eGastroenterology最新文献

Background: Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease, with significant improvements in short-term survival over the decades. However, long-term survival and trends in LT indications and outcomes remain areas of active research. This registry-based study evaluates 40 years of LT in Finland, assessing patient and graft survival, retransplantation rates, changing recipient and donor demographics, indications and benchmarking outcomes against international standards.

Methods: Data were extracted from the nationwide Finnish LT registry, covering all LTs performed in Finland between 1982 and 2024. Survival analyses were estimated using the Kaplan-Meier methodology and retransplantation rates were assessed using the cumulative incidence function. Benchmark cases were defined by international criteria.

Results: A total of 1763 LTs were performed, with a mean recipient age of 46 years. The most common aetiologies were alcohol-related liver disease (19%) and primary sclerosing cholangitis (PSC; 16%). Over time, recipient and donor age, body mass index and prevalence of diabetes increased. One-year patient survival improved from 83% in the 1980s to 96% in 2020-2024, with the overall 5-year, 10-year, 20-year and 30-year patient survival being 83%, 73%, 53% and 28%, respectively. The retransplantation rate was 13% at 30 years overall and 28% in PSC. Benchmark cases had one-year patient and graft survival rates of 97% and 96%, respectively. Acute rejection rates declined from 62% during 1980-1989 to 19% during 2022-2023. Post-transplant kidney-replacement therapy peaked at 26% in 2010-2021, thereafter decreasing to 8% after the year 2022.

Conclusion: The Finnish LT programme demonstrates sustained improvements in short- and mid-term survival, with evolving indications and recipient and donor demographics. Benchmark analyses confirm high-quality outcomes. Continued efforts are needed to optimise long-term survival and reduce the need for retransplantation, especially in PSC.

Background: Autophagy is critical for cellular homeostasis. Autophagy related 14 (ATG14) is a key regulator of autophagy initiation; however, its role in hepatocyte survival remains poorly understood. This study aimed to investigate the hepatocyte-specific function of ATG14 in vivo.

Methods: We generated Atg14 hepatocyte-specific knockout (HepKO) mice using adeno-associated virus to deliver thyroxine-binding globulin gene promoter-driven Cre into Atg14 floxed mice at an adult age and fed control and knockout mice with either normal chow or a Western diet. Blood and tissue samples were collected for biochemical and histological analyses.

Results: Atg14 HepKO mice develop severe hepatomegaly under normal dietary conditions. ATG14 deficiency leads to hepatic injury, inflammation and fibrosis. Multiple forms of cell death, including apoptosis and pyroptosis, increase significantly. When challenged with a Western diet for 4 weeks, Atg14 HepKO mice exhibit exacerbated hepatic injury, inflammation and fibrosis despite no significant lipid droplet accumulation in the liver. Transcriptomic analysis reveals upregulation of several cell death pathways, including pyroptosis, apoptosis and necroptosis. Further biochemical and microscopic analyses validate the induction of multiple cell death pathways. In addition, NLR family pyrin domain containing 3 inflammasome-mediated pyroptosis is significantly elevated in Atg14 HepKO mouse livers and ATG14-deficient hepatocytes.

Conclusion: Our data suggest that ATG14 is required for maintaining hepatocyte identity, survival and function and that hepatic ATG14 deficiency may lead to hepatomegaly, tissue injury, inflammation and fibrosis.

Cluster of differentiation 47 (CD47) is a widely expressed transmembrane protein that serves as a critical immunoregulatory checkpoint in both homeostatic and pathological conditions of the digestive system. It interacts with signal regulatory protein alpha to send a 'do not eat me' signal, thereby preventing phagocytosis and shaping immune responses. Beyond immunity, CD47 also influences cell death, growth and metabolism through interactions with integrins and thrombospondin-1. Recent studies implicate CD47 as a central nexus in the pathogenesis of diverse liver and gastrointestinal disorders, including metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, inflammatory bowel disease, liver ischaemia-reperfusion injury, drug-induced liver injury and gastrointestinal malignancies such as hepatocellular carcinoma, colorectal and pancreatic cancers. CD47 contributes to disease progression through immune modulation, endothelial dysfunction, fibrogenic activation and suppression of antitumour immunity. This review summarises current mechanistic insights into CD47 signalling across digestive diseases and highlights its emerging potential as a therapeutic target for immunometabolic and oncological interventions in gastroenterology and hepatology.

