eGastroenterology最新文献

{"title":"Gut cannabinoid receptor 1 regulates alcohol binge-induced intestinal permeability.","authors":"Luca Maccioni, Szabolcs Dvorácskó, Grzegorz Godlewski, Resat Cinar, Malliga R Iyer, Bin Gao, George Kunos","doi":"10.1136/egastro-2024-100173","DOIUrl":"10.1136/egastro-2024-100173","url":null,"abstract":"<p><strong>Background: </strong>Endocannabinoids acting via cannabinoid receptor 1 (CB1R) can elicit increased intestinal permeability (a condition also called 'leaky gut'). Alcohol binge can adversely affect digestive functions, including intestinal permeability; however, the underlying mechanisms remain incompletely understood. The current study aimed at examining whether CB1R is involved in alcohol binge-induced intestinal permeability.</p><p><strong>Methods: </strong>We developed intestinal epithelial-specific CB1R knockout (CB1^IEC-/-) mice and evaluated the <i>in vivo</i> contribution of gut CB1R in alcohol binge-induced intestinal permeability.</p><p><strong>Results: </strong>Alcohol binge increased anandamide levels in the proximal small intestine in association with increased intestinal permeability. Radioligand binding and functional assays confirmed that the genetic deletion of intestinal epithelial CB1R did not alter the density or functionality of CB1R in the brain. Additionally, a peripheral CB1R antagonist, (<i>S</i>)-MRI-1891 (INV-202/monlunabant), exhibited comparable binding affinity to CB1R in brain homogenates. An acute oral administration of (<i>S</i>)-MRI-1891 (3 mg/kg) reduced alcohol binge-induced intestinal permeability in littermate control CB1^f/f (CB1 floxed/floxed) mice but had no effect in CB1^IEC-/- mice, underscoring the role of intestinal CB1R in this phenomenon. Mechanistically, we found that alcohol activated intestinal epithelial CB1R-ERK1/2 pathway with subsequent downregulation of tight junction proteins and reduction in villi length. In addition, targeting intestinal CB1R and downstream ERK1/2 was able to reverse this process, with subsequent upregulation of tight junction proteins and increased villi length, thus improving gut barrier function. Despite the effects on intestinal permeability, deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease.</p><p><strong>Conclusion: </strong>Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 1","pages":"e100173"},"PeriodicalIF":0.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease.","authors":"Armando Andres Roca Suarez, Frank Jühling, Julien Moehlin, Laurent Mailly, Alessia Virzì, Nicolas Brignon, Sarah C Durand, Marine A Oudot, Eugenie Schaeffer, Romain Martin, Laura Meiss-Heydmann, Charlotte Bach, Zakaria Boulahtouf, Lea Girard, Emma Osswald, Carole Jamey, Daniel Brumaru, Nassim Dali-Youcef, Atish Mukherji, Maria Saez-Palma, Barbara Testoni, Fabien Zoulim, Bhuvaneswari Koneru, Naoto Fujiwara, Yujin Hoshida, Emanuele Felli, Patrick Pessaux, Michel L Tremblay, Romain Parent, Catherine Schuster, Thomas F Baumert, Joachim Lupberger","doi":"10.1136/egastro-2024-100159","DOIUrl":"10.1136/egastro-2024-100159","url":null,"abstract":"<p><strong>Abstract: </strong></p><p><strong>Objective: </strong>Impaired hepatic expression of protein tyrosine phosphatase delta (<i>PTPRD</i>) is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the <i>PTPRD</i>-expressing hepatic cell types, signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.</p><p><strong>Methods: </strong>We studied <i>PTPRD</i> expression in single-cell and bulk liver transcriptomic data from mice and humans, and established a <i>Ptprd</i>-deficient mouse model for metabolic dysfunction-associated steatohepatitis (MASH). Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays. The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to <i>PTPRD</i> expression and analysing its association with metabolic disease markers.</p><p><strong>Results: </strong>The analysis of individuals ranked according to <i>PTPRD</i> expression and <i>Ptprd</i>-deficient mice, showed that <i>PTPRD</i> levels were associated with hepatic glucose/lipid signalling and peroxisome function. Hepatic <i>PTPRD</i> expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease. We further validated PTPRD as a STAT3 phosphatase in the liver, acting as a regulator of peroxisomal fatty acid metabolism. During MASH, low PTPRD led to increased liver steatosis in <i>Ptprd</i>+/- mice and a pronounced unfolded protein response, which impacts insulin signalling. Accordingly, silencing of <i>PTPRD</i> blunted insulin-induced AKT phosphorylation. Patients with obesity and low hepatic <i>PTPRD</i> expression exhibit increased levels of metabolic risk factors.</p><p><strong>Conclusion: </strong>Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis, which is recapitulated in clinical manifestations of metabolic liver disease.