control, NET-negative, and NET-positive groups. The NET-positive group exhibited a significantly higher abundance of Proteobacteria and Fusobacteriota, particularly Haemophilus parainfluenzae, Fusobacterium periodonticum, and Fusobacterium nucleatum, whereas Firmicutes, including Streptococcus salivarius and Veillonella atypica, were significantly decreased compared with the NET-negative group. Metabolome analysis revealed a shift away from glycolysis and tricarboxylic acid cycle activity toward alternative metabolic pathways in patients with AIG. Integrated analysis of gastric microbiota signatures (GMS) and tissue metabotypes demonstrated significant associations among GMS, tissue metabotypes, and NET diagnosis.

Conclusions: These findings highlight marked shifts in gastric mucosa-associated microbiota profiles in patients with AIG who developed gastric NETs. Tissue-specific metabolic alterations may precede mucosal dysbiosis in patients with AIG and promote the development of a microenvironment implicated in NET formation.

Background: Almost a decade has passed since the previous nationwide survey on the prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in Japan was conducted in 2015. We conducted a new nationwide hospital-based survey to provide updated estimates of the patient numbers and prevalence rates of UC and CD in Japan in 2023.

Methods: Stratified random sampling was used to select hospital departments (internal medicine, surgery, pediatrics, and pediatric surgery) that routinely treat UC and CD patients. We sent questionnaires to the sampled departments to request sex-specific information on their patient numbers for UC and CD in 2023. Based on the responses, we estimated the annual patient numbers and prevalence rates of UC and CD throughout Japan. The estimates were compared with those from the previous 2015 survey.

Results: The overall survey response rate was 50.8% (1,798/3,538 departments). The estimated patient numbers were approximately 316,900 (95% confidence interval: 223,900-409,900) for UC and 95,700 (61,100-130,400) for CD, both of which represent a 1.4-fold increase over the 8-year period since 2015. The annual prevalence rates per 100,000 population were 254.8 (male: 297.5; female: 214.4) for UC and 77.0 (male: 112.9, female: 43.0) for CD. The male-to-female ratios were 1.31 for UC and 2.49 for CD, and the UC-to-CD ratio was 3.31.

Conclusions: The patient numbers and prevalence rates of UC and CD have continued to steadily increase in Japan, suggesting the need for continued monitoring and further investigation to track the disease burden.

Background: Gastric cancer (GC) remains one of the most lethal malignancies, primarily due to limited treatment efficacy and its strong metastatic potential. The identification of new molecular targets is therefore crucial for enhancing therapeutic strategies and improving clinical outcomes.

Methods: The expression of ITGA3 was investigated in clinical GC tissue samples, and its association with patient prognosis was evaluated. Both in vitro and in vivo assays were employed to investigate the functional role of ITGA3 in GC cell proliferation and invasion. To uncover the underlying molecular mechanisms, integrated proteomic and transcriptomic analyses were performed. Mechanistic validation was subsequently carried out using Western blotting, immunofluorescence, nuclear-cytoplasmic fractionation, dual-luciferase reporter, and chromatin immunoprecipitation (ChIP) assays.

Results: Elevated ITGA3 expression was strongly correlated with an unfavorable prognosis in GC patients. Functional studies revealed that ITGA3 promotes tumor cell proliferation and invasion. Multi-omics analyses revealed that ITGA3 modulates glutamine metabolism by regulating the amino acid transporter SLC1A5 and engages the JAK-STAT3 signaling pathway. Silencing ITGA3 significantly reduced STAT3 nuclear translocation, suppressing SLC1A5 transcription and decreasing glutamine uptake. Both dual-luciferase reporter and ChIP assays confirmed that STAT3 directly binds to the promoter region of SLC1A5.

Conclusions: ITGA3 acts as an oncogenic driver in GC by facilitating glutamine uptake via the STAT3-SLC1A5 signaling axis. These findings suggest that therapeutic targeting of this pathway could represent a promising approach for the clinical management of GC.