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Despite the known functional relationship between the gut and the liver, the clinical consequences of this circuit remain unclear. We assessed the hepatobiliary phenotype of cohorts with celiac disease (CeD), Crohn´s disease (CD) and ulcerative colitis (UC). Baseline liver function tests and the frequency of hepatobiliary diseases were analyzed in 2377 CeD, 1738 CD, 3684 UC subjects and 488,941 controls from the population-based UK Biobank cohort. In this cohort study associations were adjusted for age, sex, BMI, diabetes, and alcohol consumption. Compared to controls, cohorts with CeD, but not CD/UC displayed higher AST/ALT values. Subjects with CD/UC but not CeD had increased GGT levels. Elevated ALP and cholelithiasis were significantly more common in all intestinal disorders. Non-alcoholic steatohepatitis and hepatocellular carcinoma (HCC) were enriched in CeD and CD (NASH: t aOR = 4.9 [2.2–11.0] in CeD, aOR = 4.2 [1.7–10.3] in CD, HCC: aOR = 4.8 [1.8–13.0] in CeD, aOR = 5.9 [2.2–16.1] in CD), while cholangitis was more common in the CD/UC cohorts (aOR = 11.7 [9.1–15.0] in UC, aOR = 3.5 [1.8–6.8] in CD). Chronic hepatitis, autoimmune hepatitis (AIH) and cirrhosis were more prevalent in all intestinal disorders. In UC/CD, a history of intestinal surgery was associated with elevated liver enzymes and increased occurrence of gallstones (UC: aOR = 2.9 [2.1–4.1], CD: 1.7 [1.2–2.3]). Our data demonstrate that different intestinal disorders predispose to distinct hepatobiliary phenotypes. An increased occurrence of liver cirrhosis, NASH, AIH and HCC and the impact of surgery warrant further exploration.

The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut–liver axis. In this Review we discuss the gut–liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches.In this Review, Pabst and colleagues discuss the gut–liver axis, with an emphasis on the establishment and regulation of structural and functional barriers, dynamics within the axis (immune responses and microbiome) and clinical implications.

In the past decade, an exciting realization has been that diverse liver diseases — ranging from nonalcoholic steatohepatitis, alcoholic steatohepatitis and cirrhosis to hepatocellular carcinoma — fall along a spectrum. Work on the biology of the gut–liver axis has assisted in understanding the basic biology of both alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). Of immense importance is the advancement in understanding the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that enable the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review gut–liver communications in liver disease, exploring the molecular, genetic and microbiome relationships and discussing prospects for exploiting the microbiome to determine liver disease stage and to predict the effects of pharmaceutical, dietary and other interventions at a population and individual level. Although much work remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These ‘avatar mice’ could be especially useful for guiding new microbiome-based or microbiome-informed therapies.

Epithelial tight junctions define the paracellular permeability of the intestinal barrier. Molecules can cross the tight junctions via two distinct size-selective and charge-selective paracellular pathways: the pore pathway and the leak pathway. These can be distinguished by their selectivities and differential regulation by immune cells. However, permeability increases measured in most studies are secondary to epithelial damage, which allows non-selective flux via the unrestricted pathway. Restoration of increased unrestricted pathway permeability requires mucosal healing. By contrast, tight junction barrier loss can be reversed by targeted interventions. Specific approaches are needed to restore pore pathway or leak pathway permeability increases. Recent studies have used preclinical disease models to demonstrate the potential of pore pathway or leak pathway barrier restoration in disease. In this Review, we focus on the two paracellular flux pathways that are dependent on the tight junction. We discuss the latest evidence that highlights tight junction components, structures and regulatory mechanisms, their impact on gut health and disease, and opportunities for therapeutic intervention.Increased intestinal permeability owing to tight junction barrier loss could be targeted in gastrointestinal diseases associated with increased permeability. In this Review, the authors discuss the molecular components and regulation of the tight junction, and consider the relevance to gut diseases and therapeutic opportunities.

