The gastrointestinal tract harbours a vast chemical diversity of small molecules, consisting of dietary nutrients, microorganism-derived metabolites and metabolic products of the host. The latest evidence highlights a di...The gastrointestinal tract harbours a vast chemical diversity of small molecules, consisting of dietary nutrients, microorganism-derived metabolites and metabolic products of the host. The latest evidence highlights a direct involvement of different metabolites in the diverse aetiologies of intestinal diseases, ranging from inflammatory to metabolic and neoplastic conditions. The accessibility of the gastrointestinal tract to oral intervention suggests that fine-tuning the levels of intestinal metabolites might be a promising and currently underutilized therapeutic strategy. Here, we provide a conceptual overview of the recurring mechanistic themes by which metabolites shape the biology of immune cells, epithelium and neurons of the gastrointestinal tract. Additionally, we classify metabolites according to possible categories of therapeutic intervention, and summarize the latest preclinical and clinical data unveiling the roles of intestinal metabolites in the pathophysiology of major diseases of the gastrointestinal tract, including inflammatory bowel disease, irritable bowel syndrome, colorectal cancer, enteric infection, food allergy, coeliac disease, as well as obesity and metabolic syndrome. In each case, we provide an overview of the mechanisms by which intestinal metabolites have been associated with disease aetiology. In addition, we discuss possible metabolite-based strategies for intervention. Our overall goal is to provide a roadmap towards developing metabotherapies for intestinal disease.
Jones DEJ, Mitchell-Thain R, Culver EL
… +16 more, Dyson JK, Gish RG, Hansen BE, Hirschfield GM, Kowdley KV, Lleo A, Kremer AE, Mayo MJ, Swain MG, Trauner M, Trivedi PJ, Vierling JM, Weltman M, Yeoman AD, Levy C, Carbone M
The term 'gut health' is increasingly used as a catch-all phrase by many stakeholders, including scientists, health-care professionals, industry and the general public, to describe a wide range of health-related concepts...The term 'gut health' is increasingly used as a catch-all phrase by many stakeholders, including scientists, health-care professionals, industry and the general public, to describe a wide range of health-related concepts. Despite its widespread use, particularly in relation to studies on diet, fermented foods, biotics and the gut microbiome, it remains unclear what the term gut health means. Therefore, an expert panel was convened by the International Scientific Association for Probiotics and Prebiotics to address the current state of scientific and clinical knowledge on the physiology, manifestation, application and measurement of the concept of gut health. The panel evaluated the term in the context of the central role of the gastrointestinal tract in health and overall well-being and proposed a definition of gut health as "a state of normal gastrointestinal function without active gastrointestinal disease and gut-related symptoms that affect quality of life". The definition was developed mindful of the functional, subjective and extrinsic domains that contribute to gut health. In this Consensus Statement, clinically relevant and accessible metrics to assess these domains are reviewed and a comprehensive approach to gut health is proposed that is relevant to clinical practice as well as to studies of dietary and biotic interventions.
Steatotic liver diseases, encompassing metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease, affect nearly one-third of the global population and are a leading cause of cirrhosis and...Steatotic liver diseases, encompassing metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease, affect nearly one-third of the global population and are a leading cause of cirrhosis and hepatocellular carcinoma. The substantial interindividual variation in disease progression indicates important genetic contributions beyond environmental factors. Genome-wide association studies have identified multiple common variants predominantly affecting lipid metabolism, with PNPLA3 I148M representing the strongest genetic determinant across the disease spectrum. The shared genetic architecture across metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease supports convergent pathogenic mechanisms. Discoveries of somatic mosaicism in adult liver tissues have revealed convergent mutations in metabolic genes such as FOXO1, GPAM and CIDEB, conferring adaptive advantages against lipotoxicity. Also, clonal haematopoiesis of indeterminate potential is associated with the risk of chronic liver diseases, metabolic dysfunction-associated steatohepatitis and its related liver cancer risk. Inherited and somatic variants can influence hepatocellular carcinoma risk through direct effects on chronic liver disease progression and/or through specific cancer-promoting pathways involving telomere maintenance and WNT signalling. Although polygenic risk scores represent a promising approach for risk stratification, current implementations face important limitations that must be addressed before achieving their full clinical potential.
Lazarus JV, Kopka CJ, Nicolàs A
… +15 more, Karim SA, Bansal MB, Betel M, Dillon JF, Gines P, Krag A, Miller V, Moylan CA, Pedrana A, Petrone P, Schattenberg JM, Solomon SS, Terrault N, Dow E, Thiele M
Liver diseases account for 1 in 25 deaths worldwide. Owing to the asymptomatic nature across the dynamic spectrum of steatotic liver disease (SLD) and the absence of targeted screening programmes, individuals at risk of...Liver diseases account for 1 in 25 deaths worldwide. Owing to the asymptomatic nature across the dynamic spectrum of steatotic liver disease (SLD) and the absence of targeted screening programmes, individuals at risk of progression to cirrhosis or hepatocellular carcinoma (HCC) are unlikely to pursue liver disease testing. Historically, hepatitis B and C were the leading causes of liver injury that can progress to cirrhosis or HCC. Global efforts to implement screening and vaccination programmes, expand testing and treatment, and encourage active viral hepatitis case finding followed the widespread availability of curative treatment for hepatitis C and effective suppressive therapy and vaccines for hepatitis B, further supported by changes in law, regulation and public policy. With encouraging declines in new viral hepatitis infections in many countries, greater attention should turn to SLD, now the leading global indicator for cirrhosis and HCC. Screening and active case finding for SLD lag far behind its increasing prevalence, leaving most people undiagnosed. This Expert Recommendation draws on lessons learned from legal, regulatory and policy changes required to combat the viral hepatitis public health threat. Our recommendations can contribute to a concerted shift in legal frameworks and policies to enhance screening programmes, increase testing and improve health outcomes.
