Siddle M, Gallego Durán R, Goel D
… +3 more, Renquist BJ, Holt MK, Hadjihambi A
Nat Rev Gastroenterol Hepatol
· 2026 Feb · PMID 41214287
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The liver is a metabolically flexible tissue, adapting its functions to changes in nutrient availability and physiological states. This adaptability is crucial for maintaining metabolic homeostasis and likely involves co...The liver is a metabolically flexible tissue, adapting its functions to changes in nutrient availability and physiological states. This adaptability is crucial for maintaining metabolic homeostasis and likely involves communication with the central nervous system through the liver-brain axis. The liver also receives a constant influx of nutrients, hormones and microbial metabolites from the gastrointestinal tract in a multifaceted communication network, the gut-liver-brain axis. Dysregulation of this communication can lead to hepatic encephalopathy and cognitive impairments in early-stage chronic liver disease, such as metabolic dysfunction-associated steatotic liver disease, substantially affecting patient quality of life. This Review examines key signalling pathways along the liver-brain axis: humoral signalling, including metabolites, hepatokines, toxins and inflammation, and neural pathways, focusing on afferent signalling through the common hepatic branch of the vagus nerve. We discuss how each pathway might contribute to behavioural and mood changes in chronic liver disease and the development of hepatic encephalopathy. Although the humoral effects have been studied more extensively, we propose that the afferent vagus nerve is central to liver disease-associated cognitive and behavioural complications. Finally, we highlight how new techniques and tools could advance our understanding of the gut-liver-brain communication that affects behaviour.
Chica Cardenas LA, Leonard MM, Baldridge MT
… +1 more, Handley SA
Nat Rev Gastroenterol Hepatol
· 2026 Feb · PMID 41193697
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Full text
The gut virome is a complex ecosystem characterized by the interplay of diverse viral entities, predominantly bacteriophages and eukaryotic viruses. The gut virome has a critical role in human health by shaping microbial...The gut virome is a complex ecosystem characterized by the interplay of diverse viral entities, predominantly bacteriophages and eukaryotic viruses. The gut virome has a critical role in human health by shaping microbial community profiles, modulating host immunity and influencing metabolic processes. Different viral metagenomics approaches have revealed the remarkable diversity of the gut virome, showing individual-specific patterns that evolve over time and adapt dynamically to environmental factors. Perturbations in this community are increasingly associated with chronic immune and inflammatory conditions, metabolic disorders and neurological conditions, highlighting its potential as a diagnostic biomarker and therapeutic target. The early-life gut virome is particularly influential in establishing lifelong health trajectories through its interactions with diet, immune pathways and others, thereby contributing to inflammatory and metabolic regulation. This Review synthesizes current knowledge of gut virome composition, dynamics and functional relevance, critically evaluating evidence distinguishing causal from correlative roles in disease pathogenesis. The interactions of the virome with other microbiome components and host immunity are examined, and emerging translational applications, including phage therapy and biomarker development, are discussed. Integrating these insights while acknowledging methodological challenges provides a comprehensive framework for understanding the complex roles of the gut virome in health and disease.
Understanding the locations of extrinsic sensory nerve endings in the gastrointestinal tract and their mechanisms of activation is essential to advancing our understanding of how communication along the gut-brain axis af...Understanding the locations of extrinsic sensory nerve endings in the gastrointestinal tract and their mechanisms of activation is essential to advancing our understanding of how communication along the gut-brain axis affects health and disease. The gastrointestinal tract detects diverse stimuli (chemical, mechanical and thermal signals) via two major types of primary afferent (sensory) nerves: vagal and spinal afferents. Viscerofugal neurons represent a third pathway that has been indirectly implicated in gut-brain signalling. These spinal and vagal afferents transmit sensory signals to the brain through distinct pathways, and although the origins of their nerve cell bodies are known, their nerve endings remain poorly understood. New evidence indicates that single dorsal root ganglia neurons can give rise to multiple different morphological types of endings within different gut layers, and that Piezo2 channels have a major role in detecting mechanosensory stimuli by gut-projecting spinal afferents. Morphological studies suggest that substances released from enteroendocrine cells can activate the terminals of vagal and spinal afferent endings within the mucosa through a paracrine mechanism. Here, we review the distinct spinal and vagal afferent types alongside viscerofugal pathways revealed by advances in neurogenetic techniques and high-resolution anterograde tracing, linking them to their physiological role in gut-brain communication.
