Pub Date : 2024-10-07DOI: 10.1136/gutjnl-2023-331445
Solveiga Samulėnaitė, Alejandra García-Blanco, Jordi Mayneris-Perxachs, Laura Domingo-Rodríguez, Judit Cabana-Domínguez, Noèlia Fernàndez-Castillo, Edurne Gago-García, Laura Pineda-Cirera, Aurelijus Burokas, Jose Espinosa-Carrasco, Silvia Arboleya, Jessica Latorre, Catherine Stanton, Koji Hosomi, Jun Kunisawa, Bru Cormand, Jose Manuel Fernández-Real, Rafael Maldonado, Elena Martín-García
Objective: Food addiction is a multifactorial disorder characterised by a loss of control over food intake that may promote obesity and alter gut microbiota composition. We have investigated the potential involvement of the gut microbiota in the mechanisms underlying food addiction.
Design: We used the Yale Food Addiction Scale (YFAS) 2.0 criteria to classify extreme food addiction in mouse and human subpopulations to identify gut microbiota signatures associated with vulnerability to this disorder.
Results: Both animal and human cohorts showed important similarities in the gut microbiota signatures linked to food addiction. The signatures suggested possible non-beneficial effects of bacteria belonging to the Proteobacteria phylum and potential protective effects of Actinobacteria against the development of food addiction in both cohorts of humans and mice. A decreased relative abundance of the species Blautia wexlerae was observed in addicted humans and of Blautia genus in addicted mice. Administration of the non-digestible carbohydrates, lactulose and rhamnose, known to favour Blautia growth, led to increased relative abundance of Blautia in mice faeces in parallel with dramatic improvements in food addiction. A similar improvement was revealed after oral administration of Blautia wexlerae as a beneficial microbe.
Conclusion: By understanding the crosstalk between this behavioural alteration and gut microbiota, these findings constitute a step forward to future treatments for food addiction and related eating disorders.
{"title":"Gut microbiota signatures of vulnerability to food addiction in mice and humans.","authors":"Solveiga Samulėnaitė, Alejandra García-Blanco, Jordi Mayneris-Perxachs, Laura Domingo-Rodríguez, Judit Cabana-Domínguez, Noèlia Fernàndez-Castillo, Edurne Gago-García, Laura Pineda-Cirera, Aurelijus Burokas, Jose Espinosa-Carrasco, Silvia Arboleya, Jessica Latorre, Catherine Stanton, Koji Hosomi, Jun Kunisawa, Bru Cormand, Jose Manuel Fernández-Real, Rafael Maldonado, Elena Martín-García","doi":"10.1136/gutjnl-2023-331445","DOIUrl":"10.1136/gutjnl-2023-331445","url":null,"abstract":"<p><strong>Objective: </strong>Food addiction is a multifactorial disorder characterised by a loss of control over food intake that may promote obesity and alter gut microbiota composition. We have investigated the potential involvement of the gut microbiota in the mechanisms underlying food addiction.</p><p><strong>Design: </strong>We used the Yale Food Addiction Scale (YFAS) 2.0 criteria to classify extreme food addiction in mouse and human subpopulations to identify gut microbiota signatures associated with vulnerability to this disorder.</p><p><strong>Results: </strong>Both animal and human cohorts showed important similarities in the gut microbiota signatures linked to food addiction. The signatures suggested possible non-beneficial effects of bacteria belonging to the Proteobacteria phylum and potential protective effects of Actinobacteria against the development of food addiction in both cohorts of humans and mice. A decreased relative abundance of the species <i>Blautia wexlerae</i> was observed in addicted humans and of <i>Blautia</i> genus in addicted mice. Administration of the non-digestible carbohydrates, lactulose and rhamnose, known to favour <i>Blautia</i> growth, led to increased relative abundance of <i>Blautia</i> in mice faeces in parallel with dramatic improvements in food addiction. A similar improvement was revealed after oral administration of <i>Blautia wexlerae</i> as a beneficial microbe.</p><p><strong>Conclusion: </strong>By understanding the crosstalk between this behavioural alteration and gut microbiota, these findings constitute a step forward to future treatments for food addiction and related eating disorders.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1799-1815"},"PeriodicalIF":23.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141456346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The gut microbiome has been recognised as a key component in the pathogenesis of inflammatory bowel diseases (IBD), and the wide range of metabolites produced by gut bacteria are an important mechanism by which the human microbiome interacts with host immunity or host metabolism. High-throughput metabolomic profiling and novel computational approaches now allow for comprehensive assessment of thousands of metabolites in diverse biomaterials, including faecal samples. Several groups of metabolites, including short-chain fatty acids, tryptophan metabolites and bile acids, have been associated with IBD. In this Recent Advances article, we describe the contribution of metabolomics research to the field of IBD, with a focus on faecal metabolomics. We discuss the latest findings on the significance of these metabolites for IBD prognosis and therapeutic interventions and offer insights into the future directions of metabolomics research.
