eGastroenterology最新文献

Background: Liver transplantation (LTx) was once the standard of care for hereditary transthyretin amyloidosis (ATTRv), but transthyretin (TTR) stabilising and silencing therapies have supplanted it globally, partly because these therapies work in both hereditary and wild-type ATTR, avoids surgical risks and may improve outcomes across a wider patient population. LTx is now reserved for selected ATTRv cases where drug access or efficacy is limited. The Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) was established in 1993 to analyse the outcome of LTx for ATTRv to support the international transplant society with selection criteria as the indication is rare at most centres.

Methods: FAPWTR has, to date, secured data from over 30 years of follow-up. The registry holds data on 2267 patients who had LTx with various TTR variants from 82 centres in 21 countries. All patients studied presented with symptoms of polyneuropathy before LTx. The patient's pre-LTx phenotype was classified according to whether or not the heart and/or the kidney presented symptoms suggestive of amyloidotic involvement as reported by the submitting centre. The present study aims to evaluate the effect of these four different phenotypes on outcome as well as the mortality and morbidity in patients who had LTx with ATTRv.

Results: Between 1990 and 2012, before pharmacotherapy became generally available as a treatment option, 1762 patients underwent isolated LTx. Overall, 25-year survival after LTx was 32.4%. Median survival time was 20.4 years. Cardiac and cardiorenal phenotypes were poor prognostic factors, while renal phenotype was not. The cardiac phenotype had statistically significantly worse survival compared with all other phenotypes. Median survival for the cardiac, cardiorenal and polyneuropathy-only phenotype were 15.2, 20.8 and 22.7 years, respectively. Age at transplant, disease duration and modified body mass index had a statistically significant impact on survival. Deterioration of autonomic neuropathy occurred earlier than deterioration of peripheral neuropathy and deterioration of extraneurological symptoms and may be an important marker for additional pharmacological treatment in LTx recipients with disease progression.

Conclusion: The FAPWTR provides a useful tool to study late effects of LTx as a disease-modifying therapy for ATTRv and may be important for comparison and evaluation of the long-term effects of the various novel pharmacotherapies used today.

Background: Some people with multiple sclerosis display changes in their gut microbiota with separate evidence suggesting that symptoms may worsen following a high-fibre diet. We hypothesised that in people with multiple sclerosis whose gut microbiota are less able to efficiently ferment dietary fibres, unfermented β-fructans induce inflammation.

Methods: Diet data (n=48 individuals with multiple sclerosis, n=78 unaffected controls) and stool microbiome data (n=31 individuals with multiple sclerosis, n=61 unaffected controls) were previously collected from participants. Daily fibre subtype intakes were calculated and compared with faecal shotgun metagenomic sequencing in paediatric onset multiple sclerosis and unaffected persons. Response to unfermented β-fructans was examined in a germ-free experimental autoimmune encephalomyelitis (EAE) mouse model (unable to ferment fibres). Mice were fed β-fructans or control fibre diet beginning at symptom onset (day 14). EAE scores and weights were recorded daily. Intestinal and central nervous system tissues were collected at two endpoints to examine inflammatory responses and demyelinating lesions.

Results: Individuals with paediatric onset multiple sclerosis consumed less β-fructans (2.4 g/day±0.3 SD; p<0.05) than unaffected participants (3.6 g/day±0.4), which coincided with differences in the gut microbiota including lower fibre fermenting enzymes. Mice exposed to unfermented β-fructans sustained worsened EAE symptoms (day 20-28; p<0.05), immune activation in the gut and immune activation plus demyelinating lesions in the spinal cord compared with mice on control diet.

Conclusions: The gut microbiota of individuals with paediatric-onset multiple sclerosis showed reduced fibre fermenting properties, and our animal findings suggest that unfermented β-fructans can worsen demyelination and promote gut-brain axis immune activation. Lower β-fructan consumption was observed among participants with paediatric-onset multiple sclerosis. Future longitudinal studies are warranted to confirm the findings uncovered in this manuscript.

[This corrects the article DOI: 10.1136/egastro-2025-100257.].

