Barrett's oesophagus (BE) continues to rise in prevalence alongside oesophageal adenocarcinoma; understanding and identifying early neoplastic changes is critical. Crypt dysplasia (CD) in BE is an emerging concept characterised by dysplasia confined to the crypt base without surface involvement. Recent studies suggest that CD shares molecular alterations with low-grade and high-grade dysplasia, such as TP53 mutations and chromosomal instability, and may represent an early phase of neoplasia. Grading of CD remains inconsistent, with limited correlation to clinical outcomes, although classifying CD into low-grade and high-grade categories provides a practical diagnostic framework. High-grade crypt atypia typically warrants a diagnosis of CD, whereas low-grade crypt atypia poses greater diagnostic challenges and requires careful differentiation from reactive changes. This framework also incorporates exclusionary criteria, such as inflammation, ulceration and erosion. This review encompasses key features of CD, the diagnostic pitfalls encountered in clinical practice and the underlying biology driving crypt dysplasia. Future studies focusing on the natural history of CD, its molecular underpinnings and interobserver reproducibility will be pivotal in refining diagnostic criteria and improving patient outcomes in BE.

Inflammatory bowel disease (IBD) is typically diagnosed after the onset of symptoms in the context of established, characteristic patterns of intestinal inflammation. However, there is now substantial evidence pointing to a prolonged, biologically active preclinical phase of disease. Analysis of archived biological samples from large-scale longitudinal cohort studies of healthy individuals, some of whom develop incident IBD, has identified different molecular features that can be detected many years before clinical presentation. These include increased titres of antimicrobial and autoreactive antibodies and perturbations in a complex network of circulating, immunologically active proteins. As well as affording 'diagnostic' opportunities to identify individuals destined to develop IBD, an integrated view of these multiple different molecular features enables speculation of potential proximal drivers of preclinical IBD. Consistently recognised associations include dysregulated mononuclear phagocyte-lymphocyte interactions, augmented chemotaxis, frequently relating to interferon-γ-driven chemokine programmes and evidence of early tissue injury, such as increased circulating extracellular matrix components and metalloproteinases. Increased levels of circulating antibacterial and antiviral antibody responses hint towards disordered host-microbe interactions as potential prime triggers for the transition between health and early disease, although it is possible that these serological responses are an epiphenomenon linked to early mucosal damage and microbial translocation. There is now a timely opportunity to develop these different molecular features into scalable and clinically tractable biomarker panels to detect preclinical disease and enable strategies to proactively intercept IBD before it even develops.

The gut microbiota plays a crucial role in regulating host immunity, metabolism and inflammation, with accumulating evidence linking its composition and function to the development and progression of cancers in the reproductive tract. Patients with ovarian, endometrial and cervical cancers exhibit distinct alterations in their gut microbiota, characterised by reduced microbial diversity and shifts towards taxa associated with dysbiosis and chronic inflammation. Mechanistically, gut-derived metabolites and microbial translocation appear to influence systemic immune responses and oestrogen metabolism, thereby fostering a tumour microenvironment conducive to cancer growth. Beyond its role in tumourigenesis, the gut microbiota also affects treatment outcomes. Dysbiosis can reduce sensitivity to chemotherapy and alter immunotherapy responses, while antibiotic use during cancer treatment has been linked to poorer prognosis. Clinically, these insights highlight emerging applications of microbiome modulation as biomarkers for patient stratification and as adjuvant approaches to enhance therapeutic efficacy in gynaecological oncology, underscoring the therapeutic potential of targeting the microbiota-through dietary interventions, probiotics or faecal microbiota transplantation-to improve cancer treatment outcomes. However, most of these applications remain investigational, and current evidence is limited by heterogeneity across study designs, patient cohorts and cancer subtypes. This review summarises current understanding of gut microbiota profiles in reproductive tract cancers, examines potential mechanisms by which the microbiota influences malignancy, discusses its impact on therapy response and explores its emerging role in precision oncology.

