The small-intestinal epithelium must simultaneously enable functions that are spatially compartmentalized along the length of the organ: nutrient absorption and protection against environmental insults. Although regional...The small-intestinal epithelium must simultaneously enable functions that are spatially compartmentalized along the length of the organ: nutrient absorption and protection against environmental insults. Although regional differences within the intestine have been recognized for centuries, only now has a comprehensive framework emerged to define this organization at molecular, cellular and functional levels. In this Review, we highlight the epigenetic and transcriptional features of small-intestinal zonation across longitudinal and apical-basal axes, and we examine the molecular mechanisms that establish regional gene expression profiles in epithelial cells during development and that maintain these distinctions into adulthood. We integrate these molecular insights with physiological data to present a refined model of the functional landscape of nutrient absorption. Finally, we discuss gastrointestinal diseases that target specific intestinal regions, underscoring the importance of understanding local tissue environments within this highly regionalized organ.
Despite the development of novel small molecules and antibody-based therapies targeting pro-inflammatory immune pathways, the clinical management of inflammatory bowel disease (IBD) remains challenging. In this Perspecti...Despite the development of novel small molecules and antibody-based therapies targeting pro-inflammatory immune pathways, the clinical management of inflammatory bowel disease (IBD) remains challenging. In this Perspective, we highlight emerging treatment strategies with a focus on engineered cellular immunotherapies, including stem cell-based approaches, regulatory T cell and type 1 regulatory T cell therapies, as well as chimeric antigen receptor (CAR) T cell platforms (CAR T cells, CAR T cells). Early-stage studies using haematopoietic and mesenchymal stem cells have yielded promising clinical results, although the safety and efficacy of such therapies require further careful validation. Moreover, efforts in immune cell engineering are now directed towards the expansion and adoptive transfer of allogeneic IL-10-producing type 1 regulatory T cells and autologous transforming growth factor-β-secreting regulatory T cells, which are currently being evaluated in early-stage clinical trials. Notably, a recent case report demonstrated that CD19-targeted CAR T cell therapy can induce long-term remission of intestinal inflammation in ulcerative colitis, highlighting a potential pathogenic role of mucosal B cells and plasmablasts in ulcerative colitis and underscoring the transformative therapeutic potential of CAR T cell strategies in IBD. Although these approaches offer exciting therapeutic prospects in IBD, rigorous prospective and controlled clinical trials are essential to fully assess their safety and efficacy.
Fibrosis represents a pathological wound-healing response that occurs after nearly any type of organ injury and has been estimated to lead to half of all deaths in the industrialized world. Current evidence indicates tha...Fibrosis represents a pathological wound-healing response that occurs after nearly any type of organ injury and has been estimated to lead to half of all deaths in the industrialized world. Current evidence indicates that the extracellular matrix in the fibrotic lesion is primarily produced by activated fibroblasts and/or myofibroblasts. In the liver, the key fibrosis effector cell is the hepatic stellate cell (HSC), which undergoes phenotypic switching from a quiescent (normal) state to a hepatic myofibroblast (activated state). The classic signature for the activated HSC is not only upregulation of various extracellular matrix mRNAs and proteins, particularly type 1 collagen, but also the de novo expression of multiple smooth muscle mRNAs and proteins, including the smooth muscle isoform of actin (smooth muscle α-actin), which supports a robust actin cytoskeleton. Growing evidence indicates that the actin cytoskeleton has a critical role in multiple essential HSC activities during the wound-healing response, including cell migration, contraction, signal transduction and matrix gene expression. In this Review, we focus on the role of the actin cytoskeleton and the molecular processes linking this critically important cellular structure to the cell biology of fibrosis.
In the era of artificial intelligence, machines are demonstrating an unprecedented capacity to learn from massive amounts of real-world data to perform human-like cognitive processes, enabling them to recognize environme...In the era of artificial intelligence, machines are demonstrating an unprecedented capacity to learn from massive amounts of real-world data to perform human-like cognitive processes, enabling them to recognize environments, objects, and conditions and make critical decisions more accurately than ever. In the medical field, the potential to generate realistic, privacy-preserving, unbiased synthetic data can be the key to unlocking the potential of artificial intelligence in medicine and overcoming the current barriers such as data privacy concerns and high data curation costs. Advanced data-driven solutions could lead towards more robust clinical decision support systems and enhanced clinical training. This Perspective critically examines current and emerging advances in synthetic data generation, and highlights its anticipated transformational effect for early and efficient prevention, diagnosis and treatment of gastrointestinal diseases. Research challenges and directions are identified for leveraging the benefits of synthetic data as well as translating and adopting them in clinical workflows.
Metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease and metabolic dysfunction and alcohol-related liver disease represent the principal subtypes of steatotic liver disease (SLD), to...Metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease and metabolic dysfunction and alcohol-related liver disease represent the principal subtypes of steatotic liver disease (SLD), together constituting a rapidly growing global health challenge. Latin America bears a disproportionately high burden of SLD, driven by the convergence of increasing prevalence of obesity and type 2 diabetes, high levels of harmful alcohol consumption, and a high frequency of genetic risk variants, particularly in the gene encoding patatin-like phospholipase domain-containing protein 3 (PNPLA3). These factors interact synergistically to accelerate disease progression, increasing the risk of steatohepatitis, advanced fibrosis, cirrhosis and hepatocellular carcinoma. Despite this substantial burden, the region faces major structural and health-system constraints, including fragmented health-care delivery, limited hepatology capacity, restricted access to diagnostic and therapeutic technologies, and low participation in clinical trials, all of which hinder early detection and the generation of region-specific evidence. This Review summarizes current data on the epidemiology and clinical burden of SLD in Latin America, identifies critical gaps in research and surveillance, and highlights priorities for prevention, harm reduction and health-system strengthening, including the implementation of effective public policies to reduce morbidity and mortality and improve health outcomes in the region.
The rising disease burden of inflammatory bowel disease (IBD) parallels the changing dietary landscape accompanying industrialization, underscoring the growing relevance of nutritional science in disease prevention and m...The rising disease burden of inflammatory bowel disease (IBD) parallels the changing dietary landscape accompanying industrialization, underscoring the growing relevance of nutritional science in disease prevention and management. Precision nutrition has emerged as a promising approach to prevent and manage IBD through tailored dietary recommendations based on multidimensional individual characteristics, including demographics, disease natural history and multiomics traits. In this Review, we investigate the sources of heterogeneity in dietary responses and propose a stepwise framework for precision nutrition: phenotype-based precision nutrition, informed by general phenotypes in clinical and community settings; omics-based precision nutrition, targeting subgroups with shared biological features identified via omics and complementary approaches; and integrated precision nutrition, providing personalized dietary strategies informed by comprehensive, multidimensional phenotypes. Advances in large-scale longitudinal multiomics cohorts, biomarker detection and artificial intelligence are transforming data acquisition and interpretation, thereby facilitating both interventional research and real-world application of precision nutrition. Key considerations for implementing precision nutrition in IBD are discussed. This Review outlines a holistic and translational framework, aiming to advance both research and clinical practice in the prevention and management of IBD.
Pancreatic development is a dynamic process shaped by coordinated interactions between surrounding non-pancreatic tissues and intrinsic transcription factors, integrated through gene regulatory networks. Advances in sing...Pancreatic development is a dynamic process shaped by coordinated interactions between surrounding non-pancreatic tissues and intrinsic transcription factors, integrated through gene regulatory networks. Advances in single-cell genomics and lineage-tracing technologies have substantially expanded our understanding of pancreatic biology, elucidating the ontogeny of pancreatic cells, their diversity and the intercellular interactions that govern them. In this Review, we examine the emergence of pancreatic cell lineages in the embryo through the lens of cellular plasticity, emphasizing how reciprocal interactions with the microenvironment influence lineage decisions. We also draw parallels between developmental and pathological processes, highlighting the dual role of plasticity: enabling lineage specification during development and supporting regenerative responses upon injury or in disease states. A deeper appreciation of the mechanisms underlying pancreatic cell identity and plasticity holds the potential to inform the development of new therapeutic modalities for pancreatic diseases, such as diabetes and pancreatic cancer.
Cirrhosis and hepatocellular carcinoma (HCC) are interconnected outcomes of chronic liver disease, with portal hypertension playing a key part in cirrhosis decompensation, and influencing HCC prognosis and treatment. Des...Cirrhosis and hepatocellular carcinoma (HCC) are interconnected outcomes of chronic liver disease, with portal hypertension playing a key part in cirrhosis decompensation, and influencing HCC prognosis and treatment. Despite their overlap, current guidelines address portal hypertension and HCC separately, leading to suboptimal risk stratification and treatment selection. This Review proposes a stage-based, integrated approach to HCC management that incorporates the prognostic stages of cirrhosis and emphasizes clinically significant portal hypertension (CSPH) as a key stratifying factor in compensated cirrhosis. CSPH is associated with an increased risk of cirrhosis decompensation, and its presence often limits the feasibility of curative treatments such as surgical resection. Although CSPH is strictly defined as hepatic venous pressure gradient (HVPG) of ≥10 mmHg, non-invasive tools (liver stiffness and platelet count) have largely replaced HVPG in cirrhosis; in patients with HCC, emerging data suggest that these non-invasive tests are poised to replace HVPG and its traditional surrogates, imaging and endoscopy. We explore the management of both cirrhosis and HCC across all cirrhosis stages - compensated (with or without CSPH), decompensated, and further decompensated - in relation to all HCC stages (very early, early, intermediate and advanced). Future research should validate non-invasive CSPH assessment in HCC and support outcome trials stratified by cirrhosis and HCC stage to guide personalized therapy and improve outcomes.