{"title":"Untargeted faecal metabolomics for the discovery of biomarkers and treatment targets for inflammatory bowel diseases.","authors":"Arnau Vich Vila, Jingwan Zhang, Moting Liu, Klaas Nico Faber, Rinse K Weersma","doi":"10.1136/gutjnl-2023-329969","DOIUrl":"10.1136/gutjnl-2023-329969","url":null,"abstract":"<p><p>The gut microbiome has been recognised as a key component in the pathogenesis of inflammatory bowel diseases (IBD), and the wide range of metabolites produced by gut bacteria are an important mechanism by which the human microbiome interacts with host immunity or host metabolism. High-throughput metabolomic profiling and novel computational approaches now allow for comprehensive assessment of thousands of metabolites in diverse biomaterials, including faecal samples. Several groups of metabolites, including short-chain fatty acids, tryptophan metabolites and bile acids, have been associated with IBD. In this <i>Recent Advances</i> article, we describe the contribution of metabolomics research to the field of IBD, with a focus on faecal metabolomics. We discuss the latest findings on the significance of these metabolites for IBD prognosis and therapeutic interventions and offer insights into the future directions of metabolomics research.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1909-1920"},"PeriodicalIF":23.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-07DOI: 10.1136/gutjnl-2023-331447
Mrigya Babuta, Caroline Morel, Marcelle de Carvalho Ribeiro, Charles Calenda, Martí Ortega-Ribera, Prashanth Thevkar Nagesh, Christopher Copeland, Yuan Zhuang, Yanbo Wang, Yeonhee Cho, Radhika Joshi, Viliam Brezani, Danielle Hawryluk, Aditi Ashish Datta, Jeeval Mehta, Imad Nasser, Gyongyi Szabo
Objective: Alcohol use in metabolic dysfunction-associated steatohepatitis (MASH) is associated with an increased risk of fibrosis and liver-related death. Here, we aimed to identify a mechanism through which repeated alcohol binges exacerbate liver injury in a high fat-cholesterol-sugar diet (MASH diet)-induced model of MASH.
Design: C57BL/6 mice received either chow or the MASH diet for 3 months with or without weekly alcohol binges. Neutrophil infiltration, neutrophil extracellular traps (NETs) and fibrosis were evaluated.
Results: We found that alcohol binges in MASH increase liver injury and fibrosis. Liver transcriptomic profiling revealed differential expression of genes involved in extracellular matrix reorganisation, neutrophil activation and inflammation compared with alcohol or the MASH diet alone. Alcohol binges specifically increased NET formation in MASH livers in mice, and NETs were also increased in human livers with MASH plus alcohol use. We discovered that cell-free NETs are sensed via Nod-like receptor protein 3 (NLRP3). Furthermore, we show that cell-free NETs in vitro induce a profibrotic phenotype in hepatic stellate cells (HSCs) and proinflammatory monocytes. In vivo, neutrophil depletion using anti-Ly6G antibody or NET disruption with deoxyribonuclease treatment abrogated monocyte and HSC activation and ameliorated liver damage and fibrosis. In vivo, inhibition of NLRP3 using MCC950 or NLRP3 deficiency attenuated NET formation, liver injury and fibrosis in MASH plus alcohol diet-fed mice (graphical abstract).
Conclusion: Alcohol binges promote liver fibrosis via NET-induced activation of HSCs and monocytes in MASH. Our study highlights the potential of inhibition of NETs and/or NLRP3, as novel therapeutic strategies to combat the profibrotic effects of alcohol in MASH.