Carbamoyl phosphate synthetase 1 (CPS1) is primarily expressed in hepatocytes as a highly abundant mitochondrial matrix enzyme that catalyses the first step of the urea cycle that leads to renal nitrogen disposal. CPS1 is a member of the CPS family that manifests broad evolutionary expression from bacteria to humans. CPS1 expression and enzyme activity are highly regulated transcriptionally and post-translationally. Its autosomal recessive mutation leads to CPS1 deficiency, which causes encephalopathy and coma, typically neonatally, due to severe hyperammonaemia. CPS1 is physiologically secreted, apically, into bile likely via mitochondria-derived vesicles. Normally absent from serum, it is released by basolateral mistargeting and cellular injury and becomes readily detectable in serum during acute liver failure (ALF). Injury-triggered CPS1 release into blood, or media in cultured hepatocytes, is selective as compared with other mitochondrial proteins. This, coupled with its abundance and short (1-2 hours) serum half-life, renders it a prognostic serum biomarker, particularly in human acetaminophen-related ALF. Its rapid turnover is explained by its non-enzymatic role as an immune modulator via its uptake by circulating monocytes leading to differentiation of anti-inflammatory cells that home to, and protect, the injured liver. CPS1 also plays a growing role in several cancers, by CPS1 upregulation or downregulation, particularly via metabolic reprogramming which alters the tumour microenvironment and impacts cancer growth and progression. Therefore, CPS1 has multiple enzymatic and non-enzymatic touch points spanning a wide range of cellular and extracellular functions and roles, with important physiological, homoeostatic, genetic disease, diagnostic and potential therapeutic clinical implications.

Postoperative recurrence (POR) is a major challenge in the long-term management of Crohn's disease (CD), affecting up to 70% of patients within the first year after surgical resection. The multifactorial pathogenesis of POR complicates prevention, while evolving surgical techniques and different anastomotic configurations further hinder accurate prediction and monitoring.Current surveillance strategies, including standard ileocolonoscopy and faecal calprotectin, remain limited by suboptimal accuracy, the absence of validated scoring systems and the lack of standardised monitoring intervals. Recent advances in high-resolution endoscopic imaging, such as confocal laser endomicroscopy and endocytoscopy, enable real-time, in vivo microstructural assessment of the anastomosis, offering opportunities for earlier and more precise detection of recurrence. In parallel, developments in intestinal ultrasound and cross-sectional imaging are reshaping non-invasive monitoring by providing transmural evaluation. Beyond imaging, multiomics approaches, spanning genomics, transcriptomics, proteomics, metabolomics and metagenomics, are uncovering novel biological pathways linked to POR, providing new mechanistic insights.Artificial intelligence (AI) has the potential to integrate clinical, endoscopic, imaging and omics data into predictive multimodal models for POR, supporting individualised risk stratification, early detection and personalised treatment strategies. While promising, these innovations require prospective validation, methodological standardisation and integration into clinical workflows before translation into routine practice.This review summarises the current understanding of POR, highlights emerging diagnostic and monitoring technologies and explores how AI-enabled endoscopy and multi-omics approaches may transform future management, paving the way towards precision medicine for POR in CD.

IBD is rising worldwide and is now a global disease. With the expanding armamentarium of medical therapies, including biologics and small molecules, there is a decline in hospitalisation rates and IBD-related surgeries. However, high costs, injectable therapy, risk of opportunistic infections and the lifelong nature of the disease pose significant challenges in the management of IBD. Developing countries are also constrained by a lack of trained manpower, as well as economic and infrastructural limitations. Strategies aimed at the prevention of IBD may alleviate the suffering and cost of this disease. Suggested approaches include implementation of prevention and interception trials using dietary, pharmacological and precision medicine approaches. However, these would necessitate massive funding and equitable infrastructural support for identifying the population at risk (for prevention trials) and those with preclinical disease (for interception trials). Hence, these strategies are unlikely to be globally practicable or economically viable, particularly in the Global South. It is believed that IBD, like certain non-communicable diseases (NCDs) such as metabolic syndrome and cardiovascular disorders, may be preventable by modifying the risk factors. Therefore, in this review, we advocate for an alternative approach of combining evidence-based IBD prevention strategies with the time-tested strategies of NCD prevention approaches already being implemented. We suggest a sieving strategy for selecting preventive measures through a series of sieves-interventions that have evidence to support prevention, align with NCD prevention and are economically viable.

Metabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial metabolic liver disease that occurs in the context of obesity, insulin resistance and cardiometabolic comorbidities. Monotherapy targeting single pathways often provides only partial improvements in histological liver fibrosis and systemic metabolic parameters, prompting growing interest in multitargeted combination therapies. Multitargeted and combination strategies for MASH can modulate multiple and complementary pathogenic processes, potentially improving efficacy, promoting liver fibrosis regression, optimising systemic metabolic outcomes and reducing treatment-related adverse effects. Liver-directed combination therapies, such as thyroid hormone receptor-beta (THR-β) agonists along with acetyl-CoA carboxylase (ACC) inhibitors or peroxisome proliferator-activated receptor agonists, aim to improve histological features of MASH. Regimens combining systemic metabolic and liver-specific agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists with fibroblast growth factor-21 analogues or THR-β agonists, aim to optimise metabolic outcomes, including body weight, insulin resistance and plasma lipids. Thoughtfully designed drug pairings, such as diacylglycerol O-acyltransferase 2 inhibitors combined with ACC inhibitors or GLP-1 and glucagon receptor dual agonists, could improve safety and tolerability by leveraging complementary mechanisms that may mitigate adverse effects. These therapeutic strategies aim to achieve more comprehensive and durable improvements in both liver pathology and systemic health than single-agent therapy alone. This review integrates current knowledge on multitargeted and combination therapies for MASH, examines mechanistic rationales and emerging clinical evidence and addresses practical considerations for patient-centred implementation. Therefore, we aim to provide clinicians and researchers with a comprehensive framework to optimise individualised management and improve both hepatic and systemic outcomes in individuals living with MASH.

Chronic HBV infection remains a major global health burden, with current antiviral therapies effectively suppressing viral replication but rarely achieving functional cure. Adaptive immunity is central to viral clearance but is profoundly impaired during chronic infection. Inducing and enhancing adaptive immunity through therapeutic vaccines, immune checkpoint inhibitors or T cell-based therapies represents a promising approach for HBV cure strategies. However, recent preclinical and clinical studies have demonstrated only limited efficacy, underscoring major immunological challenges. In this review, we summarise current knowledge of the correlates of viral clearance and persistence, discuss key unresolved questions and outline future research directions needed to advance immune-based HBV cure strategies.

Rigorous donor screening is fundamental for the safe and effective delivery of faecal microbiota transplantion (FMT) services, whether in the treatment of Clostridioides difficile infection or within microbiome intervention clinical trials. Donor screening is of paramount importance given the potential risk of pathogen transmission-a feared complication. While rare in practice, documented cases of FMT-associated infections have resulted in significant morbidity and even mortality. Despite the importance of screening, evidence-based approaches to developing donor-screening protocols are lacking. Inadequate screening for transmissible pathogens may lead to infections in recipients, while overly cautious screening for pathogens with negligible transmission potential could strain healthcare resources and unnecessarily exclude donors, who are already in limited supply. This review aimed to evaluate the evidence underpinning current FMT donor screening protocols. We began by comparing protocols from major FMT guidelines and manufacturers, highlighting their differences in lists of screened pathogens, laboratory assays and clinical characteristics used for donor selection. We critically appraised the existing literature on transmission dynamics for pathogens. These findings were incorporated into a Delphi process with an expert panel group to develop a rational and streamlined screening approach. We further emphasised the importance of maintaining transparency with regard to donor recruitment, screening, monitoring and traceback record keeping. Finally, we explored future directions in donor screening, including approaches to monitoring emerging pathogens and the potential for integration of new technologies, such as metagenomic assays, to enhance and refine donor selection.

IBD has become a global disease in the 21st century that shifts through four epidemiological stages. Alterations in the gut microbiome consisting of a complex multikingdom community of bacteria, fungi and viruses are strongly linked to disease pathogenesis. Advances in sequencing technologies, multiomics integration and experimental approaches have shed new insights into host-microbiota interactions in IBD and characterised mechanisms through which the microbiota and its metabolites contribute to disease. We review the evolution of microbiome-based research, with a focus on genetic and environmental factors affecting the gut microbiota, the role of cross-kingdom microbiome and their bioproducts in disease development and new strategies by which microbiome-based approaches can be used to diagnose, monitor, prevent and treat IBD.

