Metabolic and alcohol-related liver disease (MetALD) is a newly defined entity within the spectrum of steatotic liver disease, characterized by the interplay of cardiometabolic risk factors and alcohol consumption. The e...Metabolic and alcohol-related liver disease (MetALD) is a newly defined entity within the spectrum of steatotic liver disease, characterized by the interplay of cardiometabolic risk factors and alcohol consumption. The evolving epidemiology and complex pathophysiology of MetALD present unique challenges and opportunities for clinical trial design. Inclusion criteria should require simultaneous evidence of metabolic dysfunction (at least two cardiometabolic features) and verified quantifiable alcohol exposure recorded over the preceding 3-6 months. Traditional histological end points are limited by invasiveness, sampling error and interpretative variability. Thus, imaging modalities, serum-based fibrosis biomarkers and quantitative measures of alcohol intake are gaining relevance as non-invasive, reproducible and patient-centric end points aiming to improve trial feasibility. Furthermore, incorporating alcohol biomarkers, stratifying patients by metabolic risk factor burden, and using adaptive designs of trials might enhance the precision and generalizability of MetALD clinical trials. Although uncertainties remain regarding optimal patient selection criteria, event rates and the dynamic interplay between metabolic dysfunction and alcohol intake, ongoing research efforts aim to refine diagnostic criteria, standardize methodologies and validate novel end points. These advances will ultimately accelerate drug development, improve trial efficiency and foster interventions to treat MetALD.
Investigations into the microbiome in human diseases have exponentially increased over the past several decades, and the microbiome has been associated with nearly every malignancy, with research moving beyond associativ...Investigations into the microbiome in human diseases have exponentially increased over the past several decades, and the microbiome has been associated with nearly every malignancy, with research moving beyond associative studies to investigations into the microbiome as a causative factor in carcinogenesis. Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is a major cause of worldwide cancer mortality owing to the lack of screening methods, late stage at diagnosis and poor response to currently available treatments. Microbiome-pancreatic cancer research has advanced, with research demonstrating that elements of the gut microbiome can modulate antitumour immune function, and microbial-derived products have been shown to influence response to chemotherapy. Additionally, microbiome-based 'signatures' have been identified that can act as biomarkers to predict PDAC and improve on currently available serum tumour markers. In this Review, how the microbiome mechanistically influences pancreatic tumours, with a focus on PDAC, and its clinical implications is described using ground-breaking historical and contemporary studies as a framework. The direction for future studies is also discussed.
Tissue-resident memory CD8 T (CD8 T) cells are localized within peripheral tissues, such as the liver, poised to provide effective immunosurveillance, as well as rapid and enhanced effector functions upon stimulation. He...Tissue-resident memory CD8 T (CD8 T) cells are localized within peripheral tissues, such as the liver, poised to provide effective immunosurveillance, as well as rapid and enhanced effector functions upon stimulation. Here we review how hepatic CD8 T cells decipher a myriad of environmental signals, ranging from cellular and soluble factors to direct interactions with the underlying stroma and structural tissue niche, which dictate their derivation, retention and function. We discuss insights from both mouse and human studies that have contributed to our understanding of how CD8 T cells can, depending on the context, provide targeted antigen-specific antiviral and antitumour immune responses and elicit antigen-independent tissue-damaging responses that contribute to liver pathology. Specifically, we discuss how the CD8 T cell functional response is shaped by multiple factors and how such environmental cues tip the balance between these dual 'Jekyll and Hyde' response modes. Finally, we examine strategies to better identify and characterize hepatic CD8⁺ T cells and how the enhanced functionality of CD8 T cells can be harnessed therapeutically in the context of hepatocellular carcinoma.