Massive hepatic necrosis (MHN), characterised by extensive loss of hepatocytes, represents the most severe pathological lesion in acute liver failure (ALF). MHN-associated ALF primarily occurs in patients with acute viral hepatitis A, B or E infections. Additionally, MHN-associated ALF can develop in patients with autoimmune hepatitis or in those taking idiosyncratic drugs. MHN-associated ALF is associated with significantly higher mortality than that caused by other aetiologies. In contrast to other forms of ALF, liver regeneration following MHN depends on liver progenitor cells (LPCs)-the smallest cholangiocytes localising in the canal of Hering and terminal biliary branches. These cells play key roles in determining the clinical outcome of patients with MHN-associated ALF. This paper reviews the pathophysiology of MHN-associated ALF and recent advances in LPC biology.

Background: Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease with complex aetiology and limited treatment options. Antimicrobial peptides (AMPs), as endogenous immune effectors, have recently emerged as promising therapeutic agents in UC. However, systematic identification and functional evaluation of AMPs remain underexplored. We aimed to discover novel AMPs with potential therapeutic efficacy in UC by leveraging machine learning-based prediction and validating their impact in an experimental colitis model.

Methods: We established a machine learning-driven pipeline to predict candidate AMPs based on their structural and functional features. Top-ranked peptides were synthesised and subjected to in vitro antibacterial assays and proteolytic stability tests. Their therapeutic potential was evaluated using a dextran sulfate sodium (DSS)-induced colitis mouse model, assessing clinical indicators, histopathology, inflammatory markers and gut microbiota alterations. Metagenomic and metabolomic analyses provided insights into microbial community dynamics and metabolic pathways. To probe the role of gut microbes in AMP-mediated gut homeostasis, we conducted Akkermansia (A.) muciniphila replenishment experiments.

Results: Several AMPs identified by machine learning exhibited potent antimicrobial activity and resistance to proteolytic degradation. In vivo, AMP administration ameliorated DSS-induced colitis symptoms, including body weight loss, Disease Activity Index and histological damage. Treatment also modulated the gut microbiome, increasing the abundance of A. muciniphila and restoring microbial balance. Functional metagenomic profiling revealed enrichment of genes involved in mucosal barrier protection and immunoregulation. These findings were supported by improved inflammatory cytokine profiles and enhanced epithelial integrity.

Conclusions: Our findings demonstrate that machine learning-guided discovery of AMPs is a viable approach to identify promising therapeutic agents for UC. By integrating multi-omics analyses, we reveal potential microbiota-mediated mechanisms underlying AMP efficacy. These insights provide a strong foundation for advancing AMP-based strategies in UC management.

Metabolic dysfunction and alcohol-associated liver disease (MetALD) is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol. MetALD is diagnosed in individuals who have at least one metabolic risk factor (such as obesity, type 2 diabetes mellitus, hypertension, etc) and consume 140-350 g/week of alcohol for women or 210-420 g/week for men. Conversely, alcohol-associated liver disease is diagnosed in individuals who consume >350 g/week of alcohol for women and >420 g/week for men. MetALD represents a heterogeneous spectrum of liver disease, with variations in clinical presentation and severity driven by differences in metabolic profiles, drinking patterns and individual susceptibility. Alcohol and metabolic risk factors are thought to act synergistically to accelerate steatohepatitis, fibrosis and hepatocellular carcinoma. However, the precise mechanisms underlying liver injury in MetALD still remain poorly understood. In this comprehensive review, we summarise the current definition, diagnostic criteria and clinical management of MetALD. We also discuss emerging insights into understanding its pathogenesis, examine relevant experimental models and highlight future challenges and research priorities in this evolving field.

Postoperative pancreatic fistula (POPF) is a critical complication following pancreatic surgeries, marked by leakage of pancreatic fluid due to anastomotic or pancreatic duct failure. Recent advancements have refined its definition, risk classification and management strategies. This review emphasises discussing new definitions, classification updates, predictive factors (both pancreatic and non-pancreatic), comparisons of surgical techniques and therapeutic advancements. Emerging trials and innovations, such as robotic-assisted surgery and personalised stents, are also addressed. The evolving understanding of POPF underscores the need for holistic and patient-centred surgical strategies.