Background: Farnesoid X receptor (FXR) has been identified as a therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH). Hepatic FXR is especially critical in suppressing liver inflammation. FXR agonism and antagonism have both proven to be beneficial in the mitigation of MASH, leading to much controversy in the field, particularly regarding FXR signalling in the gut. The objective of this study was to determine the effects of ursodeoxycholic acid (UDCA), a postulated gut FXR antagonist with liver protective effects, on the mitigation and prevention of MASH development in mice with hepatic FXR deficiency.

Methods: For this experiment, six-week-old to eight week-old male and female liver-specific FXR knockout (FXR^hep-/-) and control (FXR^{hep flox/flox}) mice were fed either a low-fat control diet (CTL) or a MASH 'Fast Food' diet (Western diet with 21% milk fat, 1.25% cholesterol and 34% sucrose) both supplemented with or without 0.1% (weight/weight; w/w) UDCA for 16 weeks.

Results: UDCA feeding tended to reduce alanine aminotransferase levels and decrease liver lipids in the male mice. Supplementation of UDCA showed a trend towards increased UDCA and tauroursodeoxycholic acid (TUDCA) levels in serum, liver and intestine, although the male mice displayed more than twice the amount of these bile acids compared with the female mice. CTL-UDCA feeding resulted in a significant induction of Fxr and Fgf15 mRNA expression in the ileum of the male mice.

Conclusion: The data strongly suggest that UDCA seems to act as an FXR agonist, especially in the ileum, which contrasts with previous reports that UDCA acts as a gut FXR antagonist. In addition, UDCA seems to be exerting liver protective effects predominantly in the male mice.

Background: Monoclonal antibodies (mAbs) targeting immune checkpoint molecules such as programmed death ligand 1 (PD-L1), which is expressed in both immune and tumour cells, are conventional immunotherapy approaches. Although approved as monotherapy for the first-line treatment of several cancers, mAbs targeting PD-L1 have shown limited efficacy in colorectal cancer (CRC). Here, we investigated if nucleic acids translated into anti-PD-L1 nanobodies (PDL1Nbs) effectively suppress CRC tumourigenesis in mouse models.

Methods: Mice were transplanted with MC-38 mouse sporadic CRC (sCRC) cells or challenged with azoxymethane and dextran sodium sulfate, a combination treatment that induces colitis-associated CRC (CAC). The tumour-bearing mice were treated with a PDL1Nb-encoding plasmid DNA (pDNA) delivered via polymers, or treated with PDL1Nb-encoding nucleoside-modified messenger RNA (PDL1Nb mRNA) delivered via lipid nanoparticles (LNP). Moreover, bone marrow haematopoietic stem cells (BMHSCs) were differentiated and maturated by treating growth factors in the presence of PDL1Nb mRNA-LNP or control luciferase mRNA-LNP with/without lipopolysaccharide. We examined sCRC tumour proliferation and growth, CAC tumour incidences and numbers, tumour infiltration of immune cells and bone marrow-derived macrophages (BMDMs).