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 1","pages":"e100159"},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional dyspepsia and gastroparesis: are they distinct disorders, a spectrum of diseases or one disease?","authors":"Stella-Maris Egboh, Kerith Duncanson, Michael Potter, Simon Keely, Nicholas J Talley","doi":"10.1136/egastro-2024-100119","DOIUrl":"10.1136/egastro-2024-100119","url":null,"abstract":"<p><p>Functional dyspepsia (FD) and gastroparesis (GP) are clinically managed as distinct upper gastrointestinal conditions but present with symptoms that are often indistinguishable. FD is a common disorder of gut-brain interaction that negatively impacts quality of life, while GP is considered a rare disease exclusively defined by delayed gastric emptying and symptoms. The degree of overlap between these disorders makes them hard to differentiate in clinical practice, thereby impacting treatment decisions. This review is focused on exploring the similarities and differences between FD and GP to guide clinician management and improve treatment outcomes. A comprehensive literature search was performed and the full texts of eligible articles were retrieved for the extraction of information reported in this review. This summary of evidence supports the hypothesis that GP and FD represent two ends of the same disease spectrum in a major subgroup. Improved understanding of the similarities, differences and overlap is likely to help guide the development of objective biomarkers and better-targeted therapies.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 1","pages":"e100119"},"PeriodicalIF":0.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modifiable factors for irritable bowel syndrome: evidence from Mendelian randomisation approach.","authors":"Di Liu, Meiling Cao, Shanshan Wu, Yiwen Jiang, Weijie Cao, Tengfei Lin, Fuxiao Li, Feng Sha, Zhirong Yang, Jinling Tang","doi":"10.1136/egastro-2024-100126","DOIUrl":"10.1136/egastro-2024-100126","url":null,"abstract":"<p><strong>Abstract: </strong></p><p><strong>Background: </strong>The potential modifiable factors influencing irritable bowel syndrome (IBS) have not been thoroughly documented. We aimed to systematically investigate the modifiable factors associated with IBS, while accounting for the impact of unobserved confounders and coexisting disorders.</p><p><strong>Methods: </strong>Genetic correlation and Mendelian randomisation (MR) analyses were integrated to identify potential modifiable factors and coexisting disorders linked to IBS. Subsequently, multiresponse MR (MR²) was employed to further examine these associations. Summary-level genome-wide association data were used. Modifiable factors and coexisting disorders (ie, gastrointestinal and psychiatric disorders) were identified based on evidence from cohort studies and meta-analysis. In all analyses, IBS was the primary outcome, while in the MR² analysis, coexisting disorders were also treated as outcomes alongside IBS.</p><p><strong>Results: </strong>Most identified modifiable factors and coexisting disorders exhibited genetic correlations with IBS. MR analyses revealed strong causation between IBS and multisite chronic pain (OR=2.20, 95% CI 1.82 to 2.66), gastro-oesophageal reflux disease (OR=1.31, 95% CI 1.23 to 1.39), well-being spectrum (OR=0.17, 95% CI 0.13 to 0.21), life satisfaction (OR=0.31, 95% CI 0.25 to 0.38), positive affect (OR=0.30, 95% CI 0.24 to 0.37), neuroticism score (OR=1.20, 95% CI 1.16 to 1.25) and depression (OR=1.50, 95% CI 1.37 to 1.66). Additionally, smoking, alcohol frequency, college or university degree, intelligence, childhood maltreatment, frailty index, diverticular disease of the intestine and schizophrenia were suggestively associated with IBS. Robust associations were found between multisite chronic pain and both IBS and coexisting disorders.</p><p><strong>Conclusions: </strong>Our study identified a comprehensive array of potential modifiable factors and coexisting disorders associated with IBS, supported by genetic evidence, including genetic correlation and multiple MR analyses. The presence of multisite chronic pain may offer a promising avenue for the concurrent prevention of IBS and its coexisting disorders.