The crypt-villus architecture of the intestinal mucosa is underpinned by dynamic interactions between distinct populations of epithelial, stromal and immune cells. Although the epithelial compartment has attracted substa...The crypt-villus architecture of the intestinal mucosa is underpinned by dynamic interactions between distinct populations of epithelial, stromal and immune cells. Although the epithelial compartment has attracted substantial attention, there is a growing appreciation for the critical role of mesenchymal cells in shaping epithelial stem cell function and dictating lineage specification. In this Review, we outline how the epithelial and mesenchymal compartments of the developing gut evolve in a mutually dependent manner to establish dynamic reciprocal signalling gradients that maintain adult tissue homeostasis. We discuss how perturbations to this delicate ecosystem result in rapid adaptive cellular responses that act to restore tissue function. Furthermore, we explore how the intricate nature of cell fate interdependence also renders the mucosa susceptible to pathological disruption. Drawing on the latest studies, we highlight the crosstalk networks between the epithelial and stromal compartments that underlie these processes and consider how these insights are informing future research directions and therapeutic strategies. In doing so, we advocate for a shift away from the conventional epithelial-centric paradigm toward a more integrated framework that considers the full spectrum of intercellular interactions maintaining intestinal tissue integrity and shaping disease progression.
Enteric dopaminergic signalling has a critical role in gastrointestinal motility, maintaining mucosal integrity and modulating the gut microbiome. In this Review, we provide an overview of dopamine metabolism and signall...Enteric dopaminergic signalling has a critical role in gastrointestinal motility, maintaining mucosal integrity and modulating the gut microbiome. In this Review, we provide an overview of dopamine metabolism and signalling pathways in the central nervous system and periphery and their effects on gastrointestinal health and disease. We describe the physiological role of enteric dopamine, including a discussion of therapeutic opportunities and future research needs. With rising interest in the gut-first hypothesis of Parkinson disease, an area of great interest is how dopaminergic depletion in the gut could indicate future neurological dysfunction. In addition, dopamine signalling has been found to influence microbiome colonization resistance against enteric pathogens and immunoregulation. Emerging data on the effect of dopamine replacement therapy on gastrointestinal symptoms, across a range of conditions from neurodegenerative disease to inflammatory bowel disease, are also explored.
The effects of diet and nutrition extend beyond individual health: food intake before conception or during pregnancy and lactation can affect the health of offspring. Diet is one of the most powerful modulators of the gu...The effects of diet and nutrition extend beyond individual health: food intake before conception or during pregnancy and lactation can affect the health of offspring. Diet is one of the most powerful modulators of the gut microbiome, influencing gene-environment interactions, with several emerging mechanisms pointing to the microbiome-metabolite-epigenome axis. In this Review, we discuss the effect of dietary changes on the gametes ('gut-germline axis') or in utero ('gut-neonatal axis') that may change the predisposition of offspring to several non-communicable diseases. Examples of diets discussed are those that detrimentally modulate the parental microbiota and lead to epigenetic changes in the progeny, including Western diets characterized by high saturated fat and low protein or fibre intake. We summarize studies using animal models, which suggest that these diets can have long-lasting effects on the offspring microbiome, epigenome and phenotype, particularly across the cardiometabolic and immune systems, and discuss the limitations of current studies as well as future directions for the field. Translational research investigating the benefits of parental dietary interventions before and during pregnancy, mainly using personalized approaches, is needed. This would, in turn, reduce rates of non-communicable diseases in generations to come.
Machine perfusion is an emerging and transformative technology for dynamic organ preservation, assessment and repair. Whereas allografts continuously degrade during static cold storage, short-term perfusion can preserve...Machine perfusion is an emerging and transformative technology for dynamic organ preservation, assessment and repair. Whereas allografts continuously degrade during static cold storage, short-term perfusion can preserve high-quality organs for hours, enabling assessment, regional transport and improved logistics. Long-term perfusion for multiple days might extend the potential of clinical machine perfusion in the future, allowing for the assessment, reconditioning and repair of marginal or injured grafts for which more time is needed. In addition, it might convert transplantation, which is now semi-elective thanks to short-term perfusion, to a fully elective procedure via customized machines and associated protocols that maintain organs ex situ for up to 2 weeks. The advent of long-term organ perfusion provides tremendous potential to improve organ evaluation and selection, to recondition or repair marginal grafts and, ultimately, to expand the pool of grafts available for transplantation. In this Perspective, we discuss design considerations, guidelines for use, and future perspectives of machine perfusion in the context of organ assessment and repair, with a focus on the liver.
