Coeliac disease is characterised by immune-mediated damage to the small intestine in response to dietary gluten in genetically predisposed individuals. Increased intestinal permeability is a central component to its pathophysiology. This review explores the evidence for increased permeability in coeliac disease and the underlying mechanisms, including the roles of zonulin, inflammatory cytokines, microbial alterations and immune responses to gliadin peptides. We also review comprehensively the therapies targeting barrier integrity and normalising intestinal permeability, including particular diets and supplements, and experimental and improved medications including larazotide acetate and IMU-856. Finally, we highlight the need for reliable biomarkers for evaluating increased permeability in coeliac disease and advocate for further research on therapies which normalise barrier function, particularly as a strategy to maintain remission.

Cholangiocytes are highly specialised cells participating in the pathobiology of various liver diseases and recognised to play a crucial role in response to liver injury. Cholangiocytes exhibit dramatic heterogeneity and plasticity, with distinct subtypes performing disparate functions during liver injury and regeneration. Acting as the liver progenitor cells, cholangiocytes can also convert to hepatocytes in the context of impaired hepatocyte proliferation. Harnessing the intrinsic regenerative ability of cholangiocytes is of great importance to alleviate liver injury and promote cholangiocyte-driven liver regeneration. Clinically, cholangiocytes and cholangiocyte organoids are expected to serve as favourable sources for cell therapy in cholangiopathies, which are known as a group of complex diseases involving the biliary system while lacking effective therapeutic options. A comprehensive understanding of the biological characteristics of cholangiocytes provides insights into developing cholangiocyte cell therapy for cholangiopathies. In this review, we discuss the critical role of cholangiocytes in liver injury and regeneration, reveal the underlying mechanism of cholangiocyte plasticity, and explore the prospects and challenges of using cholangiocytes as a source for cell therapy.

In 1998, Arlette Darfeuille-Michaud, Christel Neut and Jean-Frederic Colombel discovered a novel pathovar of Escherichia coli, adherent and invasive Escherichia coli (AIEC), in the ileum of patients with Crohn's disease (CD), that was genetically distinct from diarrheagenic E. coli, could adhere to and invade intestinal epithelial cells and survive in macrophages. The consistent association between AIEC and CD (approximately 30% across the world), their ability to exploit CD-associated genetic traits, and virulence in preclinical colitis models but not healthy hosts spurred global research to elucidate their pathogenicity. Research focused on integrating AIEC with the microbiome, metabolome, metagenome, host response and the impact of diet and antimicrobials has linked the luminal microenvironment and AIEC metabolism to health and disease. This deeper understanding has led to therapeutic trials and precision medicine targeting AIEC-colonised patients. In November 2023, prominent members of the AIEC research community met to present and discuss the many facets of basic, translational and clinical AIEC fields at 'AIEC: past, present and future' in NYC. This review is a summary of this international meeting highlighting the history of AIEC, knowledge accumulated over the past 25 years about its pathogenic properties and proposes a standardised approach for screening patients for AIEC.

The intricate interplay between the gut microbiota and the GI tract has garnered significant attention, as growing evidence has identified the inflammasome as a crucial yet underexplored master regulator in microbiota-driven diseases. Triggered by a variety of dangers, inflammasomes are supramolecular complexes that regulate immune response. A large number of bacterial-derived inducers have been characterised so far. Although structurally divergent, threats are neutralised by the inflammasome, which is then classified into three families: (1) nucleotide-binding oligomerisation domain, leucine-rich repeat-containing proteins, (2) absent in melanoma 2-like receptors and (3) pyrin. An unbalanced microbiota composition, expressed by a dysbiotic phenotype, might therefore induce undesired inflammasome activation, altering the local host homeostasis. Recent studies on the 'microbiota-inflammasome axis' have uncovered unexpected roles for inflammasome signalling in various types of GI cancer and IBD. Additionally, beyond local gut functions, microbiota influences stress responses and neurological health through aberrant secretion of inflammasome-processed cytokines, linking gut-derived signals to systemic diseases via the vagus nerve and the hypothalamic-pituitary-adrenal axis. Besides the standard experimental approaches, this complex network of interactions is now being addressed by Artificial intelligence, which emphasises the profound impact of the gut microbiota on GI health, cancer progression and brain function, opening new avenues for therapeutic intervention in GI diseases, cancer and neurological disorders. Ultimately, microbiota-inflammasome interactions manage a regulatory framework that influences inflammation, cancer progression and systemic diseases, positioning it as both a mediator and a promising therapeutic target in GI malignancies and systemic diseases of the central nervous system.

