Perturbations of the multifaceted functions of the human intestine can manifest in an extraordinarily diverse range of disease pathologies that span developmental, infectious, inflammatory and neoplastic conditions. Accordingly, there is substantial interest in treating intestinal disorders by harnessing the promise of intestinal stem cells (ISCs). From 2009 to 2024, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a multi-institution collaborative, the Intestinal Stem Cell Consortium (ISCC), that sought to leverage advances in ISC biology for clinical translation to accelerate in vivo mucosal repair and eventually generate functioning intestinal tissue ex vivo. In this Roadmap, ISCC members summarize the latest advances and current knowledge gaps both from within the ISCC working group and across the field as a whole as relevant to understanding the human ISC niche, stem cell interactions with and in response to pathogens, and cellular and humoral regenerative strategies, towards realizing stem cell-based therapy for intestinal diseases.
Even when presenting in the clinic with localized disease, patients with pancreatic ductal adenocarcinoma (PDAC) experience extremely poor survival, owing to local recurrence and/or distant progression driven by micrometastatic lesions despite aggressive systemic chemotherapy. Neither radiation therapy nor immunotherapy have yet been successful at extending the survival of patients with localized PDAC, at least in part owing to a series of (immuno)biological mechanisms of innate and acquired resistance. However, an expanding preclinical and clinical literature from PDAC and other oncological indications identifies novel approaches through which radiation therapy-immunotherapy combinations could improve local and systemic disease control in patients with PDAC. Here, we propose to reposition radiation therapy as an immunological platform rather than a purely cytotoxic treatment modality. To this aim, we critically discuss the rationale, challenges and opportunities for combining radiotherapy with immunotherapy to improve the clinical management of localized pancreatic cancer, focusing on the identification of optimal radiation therapy backbones and innovative immunotherapy approaches that might unlock superior therapeutic interactions between these treatment modalities.
A new frontier in cancer research is emerging with the exploration of 'dark DNA': the non-coding regions of the genome now recognized as essential regulators of cancer biology. Long non-coding RNAs (lncRNAs) have been increasingly acknowledged as key regulators in cancer, having crucial roles in the modulation of intracellular processes as well as in intercellular communication. These roles emphasize the importance of lncRNAs in influencing the tumour microenvironment (TME), a complex and dynamic network that contributes to cancer progression, metastasis and resistance to therapy. In this Review, we explore how lncRNAs regulate the colorectal cancer (CRC) microenvironment, focusing on their mechanisms of action and their effect on critical TME components, including immune cells, cancer-associated fibroblasts and angiogenesis. We explore the dual roles of lncRNAs as oncogenes or tumour suppressors, their involvement in immune modulation, vascular remodelling and extracellular matrix dynamics. Our comprehensive analysis elucidates the molecular pathways, identifies potential biomarkers for patient stratification and proposes new therapeutic strategies to regulate the CRC TME and prevent disease progression and resistance. Ultimately, this Review contributes to a deeper understanding of the intricate lncRNA-TME interplay and underscores their emerging relevance in clinical applications, paving the way for innovations in precision oncology.
Sexual dimorphism, which is defined as systematic differences between male and female individuals not limited to characteristics related to reproduction, has been recognized in many organ systems and is emerging as an important component of hepatic function in health and disease. Oestrogen is considered the predominant driver of sexual dimorphism in the liver. Other molecular mechanisms independent of oestrogen including epigenetic regulation and immune function contribute to differences between sexes as do other as yet unknown mechanisms. Clinically, hepatic sexual dimorphisms manifest in many ways. For example, women have a lower incidence of many liver disorders including metabolic-dysfunction-associated steatotic liver disease and liver cancer but are more susceptible to benign neoplasms and autoimmune liver diseases such as primary biliary cholangitis. Better understanding the diverse contributors to hepatic sexual dimorphism, including sociodemographic factors, could deepen our understanding of liver biology and aid in sex-specific clinical management and disease prevention. In this Review, we describe the molecular mechanisms of sexual dimorphisms in liver physiology, including oestrogen signalling, genes encoded on sex chromosomes, epigenetic effects on metabolism and immune function. We also describe hepatic sexual dimorphisms in liver pathophysiology, including in metabolic-dysfunction-associated steatotic liver disease, autoimmune diseases, viral hepatitis and liver cancer.
