Journal of Gastroenterology最新文献

Background: No licensed drugs have been established for the treatment of nonalcoholic steatohepatitis (NASH). Therefore, we aimed to explore the effect of Yes-associated protein (YAP) on NASH to provide a therapeutic target.

Methods: We constructed a mouse model of NASH, consuming either a methionine-choline deficient (MCD) or Gubra Amylin NASH (GAN) diet. Hepatocyte-specific YAP knockout (YAP^ΔHep) mice were introduced to investigate the function of hepatocyte YAP in NASH. Furthermore, detailed mechanisms were clarified using AML12 cells. Adeno-associated virus (AAV)-mediated hepatocyte YAP overexpression was used to observe the therapeutic efficacy in mice with NASH.

Results: Hepatic YAP protein levels were increased in NASH models. The YAP deletion reduced hepatic steatosis and exacerbated hepatic inflammation and fibrosis. However, YAP overexpression leads to the opposite NASH phenotype. Furthermore, the MCD or GAN diet-fed YAP^ΔHep mice also exhibited a favorable hepatic steatosis phenotype with exacerbated inflammation and fibrosis in the liver. Conversely, hepatocyte-specific YAP or YAP (5S) overexpression led to an almost complete reversal of hepatic pathologies. Mechanistically, hepatocyte-specific PCSK9 knockdown effectively reversed NASH progression in YAP^ΔHep mice. Furthermore, the oncostatin M (OSM)-JAK2-STAT3 axis was involved in the YAP-mediated regulation of PCSK9. Notably, AAV8-mediated YAP overexpression in the hepatocyte improved NASH in mice.

Conclusions: Our findings demonstrate that hepatocyte YAP mitigates NASH severity by increasing PCSK9 expression via the OSM-JAK2-STAT3 pathway independent of lipid accumulation. Therefore, hepatocyte YAP may be a promising target for the management of NASH.

Background: Despite treatment advances, intestinal surgery remains common in Crohn's disease (CD), with over half of patients experiencing postoperative recurrence. Intestinal fibrosis represents a key pathological feature underlying this clinical course. This study aimed to investigate the relationship between fibrosis severity and the risk of postoperative recurrence.

Methods: A multi-center retrospective cohort study included CD patients undergoing intestinal resection. Histopathological slides from lesion sites and resection margins were analyzed using Masson's trichrome staining to quantify the proportion of collagen fiber area, representing fibrosis extent. Postoperative endoscopic and clinical recurrence data were collected via electronic medical records and patient follow-up interviews. Multivariable Cox regression models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the associations between fibrosis severity and recurrence risk.

Results: Among 268 patients, endoscopic recurrence occurred in 84 (31.3%) and clinical recurrence in 91 (34.0%). The degree of transmural intestinal fibrosis was positively associated with postoperative endoscopic recurrence (lesion site: HR_{per SD} = 1.46, 95% CI 1.18-1.80; resection margin: HR_{per SD} = 1.35, 95% CI 1.12-1.63) and clinical recurrence (lesion site: HR_{per SD} = 1.95, 95% CI 1.59-2.39; resection margin: HR_{per SD} = 1.29, 95% CI 1.09-1.54). Significant associations persisted when analyzing fibrosis in the mucosal, submucosal, and muscularis propria layers individually.

Conclusion: The severity of intestinal fibrosis in both lesion site and resection margin independently predicted an increased risk of postoperative endoscopic and clinical recurrence in CD. Histopathological fibrosis assessment may help identify high-risk individuals prone to postoperative recurrence, potentially informing personalized postoperative management strategies.

Background: Immunoglobulin G4 (IgG4)-related cholecystitis represents gallbladder involvement in IgG4-related disease (IgG4-RD). However, localized-type IgG4-related cholecystitis is rare and remains poorly characterized. We conducted a nationwide, multicenter study to clarify the clinicopathological features of localized-type IgG4-related cholecystitis in Japan.

Methods: We collected clinical information, imaging data, and tissue slides from suspected cases of IgG4-related cholecystitis for central review, and evaluated their clinicopathological features.

