Journal of Gastroenterology最新文献

Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), is a multifaceted liver disease characterized by inflammation and fibrosis that develops from simple steatosis. Immune and inflammatory pathways have a central role in the pathogenesis of MASH, yet, how to target immune pathways to treat MASH remains perplexed. This review emphasizes the intricate role that immune cells play in the etiology and pathophysiology of MASH and highlights their significance as targets for therapeutic approaches. It discusses both current strategies and novel therapies aimed at modulating the immune response in MASH. It also highlights challenges in liver-specific drug delivery, potential off-target effects, and difficulties in targeting diverse immune cell populations within the liver. This review is a comprehensive resource that integrates current knowledge with future perspectives in the evolving field of MASH, with the goal of driving forward progress in medical therapies designed to treat this complex liver disease.

Background: Intestinal fibrosis is one of the most frequent and severe complications of Crohn's disease. Accumulating studies have reported that adipose mesenchymal stem cell-derived small extracellular vesicles (AMSC-sEVs) could alleviate renal fibrosis, hepatic fibrosis, etc., while their potential for treating intestinal fibrosis remains uncertain. Therefore, this study aims to determine the therapeutic effects of AMSC-sEVs on intestinal fibrosis and identify the mechanisms underlying these effects.

Methods: AMSC-sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blot. Whether AMSC-sEVs exert antifibrotic effects was investigated in two different murine models of intestinal fibrosis. Besides, AMSC-sEVs were co-cultured with primary human fibroblasts and CCD18co during transforming growth factor (TGF)-β1 stimulation. Label-free proteomics and rescue experiments were performed to identify candidate molecules in AMSC-sEVs. Transcriptome sequencing revealed changes in mRNA levels among different groups. Lastly, proteins related to relevant signaling pathways were identified by western blotting, and their expression and activation status were assessed.

Results: AMSC-sEVs positively expressed CD63 and Alix and presented a classical "rim of a cup" and granule shape with approximately 43-100 nm diameter. AMSCs significantly alleviated intestinal fibrosis through secreted sEVs in vitro and in vivo. The milk fat globule-EGF factor 8 (MFGE8) was stably enriched in AMSC-sEVs and was an active compound contributing to the treatment of intestinal fibrosis by AMSCs. Mechanistically, AMSC-sEV-based therapies attenuated intestinal fibrosis by inhibiting the FAK/Akt signaling pathway.

Conclusions: MFGE8-containing AMSC-sEVs attenuate intestinal fibrosis, partly through FAK/Akt pathway inhibition.

Background: Achalasia is a rare motility disorder of the esophagus often accompanied by immune dysregulation, yet specific underlying mechanisms remain poorly understood.

Methods: We utilized Mendelian randomization (MR) to explore the causal effects of cytokine levels on achalasia, with cis-expression/protein quantitative trait loci (cis-eQTLs/pQTLs) for 47 cytokines selected from a genome-wide association study (GWAS) meta-analysis and GWAS data for achalasia obtained from FinnGen. For cytokines significantly linked to achalasia, we analyzed their plasma concentrations and expression differences in the lower esophageal sphincter (LES) using enzyme-linked immunosorbent assay and single-cell RNA sequencing (scRNA-seq) profiling, respectively. We further employed bioinformatics approaches to investigate underlying mechanisms.

Results: We revealed positive associations of circulating Eotaxin, macrophage inflammatory protein-1b (MIP1b), soluble E-selectin (SeSelectin) and TNF-related apoptosis-inducing ligand (TRAIL) with achalasia. When combining MR findings with scRNA-seq data, we observed upregulation of TRAIL (OR = 2.70, 95% CI, 1.20-6.07), encoded by TNFSF10, in monocytes and downregulation of interleukin-1 receptor antagonist (IL-1ra) (OR = 0.70, 95% CI 0.59-0.84), encoded by IL1RN, in FOS_macrophages in achalasia. TNFSF10^high monocytes in achalasia displayed activated type I interferon signaling, and IL1RN^low FOS_macrophages exhibited increased intercellular communications with various lymphocytes, together shaping the proinflammatory microenvironment of achalasia.

Conclusions: We identified circulating Eotaxin, MIP1b, SeSelectin and TRAIL as potential drug targets for achalasia. TNFSF10^high monocytes and IL1RN^low macrophages may play a role in the pathogenesis of achalasia.

