Journal of Gastroenterology最新文献

Background: Elastography techniques such as two-dimensional shear wave elastography (2D-SWE) often result in missed or misdiagnoses when distinguishing between intermediate stages of liver fibrosis in clinical practice for patients with chronic hepatitis B (CHB).

Methods: Between January 2020 and August 2023, we prospectively enrolled 964 potentially eligible CHB patients from 6 hospitals who underwent liver biopsy. Finally, 598 patients with 2139 high-frequency ultrasound (HF-US) images were included. LS-Net, a deep learning network based on paired liver-spleen HF-US images was trained for distinguishing different stages of liver fibrosis against a comparison network(L-Net), 2D-SWE, and radiologist. We further simulated potential clinical utility across three clinical guidelines and conducted subgroup analyses for potential confounding factors.

Results: LS-Net demonstrated consistently superior performance for all-stage liver fibrosis classification in the validation set (AUROC: 0.94, 0.87, 0.92; p < 0.05) compared to L-Net, 2D-SWE, and radiologist assessment. In our clinical simulation focused on CHB patients, LS-Net reduced the biopsy rate to 9.9% for cirrhosis detection, increased essential referral by 40.3% for advanced fibrosis, and substantially improved treatment decision-making for significant fibrosis compared to 2D-SWE. The model maintained stable performance across subgroups (BMI, inflammation, ALT, antiviral status).

Conclusions: In this development and internal validation study in the CHB patient cohort, LS-Net demonstrated significantly higher diagnostic performance for all-stage liver fibrosis classification compared to L-Net, 2D-SWE and radiologist. Our findings indicate that LS-Net could offer potential clinical value for CHB management by reducing unnecessary biopsy rate, increasing essential referral rate, and promoting timely treatment.

The clinical landscape of chronic liver disease has changed with effective antiviral therapies, enabling the eradication of hepatitis C virus and the durable suppression of hepatitis B virus replication. Despite these advances, patients remain at risk for hepatocellular carcinoma (HCC) and other liver-related complications, but the growing burden of metabolic dysfunction-associated steatotic liver disease (MASLD) has created new challenges for clinical practice. These trends emphasize the need for reliable, noninvasive biomarkers that can stratify risk and guide long-term management across diverse etiologies. Growth differentiation factor 15 (GDF15), a stress-inducible cytokine, has attracted increasing interest as a promising biomarker. Its expression is induced by metabolic, oxidative, and inflammatory stress, and circulating levels increase with disease progression. Elevated serum GDF15 is consistently associated with fibrosis severity, HCC risk, hepatic decompensation, and mortality. Importantly, GDF15 is not merely a surrogate of fibrosis; rather, it integrates hepatocellular and stromal stress pathways and captures residual risk beyond fibrosis stage, liver function scores, and conventional biomarkers. In addition to its prognostic association, GDF15 has diverse biological effects. It may act as a protective response by limiting inflammation and cellular injury; yet, in other contexts, it contributes to fibrogenesis, tumor progression, immunosuppression, and cachexia. These dual roles highlight both the potential and the complexity of targeting GDF15 in therapeutic strategies. Collectively, the results of the current study indicate that GDF15 represents a promising biomarker in chronic hepatic diseases and is clinically independent of hepatic fibrosis. Further work is needed to clarify the underlying mechanisms, validate the prognostic utility, and determine whether GDF15 can be developed as a therapeutic target within precision medicine approaches.

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.

Background: Systemic chemotherapy with gemcitabine plus S-1 (GEM + S-1), GEM + CDDP plus S-1 (GEM + CDDP + S-1), or gemcitabine plus cisplatin (GEM + CDDP) is standard treatment for advanced biliary tract cancer (aBTC). We aimed to evaluate the efficacy and safety of combination chemotherapy in older patients with aBTC.