Results: Polymer delivery of PDL1Nb pDNA efficiently repressed sCRC progression in tumour-bearing mice. Intriguingly, LNP delivery of the quadruple PDL1Nb (qPDL1Nb) mRNA showed a greater efficacy than the delivery of the monomeric PDL1Nb (mPDL1Nb) mRNA in suppressing sCRC tumour progression. Moreover, qPDL1Nb mRNA-LNP treatment significantly reduced CAC incidence. Mechanistically, PD-L1 blockade by qPDL1Nb resulted in marked decreases in tumour-infiltrating myeloid-derived suppressor cells and tumour-associated macrophages, as well as expression of PD-L1, but increases in tumour-infiltrating CD3⁺CD8⁺ cells during CAC tumourigenesis. Notably, in vitro LNP delivery of PDL1Nb mRNA into BMHSCs significantly inhibited their differentiation and maturation into BMDMs and strikingly reduced the expression of PD-L1, CD80, CD86 and CD206 in BMDMs.

Conclusion: These results suggest that the PDL1Nb therapy is effective for both CAC and sCRC and using qPDL1Nb mRNA-LNP is a promising alternative strategy for CRC immunotherapy.

Background: Imbalance in the gut microbiome is known to play a role in colorectal cancer (CRC) development. Recent studies observed alterations in the faecal and mucosal DNA virome in CRC, but the role of mucosal virome including both DNA and RNA viruses in colorectal adenomas, the precursors to CRC, is unclear. Here, we investigated the human host transcriptome, mucosal virome and potential correlations between them in paired biopsy samples of colorectal polyps and their adjacent normal tissue.

Methods: Paired colorectal polyp and adjacent normal mucosa biopsies from the same individuals were collected from 41 patients and subjected to comprehensive multiomics profiling. Total RNA and microRNA were analysed using whole transcriptome sequencing, while virus-like particles were enriched from paired samples and profiled via shotgun metagenomic sequencing. Integrated statistical and network analyses were performed to compare expression profiles and virome composition between polyp and adjacent normal mucosa from the same individuals, and to identify host-virome associations.

Results: The host transcriptome was found to be highly altered in polyps, whereby numerous differentially expressed RNAs and microRNAs were identified compared with their paired adjacent normal mucosa from the same individuals. Pathway enrichment analysis revealed that these differentially expressed genes were enriched in metabolism and absorption, neurotransmission and cell signalling pathways. The mucosal virome was also altered in polyps, with reduced viral richness and evenness and distinct community composition compared with their paired adjacent normal mucosa from the same individuals. Poxviridae, Retroviridae and BeAn 58058 virus were enriched, whereas Caudoviricetes sp was depleted. Such mucosal virome signatures correlated with host transcriptomic signatures in polyps. Caudoviricetes sp was negatively correlated with genes involved in cancer pathways, thus is potentially CRC-protective. Conversely, Poxviridae, Retroviridae and BeAn 58058 virus were negatively correlated with genes involved in tumour suppression, thus are potentially CRC-inducing.

Conclusion: This study suggests that alterations in host transcriptomes and virome of colorectal polyps are correlated, providing a foundation for future functional studies.

