Glycans are essential components of homeostatic networks, acting as fine tuners of immunological responses, and are therefore promising targets for manipulating immune tolerance. Glycans shield the entire gut mucosa surf...Glycans are essential components of homeostatic networks, acting as fine tuners of immunological responses, and are therefore promising targets for manipulating immune tolerance. Glycans shield the entire gut mucosa surface, contributing to epithelial barrier integrity. Moreover, most microorganisms expose glycoconjugates on their surfaces, making glycans essential molecules in the crosstalk between host immune response and the gut microbiota. The vast amount of biological information encoded by mucosal glycans is deciphered by a variety of glycan-binding proteins that translate glycan recognition into either pro-inflammatory or anti-inflammatory responses. Current evidence from inflammatory bowel disease (IBD) has highlighted the prominent role of glycans in establishing and regulating key cellular and molecular pathways underlying the transition from health to intestinal inflammation, with implications for understanding IBD immunopathogenesis and for IBD prediction and prevention. In this Review, we discuss current advances, emerging challenges and future prospects in exploiting the power of the mucosal glycocalyx and the glycome as master coordinators of the immunoregulatory networks in IBD from the preclinical phase to established diagnosis. We discuss the clinical utility of the glycome as a serological biomarker with diagnostic, prognostic and predictive value, and as a potential new target for preventive intervention strategies in IBD.
Cholangiocarcinoma (CCA) is a cancer that originates within the bile ducts. Traditionally considered to be a rare neoplasm, increased awareness of CCA alongside advancements in diagnosis and the rising prevalence of cert...Cholangiocarcinoma (CCA) is a cancer that originates within the bile ducts. Traditionally considered to be a rare neoplasm, increased awareness of CCA alongside advancements in diagnosis and the rising prevalence of certain risk factors have contributed to a global increase in incidence and mortality. CCAs are highly heterogeneous from the clinical, histomorphological and molecular perspectives but commonly share a poor prognosis. These tumours usually develop and progress silently; by the time they are detected, it is often too late for curative surgical intervention. In such cases, current therapeutic approaches offer modest survival improvements and are generally considered palliative. Although well-known risk factors predispose individuals to developing CCA, the majority of cases are considered sporadic, occurring without any identifiable underlying condition. Over the past decade, substantial collaborative efforts have been made to improve our understanding of the aetiopathogenesis of these tumours, aiming to identify novel biomarkers and therapeutic targets to develop more effective treatments. The ultimate goal is to improve patient outcomes and overall well-being. However, there are significant gaps in our understanding of the molecular mechanisms that drive cholangiocarcinogenesis. In this international Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we provide a critical overview of the latest advancements in the field of CCA. We highlight the key aspects of CCA aetiopathogenesis and clinical management and provide insights into promising new treatments. Finally, we provide a set of consensus recommendations and future research priorities for CCA based on a Delphi panel questionnaire involving international experts.
Chronic abdominal pain is prevalent among individuals with inflammatory bowel disease (IBD). Substantial progress has been made in the past few decades in understanding how pain signals travel from the gut to the brain....Chronic abdominal pain is prevalent among individuals with inflammatory bowel disease (IBD). Substantial progress has been made in the past few decades in understanding how pain signals travel from the gut to the brain. Preclinical studies have greatly contributed to uncovering the mechanisms of chronic pain in IBD. However, practical applications in clinical settings are still lacking. In this Review, we present the current understanding of the pathological mechanisms of chronic pain in IBD. We explore the neuroplastic changes that occur along the afferent pain pathway from the nerve endings in the colonic mucosa to the brain. We explore the importance of new variables in chronic IBD pain, including the influence of host-microbe interactions during disease, and the effect of comorbid psychological factors, including stress and anxiety, in triggering pain. Finally, we discuss gaps in treatment strategies while proposing new directions for research to identify novel priorities that could pave the way for effective pain therapies.
As persons living with human immunodeficiency virus (HIV) infection are living longer, non-AIDS-related mortality continues to rise, with liver disease being one of the most common causes. This Review provides a synopsis...As persons living with human immunodeficiency virus (HIV) infection are living longer, non-AIDS-related mortality continues to rise, with liver disease being one of the most common causes. This Review provides a synopsis of the current burden of liver diseases, ranging from viral hepatitis to metabolic dysfunction-associated steatotic liver disease to liver cancer, and discusses the barriers and challenges to screening and treatment as well as cofactors contributing to increasing disease burden. A brief insight is provided on the potential molecular mechanisms driving hepatic inflammation and fibrosis in persons living with HIV. Given the effect of direct-acting antivirals on hepatitis C virus infection and suppressive treatment for hepatitis B virus infection, special attention is drawn to the emergence of metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis in this population, focusing on factors related to the increasing prevalence of relevant comorbidities, the role of antiretroviral therapy, and HIV-specific factors in driving liver fibrosis progression.