Background & aim: SGLT2 inhibitors (SGLT2i) improve hepatic steatosis in patients with type 2 diabetes mellitus (T2DM) and MASLD. We aimed to investigate the impact of SGLT2i on the incidence of liver-related events and extrahepatic cancer compared to DPP4 inhibitors (DPP4i) in patients with T2DM and suspected MASLD using a medical claims database in Japan.

Methods: We conducted a retrospective study using a Japanese medical claims database. Among patients with T2DM who were prescribed SGLT2i or DPP4i (n = 1,628,656), patients with suspected MASLD were classified into SGLT2i (n = 4204) and DPP4i (n = 4204) groups. Effects of SGLT2i on the following outcomes were compared to DPP4i: (1) changes in HbA1c and ALT levels after 6 months, (2) changes in hepatic fibrosis index, and (3) the incidence of liver-related events/extrahepatic cancer over 12 months.

Results: After 6 months, DPP4i significantly decreased HbA1c levels compared to SGLT2i. In contrast, SGLT2i significantly decreased ALT levels compared to DPP4i. SGLT2i significantly decreased FIB-4 index compared to DPP4i over 12 months. Although no significant difference was observed in the incidence of overall liver-related events between the two groups, SGLT2i significantly reduced the incidence of esophageal varices (HR 0.12, 95%CI 0.01-0.95, P = 0.044). Moreover, SGLT2i significantly suppressed the incidence of extrahepatic cancer (HR 0.50, 95%CI 0.30-0.84, P = 0.009) compared to DPP4i.

Conclusion: SGLT2i was more beneficial than DPP4i in improving the hepatic inflammation and fibrosis indices. Moreover, SGLT2i suppressed the incidence of esophageal varices and extrahepatic cancer compared to DPP4i. SGLT2i may suppress life-threatening events in patients with T2DM and suspected MASLD.

Background: S-1 monotherapy had previously been widely used as a second-line treatment for pancreatic cancer (PC) after gemcitabine-based chemotherapy mainly in Japan. Based on the results of the NAPOLI-1 trial, the recommended second-line therapy is now liposomal irinotecan plus fluorouracil/folinic acid (nal-IRI + 5-FU/LV). However, there have been no studies comparing nal-IRI + 5-FU/LV therapy with S-1 monotherapy.

Methods: The main objective of this study was to compare overall survival (OS) in patients treated with nal-IRI + 5-FU/LV and those treated with S-1 monotherapy as second-line treatments, using the inverse probability of treatment weighting (IPTW) method. This study was conducted in 31 institutions participating in Japan Oncology Network in Hepatobiliary and Pancreas. To minimize potential biases due to the retrospective design, IPTW analysis was performed with multiple imputation, and imputed IPTW-adjusted hazard ratios and corresponding 95% confidence intervals (CIs) were estimated using a Cox proportional hazards model and combined into pooled estimates.

Results: A total of 463 metastatic PC patients were enrolled in this study (257 in the S-1 monotherapy group and 206 in the nal-IRI + 5-FU/LV group). The median OS was 7.50 months (95% CI 4.18-12.69 months) in the nal-IRI + 5-FU/LV group and 5.72 months (95% CI 2.76-10.79 months) in the S-1 monotherapy group. In the IPTW-adjusted Cox proportional hazards model, nal-IRI + 5-FU/LV was associated with a significant OS benefit (pooled IPTW-adjusted hazard ratio, 0.779; 95% CI 0.399-0.941; p = 0.025).

Conclusion: These findings support the use of nal-IRI + 5-FU/LV as standard second-line treatment for PC patients after gemcitabine-based chemotherapy.

Background: Data regarding the prevalence of hepatic fibrotic burden across the spectrum of hypothyroidism are scarce. Hence, we aimed to evaluate the prevalence of liver fibrotic burden across the spectrum of hypothyroidism.

Methods: 30,091 individuals who attended a Health Management Centre between 2019 and 2021 were cross-sectionally analyzed. Participants were categorized as having strict-normal thyroid function, low-normal thyroid function, subclinical hypothyroidism, and overt hypothyroidism. Hepatic fibrosis was assessed by vibration-controlled transient elastography (VCTE). Significant and advanced fibrosis were defined as liver stiffness measurement in VCTE of 8.1-9.6 and 9.7-13.5 kPa, respectively.

