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.
Anorectal bacterial sexually transmitted infections, predominantly chlamydia, gonorrhoea and syphilis, represent a substantial and evolving global health challenge, with incidence rising despite widespread testing availability. In this Review, we examine the epidemiology and burden of anorectal sexually transmitted infections, explore the pathogenic mechanisms underlying infection and discuss advances in diagnosis, screening and prevention strategies. Anorectal infections are frequently asymptomatic, particularly among men who have sex with men, in which they often exceed the prevalence of urogenital infections. Asymptomatic persistence results from bacterial adaptation to rectal tissues and attenuated local immune responses that fall below symptom thresholds. Molecular diagnostics have transformed detection capabilities, yet substantial challenges persist in distinguishing viable from non-viable microorganisms, expanding point-of-care testing access and balancing screening benefits against antimicrobial stewardship concerns. Treatment approaches continue to evolve in response to emerging resistance patterns, particularly for gonorrhoea. Promising prevention innovations include doxycycline post-exposure prophylaxis, which substantially reduces chlamydia and syphilis incidence and artificial intelligence applications. However, practical implementation in diverse clinical settings remains limited. We highlight important gaps in knowledge and propose research priorities to advance effective control strategies.
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.