Microorganisms colonize various ecological niches in the human habitat, as they do in nature. Predominant forms of multicellular communities called biofilms colonize human tissue surfaces. The gastrointestinal tract is home to a profusion of microorganisms with intertwined, but not identical, lifestyles: as isolated planktonic cells, as biofilms and in biofilm-dispersed form. It is therefore of major importance in understanding homeostatic and altered host–microorganism interactions to consider not only the planktonic lifestyle, but also biofilms and biofilm-dispersed forms. In this Review, we discuss the natural organization of microorganisms at gastrointestinal surfaces, stratification of microbiota taxonomy, biogeographical localization and trans-kingdom interactions occurring within the biofilm habitat. We also discuss existing models used to study biofilms. We assess the contribution of the host–mucosa biofilm relationship to gut homeostasis and to diseases. In addition, we describe how host factors can shape the organization, structure and composition of mucosal biofilms, and how biofilms themselves are implicated in a variety of homeostatic and pathological processes in the gut. Future studies characterizing biofilm nature, physical properties, composition and intrinsic communication could shed new light on gut physiology and lead to potential novel therapeutic options for gastrointestinal diseases. In this Review, Motta, Vergnolle and colleagues describe the organization of microorganisms into planktonic, biofilm and biofilm-dispersed forms in the gastrointestinal tract. The role of the host–biofilm relationship in gut homeostasis and disease is discussed. Key points Bacteria adopt different lifestyles in their natural habitats, from single planktonic cells to biofilm communities. Polymicrobial biofilms naturally grow throughout the gastrointestinal tract, both at the epithelial surface and in the lumen as mucin-attached and food particle-attached colonies. The biofilm lifestyle influences metabolic behaviour of the microbiota but more research is needed to characterize gut biofilm-specific metabolites and their effects on the host response in health and disease. Polymicrobial and trans-kingdom interactions occur in gut biofilms; deciphering the nature of such interactions might improve our current understanding of the homeostatic relationship between the host and its gut microbiota. Abnormal biofilm features are associated with gastrointestinal diseases; characterization of biofilm alterations and cause-to-effect studies are warranted to elucidate their role in pathophysiology. Investigating biogeographical redistribution of biofilms at mucosal surfaces might provide new tools to characterize microbial alterations associated with gastrointestinal diseases and options for therapeutic intervention.

Key Points The Hippo pathway plays an important part in intestinal homeostasis and regeneration in both Drosophila melanogaster and mammals, and its dysregulation often leads to uncontrolled tissue growth In general, YAP1 and TAZ activity promotes intestinal stem cell properties, and overexpression of YAP1 induces stem cell expansion YAP1 and TAZ are crucial for intestinal tissue regeneration after injury; YAP1 depletion leads to disturbed tissue formation during regeneration Crosstalk between the Hippo pathway and other signalling pathways, such as Wnt and Notch, regulates intestinal tissue homeostasis and regeneration, although detailed mechanisms have not yet been elucidated Dysregulation of the Hippo pathway leads to tumorigenesis; YAP1 and TAZ are oncogenic in colorectal cancers, as illustrated by data from mouse models and patient specimens The Hippo pathway also has an important role in liver damage repair and tumorigenesis, and dysregulation of the Hippo pathway leads to uncontrolled growth in the liver The Hippo signalling cascade is crucial for the maintenance of tissue homeostasis and regeneration after damage. This Review describes the core components of the Hippo pathway and their role in intestinal homeostasis, regeneration and disease, and the integration of Hippo signalling with other key signalling pathways. The function of the Hippo pathway in liver physiology and disease is briefly discussed. The Hippo pathway is a signalling cascade conserved from Drosophila melanogaster to mammals. The mammalian core kinase components comprise MST1 and MST2, SAV1, LATS1 and LATS2 and MOB1A and MOB1B. The transcriptional co-activators YAP1 and TAZ are the downstream effectors of the Hippo pathway and regulate target gene expression. Hippo signalling has crucial roles in the control of organ size, tissue homeostasis and regeneration, and dysregulation of the Hippo pathway can lead to uncontrolled cell growth and malignant transformation. Mammalian intestine consists of a stem cell compartment as well as differentiated cells, and its ability to regenerate rapidly after injury makes it an excellent model system to study tissue homeostasis, regeneration and tumorigenesis. Several studies have established the important role of the Hippo pathway in these processes. In addition, crosstalk between Hippo and other signalling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this Review, we summarize studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discuss future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease.