目的:代谢功能障碍相关性脂肪性肝炎(MASH)患者饮酒与肝纤维化和肝相关死亡风险增加有关。在此,我们旨在确定在高脂肪-胆固醇-糖饮食(MASH饮食)诱导的MASH模型中,反复酗酒加剧肝损伤的机制:设计:C57BL/6小鼠在3个月内接受饲料或MASH饮食,每周酗酒或不酗酒。对中性粒细胞浸润、中性粒细胞胞外捕获物(NET)和纤维化进行评估:结果:我们发现 MASH 中的酗酒会加重肝损伤和纤维化。肝脏转录组图谱显示,与单纯饮酒或MASH饮食相比,参与细胞外基质重组、中性粒细胞活化和炎症的基因表达存在差异。酗酒特别增加了小鼠 MASH 肝脏中 NET 的形成,MASH 加酗酒也增加了人类肝脏中 NET 的形成。我们发现,无细胞的NET是通过类Nod受体蛋白3(NLRP3)感知的。此外,我们还发现,体外的无细胞NET会诱导肝星状细胞(HSCs)和促炎单核细胞的坏死表型。在体内,使用抗Ly6G抗体清除中性粒细胞或用脱氧核糖核酸酶处理NET,可抑制单核细胞和造血干细胞的活化,改善肝损伤和肝纤维化。在体内,使用 MCC950 抑制 NLRP3 或 NLRP3 缺乏症可减轻 MASH 加酒精饮食喂养小鼠的 NET 形成、肝损伤和纤维化(图解摘要):结论:酗酒通过NET诱导激活MASH中的造血干细胞和单核细胞,促进肝纤维化。我们的研究强调了抑制 NET 和/或 NLRP3 作为新型治疗策略的潜力,以对抗酒精对 MASH 的促组织坏死作用。
{"title":"Neutrophil extracellular traps activate hepatic stellate cells and monocytes via NLRP3 sensing in alcohol-induced acceleration of MASH fibrosis.","authors":"Mrigya Babuta, Caroline Morel, Marcelle de Carvalho Ribeiro, Charles Calenda, Martí Ortega-Ribera, Prashanth Thevkar Nagesh, Christopher Copeland, Yuan Zhuang, Yanbo Wang, Yeonhee Cho, Radhika Joshi, Viliam Brezani, Danielle Hawryluk, Aditi Ashish Datta, Jeeval Mehta, Imad Nasser, Gyongyi Szabo","doi":"10.1136/gutjnl-2023-331447","DOIUrl":"10.1136/gutjnl-2023-331447","url":null,"abstract":"<p><strong>Objective: </strong>Alcohol use in metabolic dysfunction-associated steatohepatitis (MASH) is associated with an increased risk of fibrosis and liver-related death. Here, we aimed to identify a mechanism through which repeated alcohol binges exacerbate liver injury in a high fat-cholesterol-sugar diet (MASH diet)-induced model of MASH.</p><p><strong>Design: </strong>C57BL/6 mice received either chow or the MASH diet for 3 months with or without weekly alcohol binges. Neutrophil infiltration, neutrophil extracellular traps (NETs) and fibrosis were evaluated.</p><p><strong>Results: </strong>We found that alcohol binges in MASH increase liver injury and fibrosis. Liver transcriptomic profiling revealed differential expression of genes involved in extracellular matrix reorganisation, neutrophil activation and inflammation compared with alcohol or the MASH diet alone. Alcohol binges specifically increased NET formation in MASH livers in mice, and NETs were also increased in human livers with MASH plus alcohol use. We discovered that cell-free NETs are sensed via Nod-like receptor protein 3 (NLRP3). Furthermore, we show that cell-free NETs in vitro induce a profibrotic phenotype in hepatic stellate cells (HSCs) and proinflammatory monocytes. In vivo, neutrophil depletion using anti-Ly6G antibody or NET disruption with deoxyribonuclease treatment abrogated monocyte and HSC activation and ameliorated liver damage and fibrosis. In vivo, inhibition of NLRP3 using MCC950 or NLRP3 deficiency attenuated NET formation, liver injury and fibrosis in MASH plus alcohol diet-fed mice (graphical abstract).</p><p><strong>Conclusion: </strong>Alcohol binges promote liver fibrosis via NET-induced activation of HSCs and monocytes in MASH. Our study highlights the potential of inhibition of NETs and/or NLRP3, as novel therapeutic strategies to combat the profibrotic effects of alcohol in MASH.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1854-1869"},"PeriodicalIF":23.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11458363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-07DOI: 10.1136/gutjnl-2024-332514
Gavin E Arteel, Bin Gao
{"title":"When alcohol and fat meet, neutrophil traps form to promote liver injury.","authors":"Gavin E Arteel, Bin Gao","doi":"10.1136/gutjnl-2024-332514","DOIUrl":"10.1136/gutjnl-2024-332514","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1778-1779"},"PeriodicalIF":23.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11458347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1136/gutjnl-2024-332619
Karol M Córdoba, Daniel Jericó, Lei Jiang, María Collantes, Manuel Alegre, Leyre García-Ruiz, Oscar Manzanilla, Ana Sampedro, Jose M Herranz, Iñigo Insausti, Antonio Martinez de la Cuesta, Francesco Urigo, Patricia Alcaide, María Morán, Miguel A Martín, José Luis Lanciego, Thibaud Lefebvre, Laurent Gouya, Gemma Quinconces, Carmen Unzu, Sandra Hervas-Stubbs, Juan M Falcón-Pérez, Estíbaliz Alegre, Azucena Aldaz, María A Fernández-Seara, Iván Peñuelas, Pedro Berraondo, Paolo G V Martini, Matias A Avila, Antonio Fontanellas
Objective: Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors.