Taylor SA, Bader GD, MacParland S
… +30 more, Mullen AC, Andrews T, Cuenca AG, DasGupta R, Gehring AJ, Grün D, Guilliams M, Gulamhusein A, Henderson NC, Hirschfield G, Huppert SS, Itzkovitz S, Jiang ZG, Lauer GM, McGilvray I, Mysore KR, Pirola CJ, Quon G, Rahbari M, Regev A, Ricciuto A, Scott CL, Sharma A, Sookoian S, Tana MM, Teichmann SA, Vallier L, Vlachos IS, Wang B, Zhen M
Extracellular proteases, originating from the host or the microbiota, are key signalling molecules involved in cellular communication with the environment. They signal through a wide array of mechanisms, ranging from rec...Extracellular proteases, originating from the host or the microbiota, are key signalling molecules involved in cellular communication with the environment. They signal through a wide array of mechanisms, ranging from receptor activation to protein transformation and even degradation. Protease signals are irreversible, as it involves the cleavage of proteins. Therefore, proteases are tightly controlled, and must be understood within the context of the complex networks in which they operate - their activity is tightly regulated by access to specific substrates and the presence of inhibitors. The intestine is particularly exposed to extracellular proteases, which have major roles in gut physiology: digestion, food antigen processing, barrier function, epithelial renewal and microbiome homeostasis. Dysregulated proteolytic balance is associated with intestinal pathologies including inflammatory bowel disease, irritable bowel syndrome, coeliac disease and colorectal cancer. Extracellular proteases are major contributors to a number of gut dysfunctions, including microbiota dysbiosis, barrier dysfunction, matrix remodelling, activation of mucosal immunity and nociceptive or motility abnormalities. Consequently, proteolytic homeostasis at the intestinal mucosa surface has become a goal for intestinal health, and new therapeutic options targeting the interplay among proteases, their inhibitors and their substrates have been explored.
Taylor SA, Bader GD, MacParland S
… +30 more, Mullen AC, Andrews T, Cuenca AG, DasGupta R, Gehring AJ, Grün D, Guilliams M, Gulamhusein A, Henderson NC, Hirschfield G, Huppert SS, Itzkovitz S, Jiang ZG, Lauer GM, McGilvray I, Mysore KR, Pirola CJ, Quon G, Rahbari M, Regev A, Ricciuto A, Scott CL, Sharma A, Sookoian S, Tana MM, Teichmann SA, Vallier L, Vlachos IS, Wang B, Zhen M
The goal of the Human Liver Cell Atlas (HLiCA) is to create a comprehensive map that defines the normal functions of diverse liver cell types and their spatial relationships over the human lifespan. This project fits wit...The goal of the Human Liver Cell Atlas (HLiCA) is to create a comprehensive map that defines the normal functions of diverse liver cell types and their spatial relationships over the human lifespan. This project fits within the goals of the Human Cell Atlas to create comprehensive reference maps of all human cells as a basis for both understanding human health and diagnosing, monitoring and treating disease. Through collection of samples from diverse individuals, data integration across technologies and overcoming liver-specific challenges for experimental methods, the HLiCA will map as many cell types and states as possible in healthy human livers from individuals across all ages and many ancestries. Establishing this HLiCA of healthy livers is a critical step to begin to understand perturbations in disease. The HLiCA will be available on an open-access platform to facilitate data sharing and dissemination. We expect that creation of the HLiCA will help to lay the foundation for new research initiatives to advance our understanding of liver disease, improve methods of tissue engineering, and identify novel prognostic biomarkers and therapies to improve patient outcomes. We describe key experimental and computational challenges to overcome in building the atlas and the potential impact of the atlas on disease research.