Results: Fifteen patients were diagnosed with localized-type IgG4-related cholecystitis. The incidence of localized-type IgG4-related cholecystitis was 0.59% (15/2560) among all IgG4-related gastroenterological diseases across 30 institutions. The median age was 62 years (range, 54-70 years), and 10 patients were men. Elevated serum IgG4 levels and other IgG4-RD lesions were observed in all 15 patients. Imaging findings demonstrated subepithelial lesions (SELs) of the gallbladder in all patients, and cystic lesions within SELs suggestive of adenomyomatosis (ADM) in nine patients. Among the 11 patients with available histopathological analyses, two distinct types of mass-forming lesions (inflammatory pseudotumors) characterized by storiform fibrosis and obliterative phlebitis were identified: ADM-type in six cases and mural hypertrophy-type in three cases. Eleven patients underwent surgery and four received glucocorticoids therapy. Within 2-4 weeks of initiating glucocorticoid therapy, complete resolution was achieved in one patient, and partial improvement in three patients.

Conclusion: Localized-type IgG4-related cholecystitis is characterized by imaging findings of SELs. It shares histopathological features of IgG4-RD, and often has unique lesions centered around ADM. It responds to glucocorticoid therapy.

Background: Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) have become a bottleneck limiting their widespread use in anti-cancer therapy. Among them, immune checkpoint inhibitor-associated liver injury (ILICI) is a unique entity of drug-induced liver injury (DILI) whose clinical management has become a notable emerging challenge in cancer therapy. Nonetheless, the exact pathological mechanisms of ILICI are still poorly understood.

Methods: We established a Lewis lung adenocarcinoma-bearing mouse model in C57BL/6 J mice treated with anti-PD-1 (αPD-1). Subsequently, liver tissues from the two mouse groups were collected for single-cell RNA sequencing (scRNA-seq), and the core pathogenic mechanisms of αPD-1-induced liver injury were subsequently validated using both animal tissues and patient specimens.

Results: Our model revealed that αPD-1 treatment induced a hepatic phenotype characterized by focal inflammatory infiltration and fibrosis, concomitant with elevated serum aminotransferase (ALT) and pro-inflammatory cytokine levels. Further scRNA-seq analysis demonstrated that hepatocytes in the αPD-1 group exhibited features of disrupted lipid metabolism and enhanced NETosis, along with expanded CD8⁺ T cells displaying increased cytotoxicity and expansion of pro-inflammatory Ly6C^high monocytes. These Ly6C^high monocyte-derived macrophages robustly recruited and activated neutrophils via the Cxcl2-Cxcr2 and C3-(Itgam/Itgb2) signaling axes. Corroborated by validation in both animal and patient tissues, we identified neutrophil extracellular traps (NETs) as a pivotal event in αPD-1-associated liver injury.

Conclusion: This study provides the first single-cell atlas of the hepatic microenvironment in a mouse model of αPD-1-induced liver injury under tumor-bearing conditions, revealing the concomitant metabolic reprogramming and profibrotic phenotype. Furthermore, our findings propose that the activation of NETosis is closely associated with the progression of liver injury, suggesting it may play a significant role in this pathological process.

Background: Gastroesophageal junction (GEJ) adenocarcinoma is aggressive with poor prognosis. Perioperative chemotherapy has become standard, but the optimal regimen remains uncertain. DOS has shown activity in gastric cancer but has not been prospectively assessed in GEJ adenocarcinoma. This study represents the first prospective trial of DOS as neoadjuvant chemotherapy in patients with resectable GEJ adenocarcinoma.

Methods: This single-arm, single-center phase I/II trial (UMIN000022210) enrolled patients with cT3-4aN0-3M0 GEJ adenocarcinoma. The phase I part established the recommended docetaxel dose (60 mg/m²); phase II evaluated efficacy and safety. The primary endpoint was R0 resection rate; and secondary endpoints included pathological response, adverse events, and 3-year survival.

Results: Forty-three patients were enrolled; 37 received DOS at the recommended dose. Of these, 83.8% completed all planned cycles. Grade ≥ 3 neutropenia occurred in 81.1%, and febrile neutropenia in 18.9%. The R0 resection rate was 94.6% (35/37; 95% CI, 81.8-99.3). Major postoperative complications occurred in 11.4%, with no operative mortality. Major pathological response was achieved in 40.5% of patients, including a pathological complete response rate of 5.4%. At 3 years, overall survival and relapse-free survival were 84.9% and 64.5%, respectively. Patients downstaged to ypStage 0 or IA had significantly better relapse-free survival than others.

Conclusions: Neoadjuvant DOS chemotherapy showed high R0 resection rates, acceptable toxicity, and favorable survival in resectable GEJ adenocarcinoma, supporting its potential as a treatment option. These findings provide important evidence from East Asia, where S-1-based regimens remain widely used, and complement Western data on perioperative FLOT therapy.