As environmental exposomes are changing with time, so are liver diseases around the globe. Due to an increasing prevalence of overnutrition and sedentary lifestyle in the global population, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis have been increasing steadily in the past decades. Alcohol consumption is another common risk factor for liver diseases such as alcohol-associated liver disease or hepatitis. For both alcohol-associated and metabolic dysfunction-associated liver diseases, hepatocyte injuries are among the early events during the development of steatotic liver disease (SLD). Hepatic inflammation and fibrosis ensue with recurring hepatic damages owing to immune responses from multiple immune cell types, particularly neutrophils, Kupffer cells and monocyte-derived macrophages in response to damage-associated and pathogen-associated molecular patterns, and extracellular matrix production predominantly from hepatic stellate cells. Both environmental and genetic factors contribute to the SLD pathogenesis. Common environmental risk factors include obesity, type 2 diabetes mellitus, unhealthy diets, sedentary lifestyle and excessive alcohol consumption. Numerous genome-wide association studies have identified multiple genetic variants associated with key traits of SLD, including patatin-like phospholipase domain containing 3 rs738409, transmembrane 6 superfamily member 2 rs58542926, membrane bound O-acyltransferase domain containing 7 rs641738 and hydroxysteroid 17 beta-dehydrogenase 13 rs72613567. Cirrhosis and liver cancer are common late-stage developments of various chronic liver diseases; however, there are pathological differences according to disease aetiologies. Therefore, preventive and therapeutic intervention strategies should align with the underlying causal and modifiable factors. Currently, multiple therapeutics have been developed or approved for treatment of SLD, including thyroid hormone receptor β agonists, glucagon-like peptide 1 receptor agonists and fibroblast growth factor 21 analogues. The concept of this review was motivated and inspired by the Seventh Annual Symposium of Chinese American Liver Society held in San Diego, California, USA on 13-14 November 2024.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally, with rising prevalence linked to metabolic syndrome (MetS). Excessive liver fat accumulation (steatosis) worsens disease progression and MASLD prognosis. Moreover, gut microbiota dysbiosis might promote steatosis, accelerating the disease progression to severe stages. Identifying gut microbiota signatures specific to steatosis severity might improve its diagnosis and inform personalised interventions in MASLD. This study aimed to characterise associations between gut microbiota composition and hepatic steatosis severity in a cohort of patients with MASLD/MetS. Ultimately, we aimed to assess the potential for microbiota features to enhance the diagnosis of severe steatosis.

Methods: A cross-sectional cohort of 61 patients with MetS with extensive clinical history was recruited at different stages of MASLD. Transient elastography was used to evaluate liver fibrosis and steatosis severity. Participants' faecal microbiota were profiled using 16S rRNA gene sequencing. Statistical analyses first identified correlations between microbiota profiles and patients' phenotypes, while disentangling important confounders such as medication. Identified features were then used to build predictive models for diagnosing severe steatosis.

Results: High steatosis severity was distinctly associated with a higher prevalence of the inflammation-associated Bacteroides 2 (Bact2)-enterotype, accompanied by a lower proportion of beneficial commensals (eg, Akkermansia) and a higher proportion of opportunistic bacteria (eg, Streptococcus). Patients harbouring a Bact2-enterotype reached severe steatosis at lower Fatty Liver Index (FLI) thresholds. Using Bact2-carrier status together with FLI in a predictive model significantly improved the classification of severe steatosis (accuracy 90%, receiver operating characteristics 96%) when compared with FLI alone.

Conclusion: Gut microbiota composition and dysbiosis (defined as Bact2-enterotype) are distinctly associated with steatosis severity in MASLD/MetS. Patient stratification by microbiota composition enhances the diagnostic classification of severe steatosis in MASLD, suggesting a potential for personalised interventions in patients with microbiota dysbiosis.

Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), is associated with several hepatobiliary manifestations, most importantly primary sclerosing cholangitis (PSC). The association between these entities is bidirectional, though not necessarily causal, making the underlying pathogenesis challenging to decipher. While not yet fully elucidated, current evidence suggests that genetic and immunological factors play key roles in the coexistence of IBD and PSC. In this review, we aim to provide a comprehensive analysis from a clinical perspective, evaluating the association between PSC, PSC-associated cholangiocarcinoma, orthotopic liver transplantation for PSC, IBD, colitis-associated neoplasia and restorative proctocolectomy with ileal pouch-anal anastomosis for UC. Despite efforts of data collection through population-based registries, much of the existing evidence is based on small cohorts, often with low event rates and limited follow-up durations. This makes it challenging to draw definitive conclusions. Acknowledging the variability and heterogeneity of prior studies, we aim to offer valuable insight for gastroenterologists and hepatologists managing this unique and often challenging scenario, which some authors consider a new entity: PSC-IBD. Longitudinal studies with extended follow-up periods are needed to better understand the disease course of PSC and UC, including the impact of medical therapy, the development, surveillance and management of neoplasia, and the outcomes of surgery for both bowel and liver diseases.