In vitro liver disease modelling, a rapidly evolving field, has become a multidimensional endeavour aimed at more precisely and effectively recapitulating the complexity of hepatic pathophysiology. This review systematically outlines the essential structural and cellular components of the liver as foundational elements for model design. Emphasising pathophysiological states rather than disease hallmarks, we discuss key liver injury paradigms, including hepatic steatosis, drug-induced hepatotoxicity, fibrogenesis, tumourigenesis and cholestatic injury. Each section integrates cellular mechanisms with model development strategies, highlighting advances in co-culture systems, multicellular organoids and liver-on-a-chip platforms. Although challenges persist, emerging platforms are increasingly capable of capturing multicellular crosstalk, structural heterogeneity and injury-response dynamics. Moving forward, model utility will depend not only on structural mimicry but on the ability to produce biologically meaningful outputs under experimentally controlled conditions.

Background: Alcohol-associated liver disease (ALD) is a global health problem without an effective treatment. Mallory-Denk body (MDB) is a protein aggregate commonly found in alcohol-associated hepatitis (AH). MDB primarily contains ubiquitinated proteins, cytokeratin 8 and sequestosome 1 (SQSTM1)/p62. Stress granule (SG) is a cytosolic, membrane-less aggregate composed of various RNA-binding proteins and untranslated mRNA. However, the role and mechanisms of MDB and SG induced by alcohol and their implications in the pathogenesis of ALD remain largely unknown.

Methods: SQSTM1/p62 whole body knockout and matched wild-type mice were subjected to the Gao-binge alcohol model or fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet alongside Gao-binge alcohol model. ALD mouse liver tissues and human AH liver tissues underwent immunohistochemistry (IHC) staining and western blot analysis for SG and MDB markers.

Results: We found that the livers of patients with AH had higher levels of SQSTM1/p62 (MDB marker) and Ras-GTPase-activating protein-binding protein 1 (an SG marker) using IHC staining, and these increased protein levels were enriched in detergent-insoluble fractions compared with healthy individuals. We further discovered that Gao-binge alcohol feeding increased insoluble SG markers, such as phosphorylated eukaryotic initiation factor 2 in mouse livers. Mice fed a DDC diet with Gao-binge alcohol had greater hepatic MDB formation and liver injury than those fed either diet alone. Loss of SQSTM1/p62 led to reduced protein aggregation involved in SGs and MDBs but increased liver injury in DDC plus Gao-binge alcohol-fed mice, indicating that SQSTM1/p62 is required for MDB formation and protects against alcohol-induced liver injury.

Conclusion: Chronic plus binge alcohol exposure increases hepatic MDBs and moderate levels of SGs. p62/SQSTM1 is critical for the formation but is not essential for the clearance of MDBs, a process that may act as an adaptive protective mechanism against ALD.

Liver metastases (LMs) pose a significant burden of morbidity and mortality, resulting in a worse prognosis for many primary malignancies. Despite advancements in cancer treatment, such as immunotherapy, molecular therapies, additional lines of chemotherapy and optimisation of surgical resection, effective therapy against hepatic metastases remains elusive. Recent studies in immuno-oncology have implicated distinct tumour microenvironment (TME) signatures in the hepatic metastatic niche, which interplay with the intrinsic microenvironmental features specific to each primary tumour or organ of origin. Regulatory T cells (Tregs) have been implicated in the immunosuppressive nature of the hepatic TME, yet the exact mechanisms of interaction have not been fully elucidated. Discrepancies in number, function and proportion of Tregs to other tumour-infiltrating lymphocytes have been documented, with conflicting findings in the LMs from different primary tumours. These results may be attributable to the underlying biology of each organ-specific tumour and the unique hepatic TME that forms during the stepwise progression of the metastatic cascade. In this review, we explore the often-contradicting findings of intrahepatic Tregs in LMs from different originating tumours and offer insight into potential mechanisms for these observed differences with implications for future therapeutic strategies.