Among tissue-resident immune cells, γδ T cells have a unique role in local immune surveillance. Under homeostatic conditions, they control tissue integrity and maintain the epithelial barrier. In contrast to conventional...Among tissue-resident immune cells, γδ T cells have a unique role in local immune surveillance. Under homeostatic conditions, they control tissue integrity and maintain the epithelial barrier. In contrast to conventional αβ T cells, γδ T cells sense stress-induced cellular alterations and, therefore, can recognize transformed cells independently of MHC (HLA in humans) molecules. In colorectal cancer and hepatocellular carcinoma, γδ T cells constitute an important part of the antitumour immune response. However, there is evidence that γδ T cells can also promote tumorigenesis. In this Review, we present basic features of γδ T cells and their distribution and function in the context of the local immune response. We discuss the ligands and antigens recognized by circulating and tissue-resident human γδ T cells, as well as the functional diversity of γδ T cell subsets within tumour-infiltrating T cells in colorectal and liver cancer. Given their potent cytotoxic activity and HLA-independent mode of action, there is increasing interest in harnessing γδ T cells for application in cancer immunotherapy. We therefore discuss the current status and future challenges of using γδ T cells as an innovative immunotherapeutic strategy for gastrointestinal and liver cancer.
The process of eating can be divided into three distinct phases of behaviour: food seeking, food consumption and non-prandial activities. The durations of, and transitions between, these behavioural phases are driven by...The process of eating can be divided into three distinct phases of behaviour: food seeking, food consumption and non-prandial activities. The durations of, and transitions between, these behavioural phases are driven by underlying interoceptive phenomena of hunger, satiation and satiety. The gut-brain axis regulates all eating phases, with the vagus nerve a primary conduit for interoceptive feedback about gut-derived mechanical and chemical cues. This Review explores the mechanisms governing each phase, focusing on how gut-derived signals are peripherally and centrally integrated to shape hunger, satiation and satiety, food preferences, and food-related learning. Chronic exposure to high-fat, high-sugar diets disrupts these mechanisms, driving a maladaptive state characterized by hyperphagia, food choice biases and habitual overeating. We examine the mechanisms underlying this maladaptive state, including vagal fibre remodelling, altered gene expression and leptin resistance, which can impair gut-brain communication, diminishing the brain's capacity to appropriately control eating behaviour and maintain energy balance. Emerging therapies, including glucagon-like peptide 1 receptor agonists, are effective in promoting weight loss but typically do not reverse the underlying causes of gut-brain axis dysfunction. By examining the mechanisms of gut-brain signalling, this Review highlights the vagus nerve as a key, yet underappreciated, target for obesity treatment.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent and rapidly growing global health concern characterized by hepatic steatosis, oxidative stress and inflammation that can progress to metabol...Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent and rapidly growing global health concern characterized by hepatic steatosis, oxidative stress and inflammation that can progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis and cirrhosis. NADPH:cytochrome P450 oxidoreductase (CPR, encoded by POR), the essential electron donor for microsomal cytochrome P450 enzymes and other redox partners, orchestrates xenobiotic detoxification, lipid metabolism, steroid and bile acid biosynthesis, and redox balance - processes disrupted in MASLD. This Perspective examines emerging evidence from genetic, biochemical, transcriptomic and clinical studies that implicate CPR in the pathophysiology of MASLD, including its roles in lipid accumulation, oxidative stress, mitochondrial dysfunction, iron homeostasis, ferroptosis and inflammatory signalling. We discuss how CPR dysfunction, driven by genetic polymorphisms or metabolic stress, contributes to disease heterogeneity and progression. These insights highlight CPR as a relevant and potentially actionable regulator of hepatic metabolism. The current FDA approval of resmetirom, a thyroid hormone receptor-β agonist, which increases POR transcription levels, provides translational proof that restoring CPR-dependent pathways can ameliorate MASH with fibrosis. A deeper understanding of the multifaceted role of CPR could inform precision medicine strategies for this complex and widespread liver disease.