Systemic therapy represents the standard of care treatment for patients with advanced hepatocellular carcinoma (HCC). Given the increased risk of death from cirrhosis-related complications in patients with advanced liver dysfunction, pivotal phase III trials traditionally limited inclusion to patients with Child-Pugh class A, where death is more likely to be attributed to HCC progression. Therefore, Western guidelines recommend the use of systemic therapies primarily in patients with preserved liver function. However, patients with HCC and Child-Pugh class B are commonly encountered in clinical practice, but due to limited prospective evidence, there is no clear guidance on their optimal management.In this recent advances article, we discuss how the clinical course of cirrhosis can affect eligibility to treatment in the modern era of systemic therapy for HCC, elaborate on strategies to improve liver function in HCC patients by targeting cirrhosis-related and tumour-related factors and summarise the current literature on systemic therapy in HCC patients with Child-Pugh class B. Based on this information, we finally propose a clinical algorithm on how to systematically approach patients with HCC and advanced liver dysfunction in clinical practice.

Faecal microbiota transplantation (FMT) has emerged as a transformative therapy for Clostridioides difficile infections and shows promise for various GI and systemic diseases. However, the poor patient acceptability and accessibility of 'conventional' FMT, typically administered via colonoscopies or enemas, hinders its widespread clinical adoption, particularly for chronic conditions. Oral administration of FMT (OralFMT) overcomes these limitations, yet faces distinct challenges, including a significant capsule burden, palatability concerns and poor microbial viability during gastric transit. This review provides a comprehensive analysis of emerging strategies that aim to advance OralFMT by: (1) refining processing technologies (eg, lyophilisation) that enable manufacturing of low-volume FMT formulations for reducing capsule burden and (2) developing delivery technologies that improve organoleptic acceptability and safeguard the microbiota for targeted colonic release. These advancements present opportunities for OralFMT to expand its therapeutic scope, beyond C. difficile infections, towards chronic GI conditions requiring frequent dosing regimens. While this review primarily focuses on optimising OralFMT delivery, it is important to contextualise these advancements within the broader shift towards defined microbial consortia. Live biotherapeutic products (LBPs) offer an alternative approach, yet the interplay between OralFMT and LBPs in clinical practice remains unresolved. We postulate that continued innovation in OralFMT and LBPs via a multidisciplinary approach can further increase therapeutic efficacy and scalability by enabling disease site targeting, co-delivery of therapeutic compounds and overcoming colonisation resistance. Realising these goals positions OralFMT as a cornerstone of personalised care across a range of diseases rooted in microbiome health.

Pouchitis, defined as inflammation of the ileal pouch, is the most common complication following restorative proctocolectomy for refractory ulcerative colitis. Antibiotics remain the first line of therapy for pouchitis, but the majority of patients develop subsequent episodes and some are refractory to antibiotic therapy. This highlights the need for more effective treatment options and points to a more complex pathophysiology beyond the role of th pouch microbiome, similar to what is seen in inflammatory bowel disease. In this review, we outline the putative mechanisms of pouchitis, including genetic predisposition, microbiome alterations, dysfunction of the intestinal barrier and the immune system and review the available animal models of pouchitis. In addition, we introduce the concept of pouchitis as a possible transmural disease and discuss the potential role of non-immune cells, including stromal cells, in perpetuating inflammation and intestinal barrier dysfunction. We discuss future directions, implications for novel therapies and propose novel multicellular disease models that can better capture the complexity of pouchitis pathogenesis.

Chronic liver disease is a cluster of disorders associated with complex haemodynamic alterations, which is characterised by structural and functional disruptions of the intrahepatic and extrahepatic vasculature. 'Vasomics' is an emerging omics discipline that comprehensively analyses and models the vascular system by integrating pathophysiology of disease, biomechanics, medical imaging, computational science and artificial intelligence. Vasomics is further typified by its multidimensional, multiscale and high-throughput nature, which depends on the rapid and robust extraction of well-defined vascular phenotypes with clear clinical and/or biological interpretability. By leveraging multimodality medical imaging techniques, vascular functional assessments, pathological image evaluation, and related computational methods, integrated vasomics provides a deeper understanding of the associations between the vascular system and disease. This in turn reveals the crucial role of the vascular system in disease occurrence, progression and treatment responses, thereby supporting precision medicine approaches. Pathological vascular features have already demonstrated their key role in different clinical scenarios. Despite this, vasomics is yet to be widely recognised. Therefore, we furnished a comprehensive definition of vasomics providing a classification of existing hepatic vascular phenotypes into the following categories: anatomical, biomechanical, biochemical, pathophysiological and composite.