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 1","pages":"e100126"},"PeriodicalIF":0.0,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Essential roles of the unfolded protein response in intestinal physiology.","authors":"Claudio Hetz, Juan Francisco Silva-Agüero, Lisa M Ellerby","doi":"10.1136/egastro-2024-100129","DOIUrl":"10.1136/egastro-2024-100129","url":null,"abstract":"<p><p>The intestinal epithelium serves as an essential interface between the host and microbiota, regulating innate and adaptive immunity, absorption of nutrients and systemic metabolism, and mediating bidirectional communication with the nervous system. The intestinal epithelium suffers constant challenges to the proteostasis machinery due to its exposure to the dynamically changing and microbial laden lumenal gut environment and to the high secretory demand placed on multiple epithelial cell types to accommodate gut and systemic physiology-especially goblet, enteroendocrine and Paneth cells. In all cases, intestinal cells require an active unfolded protein response (UPR) to sustain their physiological function, the main pathway that monitors and adjusts secretory function changes in the environment. A specialised endoplasmic reticulum (ER) stress sensor uniquely expressed in epithelial cells lining mucosal surfaces, termed inositol-requiring transmembrane kinase/endoribonuclease β, has specific roles in intestinal epithelial homeostasis, regulating mucus production and communication with microbiota. Chronic ER stress or genetic mutations affecting key UPR mediators contribute to the occurrence of inflammatory bowel disease and ulcerative colitis, in addition to colon cancer. Here, we review recent advances linking the UPR and ER stress with gut physiology and intestinal disease. Therapeutic strategies to alleviate ER stress or enforce UPR function to improve intestinal function in ageing and in bowel diseases are also discussed.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"2 4","pages":"e100129"},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Faecal microbiota transplantation for eradicating Helicobacter pylori infection: clinical practice and theoretical postulation.","authors":"Zhi-Ning Ye, Guy D Eslick, Shao-Gang Huang, Xing-Xiang He","doi":"10.1136/egastro-2024-100099","DOIUrl":"10.1136/egastro-2024-100099","url":null,"abstract":"<p><p>The sustained increase in antibiotic resistance leads to a declining trend in the eradication rate of <i>Helicobacter pylori</i> (<i>H. pylori</i>) infection with antibiotic-based eradication regimens. Administration of a single probiotic shows limited efficacy in eradicating <i>H. pylori</i> infection. This review indicates that faecal microbiota transplantation (FMT), a novel therapeutic approach, either as a monotherapy or adjunctive therapy, exhibits beneficial effects in terms of the eradication of <i>H. pylori</i> infection and the prevention of adverse events. The role of FMT in <i>H. pylori</i> eradication may be associated directly or indirectly with some therapeutic constituents within the faecal suspension, including bacteria, viruses, antimicrobial peptides and metabolites. In addition, variations in donor selection, faecal suspension preparation and delivery methods are believed to be the main factors determining the effectiveness of FMT for the treatment of <i>H. pylori</i> infection. Future research should refine the operational procedures of FMT to achieve optimal efficacy for <i>H. pylori</i> infection and explore the mechanisms by which FMT acts against <i>H. pylori</i>.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"2 4","pages":"e100099"},"PeriodicalIF":0.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic role of long non-coding RNAs in the pathogenesis of metabolic dysfunction-associated steatotic liver disease and fibrosis.","authors":"Henry Wade, Kaichao Pan, Bingrui Zhang, Wenhua Zheng, Qiaozhu Su","doi":"10.1136/egastro-2024-100115","DOIUrl":"10.1136/egastro-2024-100115","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease, encompasses a broad range of hepatic metabolic disorders primarily characterised by the disruption of hepatic lipid metabolism, hepatic lipid accumulation and steatosis. Severe cases of MASLD might progress to metabolic dysfunction-associated steatohepatitis, characterised by hepatic inflammation, hepatocyte ballooning degeneration, activation of hepatic stellate cells (HSCs) and fibrogenesis. It may further progress to hepatocellular carcinoma. In the liver, long non-coding RNAs (lncRNAs) target multiple metabolic pathways in hepatocytes, HSCs, and Kupffer cells at different stages of MASLD and liver fibrosis. In this study, we overview recent findings on the potential role of lncRNAs in the pathogenesis of MASLD and liver fibrosis via modulation of de novo lipid synthesis, fatty acid β-oxidation, lipotoxicity, oxidative stress, metabolic inflammation, mammalian target of rapamycin signalling, apoptosis, ubiquitination and fibrogenesis. We critically assess the literature reports that investigate the complex interplay between lncRNA, microRNA and key mediators in liver injury, in both human participants and animal models of MASLD and liver fibrosis. We also highlight the therapeutic potential of lncRNAs in chronic liver diseases.