Results: Among both men and women, low-normal thyroid function group, subclinical hypothyroidism group, and overt hypothyroidism group all have more liver fibrosis present, including mild fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis, than the strict-normal thyroid function group. The low-normal thyroid function group have the similar liver fibrotic burden to the subclinical hypothyroidism group. The highest liver fibrotic burden was noted in the overt hypothyroidism group. Both significant and advanced liver fibrosis were significantly associated with low-normal thyroid function, subclinical hypothyroidism, and overt hypothyroidism in both men and women.

Conclusions: Liver fibrotic burden are highly prevalent in subjects with overt hypothyroidism. Moreover, fibrotic burden increased across the spectrum of hypothyroidism even within the low normal thyroid function. These results suggested that screening for liver fibrosis in patients with hypothyroidism is necessary.

Background: Fontan-associated liver disease (FALD) is a type of progressive liver fibrosis that occurs following Fontan surgery and can be complicated by hepatocellular carcinoma (HCC). Established treatments for FALD are lacking. Therefore, we investigated the efficacy of ursodeoxycholic acid (UDCA) in patients with FALD.

Methods: This single-center retrospective study was conducted from 2003 to 2024 and involved 220 patients (103 men, 46.8%) who had been diagnosed with FALD. UDCA was administered to 113 patients presenting with liver or biliary enzyme abnormalities. We evaluated the patients' liver enzyme levels 3, 6, and 12 months after treatment. HCC developed in 10.5% and the mortality rate was 4.5%. Survival and cumulative incidence of HCC were compared between patients with and without UDCA treatment using Kaplan-Meier curves and propensity-matched analysis (n = 68 per group).

Results: UDCA treatment significantly reduced the aspartate aminotransferase (AST), alanine transaminase (ALT), and gamma-glutamyl transferase (GGT) levels at 3 months. The mean pretreatment AST/ALT/GGT levels were 26/22/323 U/L, respectively, and decreased to 19/15/102 U/L at 3 months, 18/12/88 U/L at 6 months, and 16/19/64 U/L at 12 months. However, the total bilirubin level and platelet count did not show significant differences. The survival rate was higher and the HCC rate was lower in patients with than without UDCA treatment. The 5-year incidence rate of HCC was 5.6% in the UDCA group and 24.2% in the untreated group.

Conclusions: UDCA treatment significantly reduced liver enzyme levels, including GGT, and mitigated the progression of HCC. UDCA may be beneficial for patients with FALD.

Background: The gut mycobiome might have an important influence on the pathogenesis of choledocholithiasis concurrent with cholangitis (CC). The aim of this study was to characterize the fungal mycobiome profiles, explore the correlation and equilibrium of gut interkingdom network among bacteria-fungi-metabolites triangle in CCs.

Methods: In a retrospective case-control study, we recruited patients with CC (n = 25) and healthy controls (HCs) (n = 25) respectively to analyze the gut fungal dysbiosis. Metagenomic sequencing was employed to characterize the gut mycobiome profiles, and liquid chromatography/mass spectrometry (LC/MS) analysis was used to quantify the metabolites composition.

Results: The Shannon index displayed a reduction in fungal α-diversity in CCs compared to HCs (p = 0.041), and the overall fungal composition differed significantly between two groups. The dominant 7 fungi species with the remarkable altered abundance were identified (LDA score > 3.0, p < 0.05), including CC-enriched Aspergillus_niger and CC-depleted fungi Saccharomyces_boulardii. In addition, the correlations between CC-related fungi and clinical variables in CCs were analyzed. Moreover, the increased abundance ratio of Basidiomycota-to-Ascomycota and a dense linkage of bacteria-fungi interkingdom network in CCs were demonstrated. Finally, we identified 30 markedly altered metabolites in CCs (VIP > 1.0 and p < 0.05), including low level of acetate and butyrate, and the deeper understanding on the complexity of bacteria-fungi-metabolites triangle involving bile inflammation was verified.

Conclusion: Our investigation demonstrated a distinct gut fungal dysbiosis in CCs and proposed that, beyond bacteria, the more attention should be paid to significantly potential influence of fungi and bacteria-fungi-metabolites triangle interkingdom interactions on pathogenesis of CC.