Live biotherapeutic products (LBPs) are biological products composed of living micro-organisms, developed to prevent, treat, or cure diseases. Examples include cultured strains of Akkermansia muciniphila and Christensenella minuta, as well as treatments using purified Firmicutes spores for recurrent Clostridioides difficile infections. There is a need for guidelines over the increasing interest in developing LBPs. A panel of microbiome experts from Asia-Pacific countries articulates their perspectives on key considerations for LBP development.

RNA-based therapeutics have rapidly emerged over the past decade, offering a new class of medicines that differ significantly from conventional drugs. These therapies can be programmed to target or restore defective genes, allowing for more personalised treatments and reducing side effects. Notably, RNA therapies have made significant progress in the treatment of genetic liver diseases, exemplified by small interfering RNA treatments for hereditary transthyretin amyloidosis, which use liver-targeting strategies such as GalNAc conjugation to improve efficacy and safety. RNA-based gene-editing technologies, such as base editor and prime editor clustered regularly interspaced short palindromic repeats systems, also show promise with their ability to minimise genomic rearrangements and cancer risk. While RNA therapies offer high precision, challenges remain in optimising delivery methods and ensuring long-term safety and efficacy. Lipid nanoparticle-mRNA therapeutics, particularly for protein replacement in rare diseases, have gained support from preclinical successes. Compared with viral gene therapies, mRNA therapies present a safer profile with reduced risks of genomic integration and oncogene activation. However, clinical trials, especially for rare diseases, face limitations such as small sample sizes and short observation periods. Further preclinical studies, including non-human primates, will be essential for refining trial designs. Despite their potential, the high costs of RNA therapies pose a challenge that will require cost-utility models to guide pricing and accessibility. Here, we discuss the fundamental aspects of RNA-based therapeutics and showcase the most relevant preclinical and clinical developments in genetic liver metabolic diseases.

The link between gut microbiome and eating behaviours, especially palatable food intake, is a growing focus of scientific investigation. The complex ecosystem of microorganisms in the gut influences host metabolism, immune function and neurobehavioural signalling. This review explores the role of neuroinflammation in dysregulations of food-induced reward signalling and the potential causal role of the gut microbiota on these proinflammatory processes. Particular attention is given to eating disorders (ED, specifically anorexia nervosa, binge eating disorder and bulimia nervosa) and potential links with the gut microbiota, food reward alterations and neuroinflammation. Finally, we propose gut microbiota modulation as a promising therapeutic strategy in food reward alterations and ED.

Inflammatory bowel diseases (IBDs), which include ulcerative colitis (UC) and Crohn's disease (CD), are chronic conditions characterised by inflammation of the intestinal tract. Alterations in virtually all intestinal cell types, including immune, epithelial and stromal cells, have been described in these diseases. The study of IBD has historically relied on bulk transcriptomics, but this method averages signals across diverse cell types, limiting insights. Single-cell omic technologies overcome the intrinsic limitations of bulk analysis and reveal the complexity of multicellular tissues at a cell-by-cell resolution. Within healthy and inflamed intestinal tissues, single-cell omics, particularly single-cell RNA sequencing, have contributed to uncovering novel cell types and cell functions linked to disease activity or the development of complications. Collectively, these results help identify therapeutic targets in difficult-to-treat complications such as fibrostenosis, creeping fat accumulation, perianal fistulae or inflammation of the pouch. More recently, single-cell omics have gradually been adopted in studies to understand therapeutic responses, identify mechanisms of drug failure and potentially develop predictors with clinical utility. Although these are early days, such studies lay the groundwork for the implementation in clinical practice of new technologies in diagnostics, monitoring and prediction of disease prognosis. With this review, we aim to provide a comprehensive survey of the studies that have applied single-cell omics to the study of UC or CD, and offer our perspective on the main findings these studies contribute. Finally, we discuss the limitations and potential benefits that the integration of single-cell omics into clinical practice and drug development could offer.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is the most common cause of chronic liver disease in children. MASLD encompasses a spectrum of liver disease and can be severe, with 10% of affected children presenting with advanced fibrosis. While biopsy remains the most accurate method for diagnosing and staging the disease, MRI proton density fat fraction and magnetic resonance elastography are the most reliable non-invasive measures for assessing steatosis and fibrosis, respectively. MASLD is associated with multiple comorbidities including type 2 diabetes, hypertension, dyslipidaemia, decreased bone mineral density, obstructive sleep apnoea, anxiety and depression. Currently, there are no pharmacological treatments available for children, highlighting the urgent need for paediatric clinical trials. A diet low in free sugars is promising for reducing steatosis and decreasing alanine aminotransferase, a surrogate marker for hepatic inflammation. Emerging data indicate that steatosis can be present in children under 6 years of age, which was previously considered rare. The intricate interplay of genetics may inform future therapeutics and prognostication, with the PNPLA3 gene showing the most evidence for association with the risk and severity of steatotic liver disease and steatohepatitis. MASLD is a complex disease affecting one in ten children and is associated with increased early mortality risk. More dedicated studies are needed in children to advance our understanding of this disease and find effective treatments.

Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, carrying a greater risk of developing cirrhosis and its complications. For decades, pegylated interferon alpha (PegIFN-α) has represented the only therapeutic option, with limited virological response rates and poor tolerability. In 2020, the European Medicines Agency approved bulevirtide (BLV) at 2 mg/day, an entry inhibitor of hepatitis B virus (HBV)/hepatitis delta virus (HDV), which proved to be safe and effective as a monotherapy for up to 144 weeks in clinical trials and real-life studies, including patients with cirrhosis. Long-term BLV monotherapy may reduce decompensating events in patients with cirrhosis. The combination of BLV 2 mg with PegIFN-α increased the HDV RNA undetectability rates on-therapy but not off-therapy, compared with PegIFN monotherapy. However, combination therapy, but not BLV monotherapy, may induce hepatitis B surface antigen (HBsAg) loss in some patients. The PegIFN lambda study has been discontinued due to liver toxicity issues, while lonafarnib boosted with ritonavir showed limited off-therapy efficacy in a phase 3 study. Nucleic acid polymer-based therapy is promising but large studies are still lacking. New controlled trial data come from molecules, such as monoclonal antibodies and/or small interfering RNA, that target HBsAg or HBV RNAs, which demonstrated not only profound HDV suppression, but also HBsAg decline.While waiting for new compounds to be approved as monotherapy or in combination, BLV monotherapy 2 mg/day remains the only approved therapy for CHD, at least in the European Union region.

Immune checkpoint inhibitors (ICI) have led to breakthrough improvements in the management of malignancy including hepatocellular (HCC) and biliary tract cancer, improving decades-old standards of care and increasing patient survival. In both liver tumour types, which commonly arise in the context of liver inflammation and underlying functional impairment, the lack of validated predictors of response underscores the need to balance predicted gains in survival with risk of treatment-related hepatoxicity and decompensation of underlying chronic liver disease.In addition, the liver is implicated in the toxicity associated with ICI therapy for non-liver cancers, which exhibits a high degree of variability in presentation and severity. An accurate assessment is mandatory for the diagnosis and management of ICI-induced liver injury.In this Recent Advances article, we provide an overview of the mechanisms of efficacy and toxicity of anticancer immunotherapy in liver tumours and liver toxicity in extrahepatic malignancies.We compare and contrast characteristics, management strategies and outcomes from immune-related liver injury in patients with chronic hepatitis/cirrhosis or with an underlying healthy liver and discuss the latest findings on how toxicity and decompensation may impact the outlook of patients with liver tumours and extrahepatic malignancies offering insights into the future directions of clinical research and practice in the field.

Perturbation of mRNA splicing is commonly observed in human cancers and plays a role in various aspects of cancer hallmarks. Understanding the mechanisms and functions of alternative splicing (AS) not only enables us to explore the complex regulatory network involved in tumour initiation and progression but also reveals potential for RNA-based cancer treatment strategies. This review provides a comprehensive summary of the significance of AS in liver cancer, covering the regulatory mechanisms, cancer-related AS events, abnormal splicing regulators, as well as the interplay between AS and post-transcriptional and post-translational regulations. We present the current bioinformatic approaches and databases to detect and analyse AS in cancer, and discuss the implications and perspectives of AS in the treatment of liver cancer.

Eosinophilic oesophagitis (EoE) is a chronic, immune-mediated condition characterised by eosinophilic infiltration of the oesophagus, leading to significant morbidity due to oesophageal dysfunction. The pathogenic course of EoE begins with tissue injury, marked by the intricate interplay of oesophageal barrier dysfunction and T helper 2-mediated inflammation. In response to tissue damage, a subsequent phase of tissue remodelling features a complex interaction between epithelial cells and stromal cells, aimed at tissue repair. The persistence of inflammation drives these mechanisms towards oesophageal fibrostenosis, mainly through the transforming growth factor-dependent, myofibroblast-driven accumulation of the extracellular matrix. Currently, treatment options for EoE are limited, with dietary intervention, proton pump inhibitors and oral steroids serving as first-line therapies. Dupilumab, an antiinterleukin (IL) 4/IL-13 agent, is the only biologic that has been approved by European and American regulatory authorities. However, emerging OMIC technologies significantly advance our understanding of EoE pathogenesis, revealing novel cellular and molecular mechanisms driving the disease. This progress has accelerated the identification of new therapeutic targets and agents, some already under clinical investigation, potentially expanding our therapeutic arsenal and paving the way for more personalised approaches. In this evolving landscape, artificial intelligence (AI) has shown great potential to further elaborate on the complexities of EoE heterogeneity, offering standardised tools for diagnosis, disease phenotyping, and prediction of treatment response. Though still in their early stages, integrating OMICs and AI marks a pivotal step towards precision medicine in EoE.