The burden of gastric cancer remains substantial in Asia. Gastric premalignant conditions, including chronic atrophic gastritis, intestinal metaplasia and dysplasia, are important intermediate stages in the gastric carcinogenesis cascade. The sojourn time allows endoscopic surveillance to have a pivotal role in early detection and timely intervention.

The clinical and molecular heterogeneity of IBD-both between patients and within the same individual over time-continues to pose a significant challenge to the implementation of truly personalised treatment strategies. Unlike oncology, where somatic mutation patterns define an actionable information layer, IBD lacks detectable dominant molecular drivers that can guide therapeutic choices. Although the therapeutic landscape has broadened with the advent of numerous biologics and small molecule drugs, predictive (ex ante) biomarkers for treatment response remain elusive. In this review, we assess the current progress and limitations of biomarker-guided precision therapy in IBD. We argue that traditional binary response definitions at single landmark endpoints fail to reflect the multidimensional and dynamic nature of therapeutic outcomes. We hence propose combined, and thus individualised, endpoints such as comprehensive disease control as a more holistic and responsive therapy goal in IBD. We propose to integrate the individual longitudinal dynamics of treatment response, and also continuous, objective monitoring of subclinical residual inflammation, analogous to the concept of minimal residual disease in oncology. In this concept, longitudinal assessment of patient-reported outcomes and molecular profiling in response to therapy may serve as early predictors of long-term outcomes, guide early therapeutic adjustments and reveal mechanisms that open new therapeutic avenues, such as adjunct or combination treatments. Adopting this dynamic, data-driven approach to treatment adaptation could shift management of IBD from reactive to proactive and substantially improve long-term outcomes with the vision to fully control a life-long disease.

Colorectal cancer (CRC) is one of the most common malignant cancers and its incidence is steadily rising particularly in young patients. While screening measures and the widespread availability of surgical treatment have led to an impressive improvement of prognosis within the overall CRC population, patients with metastatic CRC still face 5-year survival rates of around 10-25%. Despite continuous development of new systemic treatment strategies that include cytotoxic chemotherapy and targeted therapy, most patients with metastatic CRC eventually progress. However, a small proportion of patients with mismatch repair-deficient or microsatellite unstable CRC responds exceptionally well to treatment with immune checkpoint inhibitors, thereby proving that CRC is in principle amenable to immunotherapy and showing that long-term disease stabilisation can be achieved even in metastasised stages. However, the reasons for the lack of response to immunotherapy in the vast majority of CRC cases remain to be elucidated. Yet, recent evidence suggests that the tumour stroma, which includes non-immune cells in the colorectal tumour microenvironment, mediates immunosuppressive mechanisms that prevent effective immunotherapy. These findings open new avenues for the development of advanced immunotherapies for CRC. In this review, we summarise major developments in the systemic therapy of CRC within the last couple of decades, provide an overview of emerging and soon-to-be implemented therapeutic strategies and present concepts from clinical and preclinical research to manipulate tumour cells and the tumour stroma to sensitise microsatellite stable colorectal tumours to immunotherapy.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, largely due to the limited efficacy of current therapies in advanced stages of the disease. Most cases of HCC develop in the setting of chronic liver disease, particularly cirrhosis, where ongoing cycles of inflammation, hepatocyte death and regeneration foster the gradual accumulation of genetic and epigenetic alterations that promote malignant transformation. These molecular changes contribute to the high degree of tumour heterogeneity observed in HCC, a major factor underlying resistance to current treatments. As a result, sustained clinical responses to existing therapies, such as tyrosine kinase inhibitors, anti-angiogenic agents and immune checkpoint inhibitors, remain uncommon. In this context, a growing body of evidence has identified epigenetic dysregulation as a key driver of tumour progression and therapeutic resistance, highlighting a new frontier for intervention. This review provides clinicians and researchers with a comprehensive overview of the emerging field of epigenetic therapies in HCC, summarising results from both completed and ongoing clinical trials involving the so-called 'epidrugs'. Importantly, we discuss how targeting epigenetic mechanisms may not only suppress tumour growth but also enhance the effectiveness of current therapies by reversing resistance pathways. By translating complex molecular insights into tangible therapeutic strategies, epigenetics is poised to reshape the future of HCC management, offering renewed hope for more durable and personalised treatment responses in a disease where progress is urgently needed.