Methods: This multicenter prospective observational study (JON2104-B, UMIN000045156) included patients aged ≥ 70 years with aBTC. Inverse-probability weighting propensity-score analyses (IPW) were used to compare overall survival (OS) as the primary endpoint and progression-free survival (PFS) across treatment groups.

Results: This study included 305 patients between August 2021 and January 2023. Of them, 75, 131, 26, 52, and 10 received GEM + CDDP + S-1, GEM + CDDP, GEM + S-1, gemcitabine, and S-1; their median ages were 74, 75, 77.5, 80, and 80 years, and approximately 24%, 16.8%, 23.1%, 9.6%, and 0% had G-8 scores of > 14, respectively. GEM + CDDP had a safety profile comparable to that of GEM + CDDP + S-1 but was more toxic than gemcitabine. Per IPW, the hazard ratio (HR) for GEM + CDDP + S-1 versus GEM + CDDP was 0.80 for OS (95% confidence interval [CI], 0.55-1.17) and 0.55 for PFS (95% CI 0.38-0.80). The HR for GEM + CDDP versus gemcitabine was 0.74 for OS (95% CI 0.42-1.29) and 0.79 for PFS (95% CI 0.42-1.49).

Conclusions: GEM + CDDP + S-1 was associated with longer PFS without additional toxicity than GEM + CDDP for fit older patients. However, the OS for both were not statistically different. The efficacies of GEM + CDDP and gemcitabine for vulnerable older patients did not also differ significantly. These findings highlight the importance of vulnerability in patients with aBTC.

Background: Dietary fatty acids are involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). We examined the mechanism by which dietary fatty acid composition affects MASLD pathogenesis.

Methods: The MASLD mouse model was developed by feeding a high-fat diet (HFD) rich in palmitic acid (PA), trans-fatty acids (TFAs), or oleic acid (OA). For in vitro experiments, Hepa 1-6 cells were exposed to PA, elaidic acid (a representative TFA), and OA. Glycerol-3-phosphate acyltransferase 1 (GPAM) expression in Hepa 1-6 cells was manipulated using a plasmid encoding GPAM and GPAM-specific siRNAs. In addition, GPAM depletion in the liver of HFD-fed mice was achieved using a pH-sensitive multifunctional envelope-type nanodevice as a siRNA carrier. Liver specimens from patients with MASLD were also analyzed.

Results: The TFA group displayed higher serum alanine-aminotransferase and hepatic triglyceride content but lower serum fasting triglyceride and visceral adipose tissue (VAT) compared with that in the PA and OA groups. Hepatic GPAM expression in the TFA group was higher than in the PA group. Consistently, TFA-treated Hepa 1-6 cells showed a greater GPAM increase than that with OA and PA. GPAM-overexpressing Hepa 1-6 cells showed increased triglyceride accumulation, whereas GPAM-deficient cells failed to accumulate triglyceride. Hepatic GPAM knockdown in HFD-fed mice suppressed steatosis and increased VAT. Notably, hepatic GPAM gene expression was higher in patients with severe steatosis than in those with non-severe steatosis.

Conclusions: A TFA-rich HFD increased hepatic GPAM expression, exacerbated steatosis, and decreased VAT. Therefore, GPAM may regulate systemic fat accumulation in the body.

Metastatic liver tumors are more common than primary liver cancers and are the most common liver malignancies. Performing B-mode ultrasonography and contrast-enhanced computed tomography is generally necessary for the diagnosis of liver metastases. However, various modalities, including dynamic contrast-enhanced computed tomography and magnetic resonance imaging using liver-specific contrast agents such as gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid, fluorodeoxyglucose positron emission tomography, and a combination of positron emission tomography and computed tomography, are also used. Improvements in imaging technology have made the detection of small liver masses possible, and liver metastases are being diagnosed more frequently, both before and after primary tumor treatment. The diagnosis of liver metastasis is related to treatment, and the benefits of liver resection depend on the primary tumor. For colorectal cancer, resection of liver metastases is beneficial. However, resection is not recommended for pancreatic or biliary tract cancers.