The Little Brain Big Brain meeting was established more than 30 years ago as an opportunity for early career researchers to meet, present and discuss exciting new developments in the field of enteric neuroscience and neu...The Little Brain Big Brain meeting was established more than 30 years ago as an opportunity for early career researchers to meet, present and discuss exciting new developments in the field of enteric neuroscience and neurogastroenterology. Crucially, the meeting is organized by young investigators, for young investigators. In this Viewpoint, past attendees and organizers of the Little Brain Big Brain meeting discuss their research interests, share their experience with this unique meeting and provide insights into progress in the field of enteric neuroscience and neurogastroenterology and its future outlook.
Clinical decision making in gastroenterology and hepatology has become increasingly complex and challenging for physicians. This growing complexity can be addressed by computational tools that support clinical decisions....Clinical decision making in gastroenterology and hepatology has become increasingly complex and challenging for physicians. This growing complexity can be addressed by computational tools that support clinical decisions. Although numerous clinical decision support systems (CDSS) have emerged, they have faced difficulties with real-world performance and generalizability, resulting in limited clinical adoption. Generative artificial intelligence (AI), particularly large language models (LLMs), are introducing new possibilities for CDSS by offering more flexible and adaptable support that better reflects complex clinical scenarios. LLMs can process unstructured text, including patient data and medical guidelines, and integrate various information sources with high accuracy, especially when augmented with retrieval-augmented generation. Thus, LLMs can provide dynamic, context-specific support by generating personalized treatment recommendations, identifying potential complications based on patient history, and enabling natural language interactions with health-care providers. However, important challenges persist, particularly regarding biases, hallucinations, interoperability barriers, and proper training of health-care providers. We examine the parallel evolution of the complexity in clinical management in gastroenterology and hepatology, and the technical developments leading to current generative AI models. We discuss how these advances are converging to create effective CDSS, providing a conceptual basis for further development and clinical adoption of these systems.
Caminero A, Tropini C, Valles-Colomer M
… +8 more, Shung DL, Gibbons SM, Surette MG, Sokol H, Tomeo NJ, Scientific Advisory Board of the Center for Gut Microbiome Research and Education of the American Gastroenterological Association, Tarr PI, Verdu EF
The microbiome has critical roles in human health and disease. Advances in high-throughput sequencing and metabolomics have revolutionized our understanding of human gut microbial communities and identified plausible ass...The microbiome has critical roles in human health and disease. Advances in high-throughput sequencing and metabolomics have revolutionized our understanding of human gut microbial communities and identified plausible associations with a variety of disorders. However, microbiome research remains constrained by challenges in establishing causality, an over-reliance on correlative studies, and methodological and analytical limitations. Artificial intelligence (AI) has emerged as a powerful tool to address these challenges; however, the seamless integration of preclinical models and clinical trials is crucial to maximizing the translational impact of microbiome studies. This manuscript critically evaluates best methodological practices and limitations in the field, focusing on how emerging AI tools can bridge the gap between microbial insights and clinical applications. Specifically, we emphasize the necessity of rigorous, reproducible methodologies that integrate multiomics approaches, preclinical models and clinical trials in the AI-driven era. We propose a practical framework for applying AI to microbiome studies, alongside strategic recommendations for clinical trial design, regulatory pathways, and best practices for microbiome-based informed diagnostics, AI training and clinical interventions. By establishing these guidelines, we aim to accelerate the translation of microbiome research into clinical practice, enabling precision medicine approaches informed by the human microbiome.