Recent advances in high-throughput microbiome profiling have generated expansive data sets that offer unprecedented opportunities to investigate the role of microbes in human health. However, the complexity and high dimensionality of these data present significant analytical challenges that often exceed the capabilities of traditional computational methods. Artificial intelligence (AI), encompassing both classical machine learning and modern deep learning approaches, has emerged as a powerful solution to these challenges. In this review, we systematically explore AI-driven methodologies in microbiome research, including clustering algorithms, dimensionality reduction techniques, convolutional and recurrent neural networks, and emerging large language models. We assess how these approaches enable the extraction of meaningful biological patterns from complex microbial data from a multiscale perspective, facilitating insights into community dynamics, host-microbe interactions and functional genomics. Additionally, we explore the transformative impact of AI on translational applications across both academic research and real-world clinical settings, including disease diagnostics, therapeutic development and precision microbiome engineering. By critically evaluating the current capabilities and limitations of AI in this context, this review aims to chart a path forward for the integration of AI into microbiome research, ultimately accelerating innovations in personalised medicine and deepening our understanding of host-microbiome relationships.

To convene a global consensus on Helicobacter pylori (H pylori) screening and eradication strategies for gastric cancer prevention, identify key knowledge gaps and outline future research directions.

Pregnancy can be a complex and risk filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data.

The liver is a highly multifunctional organ that can perform many metabolic and immunological functions due to a highly complex spatially organised microarchitecture that is disturbed in many liver diseases. Recent methodological advances in spatial omics technologies enable the comprehensive study of the intrahepatic proteome, transcriptome and metabolome at near single-cell and subcellular resolution. The spatial resolution adds an additional dimension to our understanding of the liver, with the potential to revolutionise our insights into the cellular and molecular mechanisms underlying liver physiology and their dysregulation in liver disease. The identification of spatial niches and interactions is empowered by advanced bioinformatics approaches facilitating spatial cellular and network-level analysis and providing novel opportunities for clinical translation. A recent example in immuno-oncology is the use of spatial architecture-based immune classifications, which can improve patient stratification. In this review, we provide an overview of the current methodology and novel spatial insights into metabolic, infectious, immune-mediated, toxic and malign liver diseases and discuss perspectives for clinical translation.

The integration of advanced endoscopy within the practice of hepatology is nowadays heralded in the concept of 'endohepatology' and is dichotomised in applications intervening for disorders of the hepatic parenchyma and vasculature and for biliary tract disease. Current applications under the umbrella of endohepatology focus on advanced diagnostics and vascular, metabolic and hepatobiliary interventions. These involve, among others, endoscopic ultrasound (EUS)-guided liver biopsy, EUS-guided portal pressure gradient measurement, coil and glue embolisation of gastric varices and spontaneous portosystemic shunts, artificial-assisted cholangioscopy.In this review, we aim to focus on different applications within endohepatology which are at the benchtop (or coming close by) and attempt to prognosticate potential future techniques within this rapidly evolving field.

With the recent conditional approval of resmetirom by the US Food and Drug Administration, the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) has potentially entered a new era, requiring a comprehensive understanding of the strengths and weaknesses of non-invasive tests (NITs) for diagnosing and monitoring MASLD-related fibrosis. This article focuses on F2/F3 liver fibrosis and summarises the current application status of NITs, including serum biomarkers, imaging methods and their combined use in the management of MASLD. The article highlights the application of NITs in several areas, including diagnosis and baseline stratification, monitoring progression of fibrosis, prediction of liver-related clinical events, as well as assessment of disease regression, remission and long-term liver-related outcomes. Furthermore, we compare the advantages and limitations of NITs and propose practical strategies for integrating them into clinical practice. Additionally, we highlight the main challenges currently faced in the application of these NITs and potential future research avenues. We suggest that future studies prioritise the validation of NITs across diverse ethnic populations. We believe it essential to explore the role of NITs in dynamic monitoring and integration of multiomics technologies, artificial intelligence and personalised risk models to improve diagnostic accuracy and treatment planning.