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"2 4","pages":"e100115"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endocrine pathology in young rabbits with cystic fibrosis.","authors":"Xiubin Liang, Xia Hou, Y Eugene Chen, Jian-Ping Jin, Kezhong Zhang, Jie Xu","doi":"10.1136/egastro-2024-100102","DOIUrl":"10.1136/egastro-2024-100102","url":null,"abstract":"<p><strong>Background: </strong>Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the <i>CF</i> transmembrane conductance regulator gene. CF-related pancreatic lesions are known to cause exocrine dysfunctions such as pancreatic insufficiency, and endocrine dysfunctions, including CF related diabetes. In a previous study, we generated CF rabbits using CRISPR/Cas9-mediated gene editing.</p><p><strong>Methods: </strong>CF rabbits were subjected to histological analysis with a focus on CF associated pancreatic lesions. Endocrine function related assays were conducted to evaluate CF related pancreatic endocrine disorders in these animals.</p><p><strong>Results: </strong>We report that CF rabbits develop spontaneous pancreatic lesions at a young age, characterised by pancreatic inflammation and fibrosis, vacuolar degeneration, epithelium mucus-secretory cell metaplasia, and pancreatic duct dilation. The size of the pancreatic islets in the CF rabbits is significantly smaller than that of the wild type animals. Consistent with these pathological findings, young CF rabbits exhibited signs of pancreatic endocrine related disorders such as lower insulin levels and impaired glucose metabolism.</p><p><strong>Conclusions: </strong>Our results suggest that the CF rabbit could serve as a valuable model for translational research on CF related pancreatic endocrine dysfunction.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11594368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early clinical predictors of infected pancreatic necrosis: a multicentre cohort study.","authors":"Kai Song, Wenhua He, Zuoyan Wu, Jie Meng, Wei Tian, Shicheng Zheng, Dong Mu, Ruifeng Wang, Hongda Chen, Yin Zhu, Dong Wu","doi":"10.1136/egastro-2024-100095","DOIUrl":"10.1136/egastro-2024-100095","url":null,"abstract":"<p><strong>Background: </strong>Infected pancreatic necrosis (IPN) exacerbates complications in patients with acute pancreatitis (AP), increasing mortality rates if not treated promptly. We aimed to evaluate the predictive value of clinical characteristics within 24 hours of admission for IPN prediction.</p><p><strong>Methods: </strong>We conducted a retrospective, multicentre cohort study including 3005 patients with AP from eight hospitals in China. Clinical variables collected within 24 hours after admission were analysed using least absolute shrinkage and selection operator regression (10 cross-validations) for variable selection, followed by multivariate logistic regression to develop an IPN prediction model. Internal cross-validation of the development set and validation of the validation set were performed to ensure robustness. Decision curve analysis was used to evaluate its clinical utility.</p><p><strong>Results: </strong>IPN occurred in 176 patients (176/3005, 5.9%). The final model included temperature, respiratory rate, plasma calcium ion concentration, serum urea nitrogen and serum glucose. The area under the receiver operating characteristics curve (AUC) was 0.85 (95% CI 0.81 to 0.89), outperforming widely used severity scoring systems. The model demonstrated robust performance on the internal validation cohort (mean AUC: 0.84) and external validation cohort (AUC: 0.82, 95% CI 0. 77 to 0.87).</p><p><strong>Conclusion: </strong>We developed a simple and robust model for predicting IPN in patients with AP, demonstrating strong predictive performance and clinical utility.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"2 4","pages":"e100095"},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-target Mendelian randomisation applied to metabolic dysfunction-associated steatotic liver disease: opportunities and challenges.","authors":"Shan Luo, Ming-Hua Zheng, Vincent Wai-Sun Wong, Shiu Lun Au Yeung","doi":"10.1136/egastro-2024-100114","DOIUrl":"10.1136/egastro-2024-100114","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population. Despite the recent evolution of new nomenclature and diagnostic criteria for MASLD, progress in drug development for this condition remains limited. This review highlights the potential of drug-target Mendelian randomisation (MR), a study design that leverages human genetics and genomics, for the discovery, repositioning and safety assessment of drug targets in MASLD. We summarised key aspects of designing and appraising a drug-target MR study, discussing its inherent assumptions and considerations for instrument selection. Furthermore, we presented real-world examples from studies in MASLD which focused on opportunities and challenges in identifying novel drug targets, repositing existing drug targets, informing adjunctive treatments and addressing issues in paediatric MASLD.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"2 4","pages":"e100114"},"PeriodicalIF":0.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}