Giant mitochondria are peculiarly shaped, extremely large mitochondria in hepatic parenchymal cells, the internal structure of which is characterised by atypically arranged cristae, enlarged matrix granules and crystalline inclusions. The presence of giant mitochondria in human tissue biopsies is often linked with cellular adversity, caused by toxins such as alcohol, xenobiotics, anti-cancer drugs, free-radicals, nutritional deficiencies or as a consequence of high fat Western diets. To date, non-alcoholic fatty liver disease is the most prevalent liver disease in lipid dysmetabolism, in which mitochondrial dysfunction plays a crucial role. It is not well understood whether the morphologic characteristics of giant mitochondria are an adaption or caused by such dysfunction. In the present study, we employ a complementary multimodal imaging approach involving array tomography and transmission electron tomography in order to comparatively analyse the structure and morphometric parameters of thousands of normal- and giant mitochondria in four patients diagnosed with non-alcoholic fatty liver disease. In so doing, we reveal functional alterations associated with mitochondrial gigantism and propose a mechanism for their formation based on our ultrastructural findings.

As an important protein source, soybean products can cause intestinal inflammation and injury in many animals including human beings, particularly infants and juvenile individuals. Research in this field has been performed for terrestrial animals and fish, but still lacks integrity and systematicness. In this study, the main biological processes in the intestinal tract of marine fish juvenile pearl gentian grouper in the state of soybean meal-induced enteritis (SBMIE) were analyzed. A total of 720 groupers with an approximate initial weight of 12.5 g were randomly divided into three groups: the fish meal (FM) control group, the 20% SBM group (SBM20), and the SBM40 group (n = 4). Three iso-nitrogenous and iso-lipidic diets were prepared and fed to fish for 10 weeks. Each barrel contained a water volume of about 1 m 3 in and was exposed to natural light and temperature. Results indicated that the growth and physiology of groupers fed with SBM were significantly negatively affected, with the gene expressions of intestinal structural protein abnormal. 16SrDNA high-throughput sequencing showed that the intestinal microflora played an important role in the pathogenesis of pearl gentian grouper SBMIE, which may activate a variety of pathogen pattern recognition receptors, such as toll-like receptors (TLRs), RIG-I-like receptors, and nod-like receptors. Transcriptome analysis revealed that changes of the SBMIE signaling pathway in pearl gentian groupers were conservative to some extent than that of terrestrial animals and freshwater fish. Moreover, the TLRs-nuclear factor kappa-B signaling pathway becomes activated, which played an important role in SBMIE. Meanwhile, the signal pathways related to nutrient absorption and metabolism were generally inhibited. Metabolomics analysis showed that isoflavones and saponins accounted for a large proportion in the potential biomarkers of pearl gentian grouper SBMIE, and most of the biomarkers had significantly positive or negative correlations with each other; 56 metabolites were exchanged between intestinal tissues and contents, which may play an important role in the development of enteritis, including unsaturated fatty acids, organic acids, amino acids, vitamins, small peptides, and nucleotides, etc. These results provide a basic theoretical reference for solving the intestinal issues of fish SBMIE and research of inflammatory bowel disease in mammals.