Regulated cell death is a hallmark of inflammatory liver disease, and its intensity influences disease progression and severity. However, it is now clear that the form of cell death could also have an important role. In...Regulated cell death is a hallmark of inflammatory liver disease, and its intensity influences disease progression and severity. However, it is now clear that the form of cell death could also have an important role. In addition to apoptosis, various forms of regulated necrosis are increasingly reported to contribute to inflammatory liver disease due to their lytic nature. In this Review, we discuss the key regulatory molecules that govern regulated necrosis pathways and summarize our current understanding of the involvement of necroptosis, pyroptosis and ferroptosis in liver injury in preclinical murine models of acute and chronic liver disease and liver cancer development. Furthermore, we highlight the existing controversies and knowledge gaps regarding the relevance of these cell death modalities in hepatocytes and non-hepatocytic liver cells as well as the emerging mechanisms controlling these pathways. Finally, we discuss efforts to specifically modulate these regulated cell death pathways in liver disease and hepatocarcinogenesis in the attempt to prevent liver disease progression or to elicit more potent antitumour immune responses. Outstanding issues and methodological advances that will help to translate preclinical findings into therapeutic applications are also presented.
Asombang AW, Antwi SO, Omonisi A
… +13 more, Cooley MA, Nartey YA, VanLith CJ, Desalegn H, Okeke E, Rubagumya F, Africa HepatoPancreatoBiliary Cancer Consortium (AHPBCC), Yonli AT, El-Kassas M, Chipaila J, Nagalo BM, Omar A, Roberts LR
Hepatopancreatobiliary (HPB) cancers are a major cause of morbidity and mortality worldwide, particularly in Africa, where the risk factors, tumour characteristics, treatment-related factors and survival outcomes are poo...Hepatopancreatobiliary (HPB) cancers are a major cause of morbidity and mortality worldwide, particularly in Africa, where the risk factors, tumour characteristics, treatment-related factors and survival outcomes are poorly characterized. Despite the high incidence and mortality rates of HPB cancers in Africans, there is a dearth of data on the genetic and non-genetic risk factors for HPB cancers in Africa. The incidence and mortality rates of HPB cancers in Africans can only be substantially reduced by increasing our understanding of the population-specific risk factors and potentially unique underlying tumour biology. Pursuing this goal requires the establishment of robust clinical and population-based registries across the African continent for risk assessment, which will enable the development of strategies for HPB cancer prevention and implementation of surveillance programmes for early cancer detection in individuals at high risk. This goal was the premise for establishing the Africa HepatoPancreatoBiliary Cancer Consortium (AHPBCC). In this Roadmap article, we discuss the AHPBCC's collaborative efforts to increase knowledge about HPB cancers in Africans and to promote Africa-focused research on HPB cancers. We also provide in-depth discussions on the establishment of cancer registries in Africa, including the challenges, best practices and areas for growth, to improve HPB cancer outcomes in Africa.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Curative-intent treatments offer the best long-term outcomes for selected patients. However, recurrence rates after resection appro...Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Curative-intent treatments offer the best long-term outcomes for selected patients. However, recurrence rates after resection approach 70% at 5 years, and access to transplantation remains limited by donor scarcity and stringent eligibility criteria. Emerging data reveal that recurrence is a reflection of underlying tumour biology, immune evasion and microenvironmental permissiveness. Advances in immunogenomic profiling, liquid biopsy and functional imaging are reshaping the concept of surgical eligibility, enabling biological risk stratification beyond conventional staging. At the same time, innovations in perioperative immunotherapy, graft preservation using machine perfusion and integrated multidisciplinary care are expanding the boundaries of curative treatment. These developments herald a shift from static criteria to dynamic, biology-driven paradigms that personalize surgical and transplant strategies. In this Review, we examine the evolving landscape of surgical treatment for HCC. We highlight the limitations of current selection frameworks, discuss how biological insights can inform resection and transplant decision-making and explore the role of perioperative and neoadjuvant therapies in reducing the recurrence of disease. Finally, we outline a future precision oncology model that integrates tumour genomics, immune phenotype and regenerative biology to improve outcomes in patients undergoing curative-intent treatment for HCC.
Inflammation has a fundamental role in many disorders of the gastrointestinal tract and the liver. Why these organs are particularly prone to acute, but especially chronic, immune-mediated disorders remains unclear; howe...Inflammation has a fundamental role in many disorders of the gastrointestinal tract and the liver. Why these organs are particularly prone to acute, but especially chronic, immune-mediated disorders remains unclear; however, the complex exposure to environmental triggers, including the gut microbiota, might be particularly relevant. Cytokines are considered key regulators of inflammatory processes, with IL-1β being one of the first cytokines discovered, more than four decades ago. A whole family of IL-1-related cytokines has been discovered, and their crucial role in many gastrointestinal and liver diseases has been studied in detail. Today, the IL-1 family comprises 22 members, including 11 cytokines and 11 receptors. IL-1 signalling cascades share similarities with Toll-like receptors, initiating acute-phase reactions to environmental and endogenous threats, and are particularly involved in orchestrating innate immune responses, which are the basis of many gastrointestinal and liver disorders. In this article, we discuss the role of the main IL-1 family members in gastrointestinal and liver diseases, focusing on preclinical and clinical research, and we contemplate opportunities for clinical applications.