Clinically effective pharmacological treatment(s) for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) represent a largely unmet need in medicine. Since glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been licensed for the treatment of type 2 diabetes mellitus and obesity, they were one of the first drug classes to be examined in individuals with MASLD/MASH. Successful phase 2 randomised clinical trials with these agents have resulted in progression to phase 3 clinical trials (principally testing the long-term efficacy of subcutaneous semaglutide). Over the last few years, in addition to GLP-1RAs, newer agents with glucose-dependent insulinotropic peptide and/or glucagon receptor agonist functions have been tested, with increasing evidence from phase 2 randomised clinical trials of histological improvements in MASLD/MASH, as well as benefits on MASLD-related extrahepatic complications. Based on this background of evidence, single, dual or triple incretin receptor agonists are becoming an attractive and promising treatment option for MASLD or MASH, particularly in individuals with coexisting obesity or type 2 diabetes mellitus. In this narrative review, we examine the rapidly expanding body of clinical evidence supporting a role of incretin-based pharmacotherapies in delaying or reversing MASH progression. We also discuss the biology of incretins and the putative hepatoprotective mechanisms of incretin-based pharmacotherapies for managing MASLD or MASH.

Many patients with IBD report persisting symptoms, despite resolution of the inflammatory process. Although by definition, a diagnosis of IBS cannot be made, the prevalence of 'IBS in IBD' surpasses the rate of IBS in the global population by fivefold. Because IBS-like symptoms are associated with a decreased quality of life and increased healthcare utilisation in IBD, diagnosis and treatment are necessary. In this review, we summarise the current knowledge on IBS-like symptoms in IBD. A pathophysiological common ground is present, which includes genetic susceptibility, environmental triggers, gut microbial dysbiosis, increased intestinal permeability, visceral hypersensitivity and involvement of brain-gut interaction. When symptoms persist after resolution of inflammation, other GI diseases should be excluded based on the chief complaint, considering any possible psychological co-morbidity early in the diagnostic work-up. Subsequent treatment should be initiated that is evidence-based and often multimodal, including classical and non-classical pharmacological agents as well as lifestyle and microbiota-based approaches, spanning the breadth of the gut, brain and its interaction. Treatment goals in this substantial part of the IBD population should be adapted to not only focus on treating the inflammation but taking care of the patient.

The understanding that changes in microbiome composition can influence chronic human diseases and the efficiency of therapies has driven efforts to develop microbiota-centred therapies such as first and next generation probiotics, prebiotics and postbiotics, microbiota editing and faecal microbiota transplantation. Central to microbiome research is understanding how disease impacts microbiome composition and vice versa, yet there is a problematic issue with the term 'dysbiosis', which broadly links microbial imbalances to various chronic illnesses without precision or definition. Another significant issue in microbiome discussions is defining 'healthy individuals' to ascertain what characterises a healthy microbiome. This involves questioning who represents the healthiest segment of our population-whether it is those free from illnesses, athletes at peak performance, individuals living healthily through regular exercise and good nutrition or even elderly adults or centenarians who have been tested by time and achieved remarkable healthy longevity.This review advocates for delineating 'what defines a healthy microbiome?' by considering a broader range of factors related to human health and environmental influences on the microbiota. A healthy microbiome is undoubtedly linked to gut health. Nevertheless, it is very difficult to pinpoint a universally accepted definition of 'gut health' due to the complexities of measuring gut functionality besides the microbiota composition. We must take into account individual variabilities, the influence of diet, lifestyle, host and environmental factors. Moreover, the challenge in distinguishing causation from correlation between gut microbiome and overall health is presented.The review also highlights the resource-heavy nature of comprehensive gut health assessments, which hinders their practicality and broad application. Finally, we call for continued research and a nuanced approach to better understand the intricate and evolving concept of gut health, emphasising the need for more precise and inclusive definitions and methodologies in studying the microbiome.