Key Points Acute-on-chronic liver failure (ACLF) is a distinct clinical syndrome characterized by liver failure due to an acute hepatic injury on an underlying chronic liver disease with high 28-day mortality Acute insults include alcohol, hepatotropic viruses and drugs whereas the underlying chronic liver disease is generally cirrhosis due to alcohol, hepatitis B or C, or NASH After an acute insult, persistent inflammation, systemic inflammatory response syndrome and the cytokine storm have a central role in the pathogenesis of liver failure and subsequent organ failure A short 'golden window' precedes sepsis development and organ(s) failure, providing opportunity for immunomodulation with granulocyte-colony stimulating factor and other interventions; extrahepatic organ failure indicates severity of illness, prognosis and helps guide management Abstinence, antiviral therapy and withdrawal of harmful drug are specific therapies that could help ameliorate or reverse the liver failure Liver transplantation is the definitive treatment and a good outcome is achieved with early transplantation in carefully selected patients; liver dialysis and plasmapheresis can help as 'bridge therapies' Acute-on-chronic liver failure (ACLF) is a distinct clinical entity with a serious risk of death. However, much debate surrounds the pathogenesis and definitions of this disease. Sarin and Choudhury describe the differences and similarities between Eastern and Western definitions of ACLF and present a common approach to manage these patients for better clinical outcomes. Acute-on-chronic liver failure (ACLF) is a distinct clinical entity and differs from acute liver failure and decompensated cirrhosis in timing, presence of acute precipitant, course of disease and potential for unaided recovery. The definition involves outlining the acute and chronic insults to include a homogenous patient group with liver failure and an expected outcome in a specific timeframe. The pathophysiology of ACLF relates to persistent inflammation, immune dysregulation with initial wide-spread immune activation, a state of systematic inflammatory response syndrome and subsequent sepsis due to immune paresis. The disease severity and outcome can be predicted by both hepatic and extrahepatic organ failure(s). Clinical recovery is expected with the use of nucleoside analogues for hepatitis B, and steroids for severe alcoholic hepatitis and, possibly, severe autoimmune hepatitis. Artificial liver support systems help remove toxins and metabolites and serve as a bridge therapy before liver transplantation. Hepatic regeneration during ongoing liver failure, although challenging, is possible through the use of growth factors. Liver transplantation remains the definitive treatment with a good outcome. Pre-emptive antiviral agents for hepatitis B before chemotherapy to prevent viral reactivation and caution in using potentially hepatotoxic drugs can prevent the development of ACLF.

Despite a lack of evidence, patients are often not fed for 48–96 h after upper gastrointestinal bleeding (UGIB); however, many trials have demonstrated the benefits of early nutrition (EN). We conducted a meta-analysis of randomized controlled trials (RTCs) to evaluate the outcomes of EN compared to delayed nutrition (DN) after UGIB. The protocol was registered on PROSPERO (CRD42022372306). PubMed, Embase, CENTRAL, Scopus, and Web of Science were searched on the 27th of April 2024 to identify eligible RCTs. The primary outcomes were early (within 7 days) and late (within 30–42 days) mortality and rebleeding. Pooled risk ratios (RR), mean differences (MD), and corresponding 95% confidence intervals (CI) were calculated using a random-effects model. A total of 10 trials with 1051 patients were included in the analysis. Early mortality was not significantly different between the two groups (RR 1.20, CI 0.85–1.71, I 2  = 0%), whereas late mortality was reduced to a clinically relevant extent in the EN group (RR 0.61, CI 0.35–1.06, I 2  = 0%). When comparing the two groups, we found no significant difference in terms of early and late rebleeding (RR 1.04, CI 0.66–1.63, I 2  = 0% and RR 1.16, CI 0.63–2.13, I 2  = 0%, respectively). Our analysis also showed that the length of hospital stay was reduced in the EN group compared to the DN group (MD −1.22 days, CI: −2.43 to −0.01, I 2  = 94%). In conclusion, compared with DN, EN (within 24 h) appears to be a safe intervention and could reduce the length of hospital stay without increasing the risk of complications after UGIB.