Over the past decade, advances in organoid culturing methods have enabled the growth of three-dimensional cellular cultures in vitro with increasing fidelity with respect to the cellular composition, architecture and fun...Over the past decade, advances in organoid culturing methods have enabled the growth of three-dimensional cellular cultures in vitro with increasing fidelity with respect to the cellular composition, architecture and function of in vivo organs. The increased accessibility and ability to manipulate organoids as an in vitro system have led to a shift in the landscape of experimental biology. Whether derived from stem cells or tissue-resident cells, organoids are now routinely used in studies of development, homeostasis, regeneration and disease modelling, including viral infection and cancer. These applications of organoids are highly relevant for gastrointestinal tissues, including the liver and pancreas. In this Review, we explore the current and emerging advances in liver and pancreas organoid technologies for both discovery and clinical translation research and provide an outlook on the challenges ahead.
WNT-β-catenin activation is observed in around 50% of all patients with hepatocellular carcinoma (HCC), through either gain-of-function mutations in CTNNB1 (which encodes β-catenin) or loss-of-function mutations in AXIN1...WNT-β-catenin activation is observed in around 50% of all patients with hepatocellular carcinoma (HCC), through either gain-of-function mutations in CTNNB1 (which encodes β-catenin) or loss-of-function mutations in AXIN1 or APC. Currently, first-line therapies for HCC are immune checkpoint inhibitor (ICI) combinations, and β-catenin-active HCCs have garnered increased attention due to their unique tumour immune microenvironment (TIME). This pathway is known to drive an immune-excluded TIME, but clinical investigations have provided a more nuanced perspective, with the emergence of a new 'immune-like' subclass of HCC that is paradoxically enriched for CTNNB1 mutations and has high levels of T cell infiltration. As such, patients and animal models with β-catenin activation treated with ICIs exhibit heterogeneous responses. Additionally, these tumours exhibit higher fatty acid oxidation to fuel tumour growth owing to a unique metabolic milieu shaped by zone 3 metabolism, which is a physiological function of WNT-β-catenin signalling in the liver lobule. Biomarkers to detect molecular subclasses of patients for targeted therapies are being developed. In this Review, we discuss advances in our understanding of the TIME and metabolism of β-catenin-active HCC, driven by in vitro and in vivo models and single-cell and spatial sequencing, and their implications for the treatment of a subset of HCCs using precision therapies against WNT-β-catenin signalling.
Decompensated cirrhosis describes an advanced clinical stage with clinical complications, such as ascites, variceal bleeding or hepatic encephalopathy, associated with considerable mortality. Portal hypertension is the m...Decompensated cirrhosis describes an advanced clinical stage with clinical complications, such as ascites, variceal bleeding or hepatic encephalopathy, associated with considerable mortality. Portal hypertension is the main risk factor for developing decompensation in patients with compensated cirrhosis, whereas systemic inflammation is the key driving force for organ failure, that is, for acute-on-chronic liver failure in later stages of cirrhosis. As portal hypertension and systemic inflammation coexist in patients with cirrhosis, an improved understanding of their interaction and dynamic role in distinct stages of cirrhosis is an important step forward towards the development of urgently needed therapeutic interventions. Based on emerging evidence from clinical and translational studies, a novel concept of different predominant pathomechanisms of decompensated cirrhosis is presented, which includes portal hypertension-predominant, systemic inflammmation-predominant and mixed portal hypertension-systemic inflammation phenotypes. A comprehensive set of biomarkers and surrogates of portal hypertension and systemic inflammation might assist clinicians in identifying a predominance of one over the other cirrhosis phenotype. As survival rates of patients with decompensated cirrhosis have remained detrimental without liver transplantation over the past decades, future studies should build on this knowledge to develop effective portal hypertension and systemic inflammation-directed therapies for this underserved population.