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses liver steatosis and metabolic dysfunction-associated steatohepatitis (MASH), which can result in fibrosis and/or cirrhosis and increase the ris...Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses liver steatosis and metabolic dysfunction-associated steatohepatitis (MASH), which can result in fibrosis and/or cirrhosis and increase the risk of hepatocellular carcinoma (HCC). The latest Clinical Practice Guidelines acknowledge the importance of systemic metabolic dysfunction as a driver of hepatic lipid accumulation and disease progression. To ensure translational relevance of preclinical models, they need to faithfully replicate the key human pathophysiological characteristics of MASLD and its progression to fibrosis and HCC. This Review discusses the strengths and weaknesses of prevalent MASLD and MASH-HCC preclinical models, expanding the discussion to the latest advances in vivo (for example, genetically altered, humanized and large animals) and in vitro (for example, organoids or spheroids, 3D-bioprinted livers, precision-cut liver slices, organs-on-a-chip and decellularized scaffolds). Evidence will be critically re-assessed according to the new MASLD definition, paving a consensus in the field for nomenclature, expected limitations and how to conduct a systematic validation of new models against human-relevant disease outcomes. We also propose a standardized pipeline for preclinical studies in MASLD and MASH-HCC. This Review aims to help researchers make informed decisions when choosing an experimental design that best aligns with the specific requirements of their projects, whilst meaningfully replicating human disease.
Protein is an essential nutrient in the human diet. Global Westernization and modern dietary trends have seen protein become a more substantial contributor to the Western diet, with dietary sources expanding beyond tradi...Protein is an essential nutrient in the human diet. Global Westernization and modern dietary trends have seen protein become a more substantial contributor to the Western diet, with dietary sources expanding beyond traditional wholefoods to a myriad of processed protein-enriched food products. Although dietary protein is critical for human health, it has also been implicated in colonic health and disease both directly via the microbial fermentation of protein entering the colonic environment and indirectly by affecting the intake of other nutrients in the diet such as fibre. Although protein digestion in the small intestine is highly efficient, there are numerous factors that can influence the capacity for protein digestion and absorption, particularly dietary factors representative of modern-day protein intakes such as high protein diets and food manufacturing. The subsequent fermentation of protein and production of microbial metabolites in the colon is in turn affected by the source of protein entering the colon and the presence of fibre. In this Review, we examine factors that influence human digestion and absorption of protein in the small intestine and protein fermentation in the colon, describing implications for colonic health and disease.
Increasingly, cholesterol is implicated in diseases beyond the cardiovascular system. Major diseases of the gastrointestinal tract and liver are a case in point and are a focus of this Review. Particularly active in whol...Increasingly, cholesterol is implicated in diseases beyond the cardiovascular system. Major diseases of the gastrointestinal tract and liver are a case in point and are a focus of this Review. Particularly active in whole-body cholesterol metabolism, the gut and liver are the major organs that produce and secrete plasma lipoproteins, specifically chylomicrons, very-low-density lipoprotein and high-density lipoprotein. In addition, the liver is the only organ in which cholesterol is converted into bile acids. In this Review, we summarize how the liver and gut handle cholesterol to achieve homeostasis. A multitude of diverse and elaborate mechanisms strictly regulate whole-body cholesterol homeostasis by maintaining crucial liver and gut functions, notably cholesterol biosynthesis, absorption, metabolism, transport and excretion. Perturbation of cholesterol homeostasis is associated with liver and gut diseases, including metabolic dysfunction-associated steatotic liver disease, hepatocellular carcinoma and colorectal cancer. Therefore, the molecular machinery involved in cholesterol regulation is of great therapeutic interest. We provide an overview of how cholesterol balance is normally maintained, how its dysregulation can contribute to liver and gut diseases, and how cholesterol homeostasis is targetable to combat these diseases.
Acute-on-chronic liver failure (ACLF) is a complex syndrome characterized by acute hepatic decompensation superimposed on pre-existing chronic liver disease or cirrhosis that is associated with acute worsening of portal...Acute-on-chronic liver failure (ACLF) is a complex syndrome characterized by acute hepatic decompensation superimposed on pre-existing chronic liver disease or cirrhosis that is associated with acute worsening of portal hypertension, increased risk of infection, organ dysfunction and high short-term mortality. This Review provides a comprehensive update on definitions, pathophysiological mechanisms, clinical presentation and management of ACLF. The severe hepatic injury in ACLF triggers systemic inflammation, which is driven by damage-associated molecular patterns, gut-derived microbial products, and immunometabolic and functional dysregulation. Immune dysfunction can range from hyperinflammation and hypercytokinaemia to immune paresis, which in turn predisposes patients to infection and organ failure. The principles of ACLF management prioritize ameliorating the acute hepatic insult, managing portal hypertension, preventing organ failure and optimizing patients who are eligible for liver transplantation. Emerging options include novel therapies targeting immune modulation and liver regeneration, therapeutic plasma exchange and artificial liver support systems. Well-defined criteria for prompt interventions and selection of patients for transplantation within the first week after diagnosis - the 'golden window' - have improved outcomes of liver transplantation in patients with ACLF. The Kyoto ACLF Consensus reflects global efforts on unifying definitions, simplifying treatment end points, refining prediction tools, and filling the void of targeted non-transplantation interventions to improve outcomes in patients with ACLF; however, large knowledge gaps remain and further research is needed.