Steatotic liver disease (SLD) comprises metabolic dysfunction-associated SLD, metabolic and alcohol-related liver disease, and alcohol-related liver disease, conditions that frequently overlap rather than fall into distinct categories. Cardiometabolic risk factors (CMRFs), including obesity, type 2 diabetes, hypertension and dyslipidaemia, are highly prevalent across SLD subtypes, with most patients exhibiting multiple metabolic abnormalities. These risks interact synergistically with alcohol exposure, accelerating fibrosis progression to cirrhosis and liver mortality. Importantly, both alcohol consumption and metabolic risks are dynamic and can fluctuate over time, leading to transitions across the SLD spectrum that static diagnostic thresholds might not adequately capture. Misclassification is common, particularly due to under-reporting of alcohol intake, underscoring the value of objective alcohol biomarkers such as phosphatidylethanol. Accurate risk stratification, therefore, requires an integrated approach combining systematic alcohol screening, structured evaluation of CMRFs and non-invasive fibrosis assessment. Management must be multidisciplinary, combining alcohol reduction strategies, optimization of metabolic control and liver-directed therapies. However, most emerging pharmacotherapies for metabolic dysfunction-associated steatohepatitis exclude individuals with concurrent alcohol use, creating a gap between clinical trial populations and real-world practice. A dynamic, spectrum-based framework incorporating repeated reassessment of alcohol and metabolic risks offers the most pragmatic path for diagnosis, treatment and equitable care delivery in SLD.
The lack of harmonization for microbiome-based clinical studies represents a critical issue for microbiome researchers and stakeholders, although microbiome research and clinical studies on the gut microbiome have been intensively conducted for more than a decade. The selection of a minimum metadata set to be analysed and reported during clinical studies with microbiome outcomes, the identification of reference materials, the definition of standardized sampling procedures and data analysis protocols, and the choice of unified clinical end points are still lacking. The two-round Delphi survey, conducted within the framework of the Horizon Europe Human Microbiome Action (HMA) consortium, aimed to standardize metadata collection, sampling procedures, data generation and sharing, and standard operating procedures for aspects of gut microbiome-based clinical studies beyond outcomes. The process involved 72 scientists and experts worldwide in the first round and 61 experts in the second round, with an 85% participation rate from the first to the second round. On the basis of the outcome of the Delphi survey, the HMA consortium provided 15 recommendations that might be taken up by the community at large to promote coherence and harmonization in the way microbiome clinical research is and will be performed. The recommendations mainly focus on the gut microbiome and diseases associated with the gastrointestinal tract and gut-organ axes.
Two independent Delphi-driven consensus initiatives have established the first standardized frameworks for defining, measuring and managing intrapancreatic fat. Their areas of agreement provide a foundation for clinical recognition, while key divergences in terminology, thresholds and evidence appraisal highlight critical questions that must be resolved through rigorous collaborative research.
Intrapancreatic fat deposition (IPFD) has garnered appreciable attention across diverse medical disciplines amid the rising global burden of pancreatitis, pancreatic cancer and type 2 diabetes mellitus. Despite growing interest in the field, there remains no conceptual framework for it. To address this gap, 25 experts from 6 continents were brought together to develop guidance. Drawing on multiple peer-reviewed systematic reviews and applying an iterative, anonymous Delphi process, a consensus document was developed and ratified in Melbourne, Australia. The final document contains 58 recommendations - 30 reached unanimous agreement and 28 attained 90-99% agreement. The consensus formally defines fatty pancreas disorder (FPD) as a distinct pathological state, characterized by excessive IPFD that poses a risk to health. Assessment of IPFD is best performed with MRI. Expert-established diagnostic criteria enable identification and classification of FPD. Recognition of type 1 FPD (in individuals without excess body fat mass) and type 2 FPD (in individuals with excess body fat mass) is instrumental in gaining novel insights and tailoring preventive strategies to the individual. The Melbourne consensus is foundational in operationalizing the dissemination of new knowledge in the field, fostering intercontinental collaborations and, ultimately, addressing the global burden of diseases of the pancreas.
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 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 Treg 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 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 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), 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.