Design: We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic PBGD gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue.
Results: Intrahepatic administration of a recombinant adeno-associated viral vector containing short hairpin RNA against endogenous PBGD mRNA resulted in sustained PBGD activity inhibition in liver tissue for up to 7 months postinjection. The administration of porphyrinogenic drugs to NHPs induced hepatic heme synthesis, elevated urinary porphyrin precursors and reproduced acute attack symptoms in patients with AIP, including pain, motor disturbances and increased brain GABAergic activity. The model also recapitulated functional anomalies associated with AIP, such as reduced brain perfusion and cerebral glucose uptake, disturbances in hepatic TCA cycle, one-carbon metabolism, drug biotransformation, lipidomic profile and abnormal mitochondrial respiratory chain activity. Additionally, repeated systemic administrations of hPBGD mRNA in this AIP NHP model restored hepatic PBGD levels and activity, providing successful protection against acute attacks, metabolic changes in the liver and CNS disturbances. This approach demonstrated better efficacy than the current standards of care for AIP.
Conclusion: This novel model significantly expands our understanding of AIP at the molecular, biochemical and clinical levels and confirms the safety and translatability of multiple systemic administration of hPBGD mRNA as a potential aetiological AIP treatment.
{"title":"Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates.","authors":"Karol M Córdoba, Daniel Jericó, Lei Jiang, María Collantes, Manuel Alegre, Leyre García-Ruiz, Oscar Manzanilla, Ana Sampedro, Jose M Herranz, Iñigo Insausti, Antonio Martinez de la Cuesta, Francesco Urigo, Patricia Alcaide, María Morán, Miguel A Martín, José Luis Lanciego, Thibaud Lefebvre, Laurent Gouya, Gemma Quinconces, Carmen Unzu, Sandra Hervas-Stubbs, Juan M Falcón-Pérez, Estíbaliz Alegre, Azucena Aldaz, María A Fernández-Seara, Iván Peñuelas, Pedro Berraondo, Paolo G V Martini, Matias A Avila, Antonio Fontanellas","doi":"10.1136/gutjnl-2024-332619","DOIUrl":"10.1136/gutjnl-2024-332619","url":null,"abstract":"<p><strong>Objective: </strong>Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors.</p><p><strong>Design: </strong>We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic <i>PBGD</i> gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue.</p><p><strong>Results: </strong>Intrahepatic administration of a recombinant adeno-associated viral vector containing short hairpin RNA against endogenous PBGD mRNA resulted in sustained PBGD activity inhibition in liver tissue for up to 7 months postinjection. The administration of porphyrinogenic drugs to NHPs induced hepatic heme synthesis, elevated urinary porphyrin precursors and reproduced acute attack symptoms in patients with AIP, including pain, motor disturbances and increased brain GABAergic activity. The model also recapitulated functional anomalies associated with AIP, such as reduced brain perfusion and cerebral glucose uptake, disturbances in hepatic TCA cycle, one-carbon metabolism, drug biotransformation, lipidomic profile and abnormal mitochondrial respiratory chain activity. Additionally, repeated systemic administrations of hPBGD mRNA in this AIP NHP model restored hepatic PBGD levels and activity, providing successful protection against acute attacks, metabolic changes in the liver and CNS disturbances. This approach demonstrated better efficacy than the current standards of care for AIP.</p><p><strong>Conclusion: </strong>This novel model significantly expands our understanding of AIP at the molecular, biochemical and clinical levels and confirms the safety and translatability of multiple systemic administration of hPBGD mRNA as a potential aetiological AIP treatment.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1136/gutjnl-2024-333765
Sarah Manning, Rashmi Sinha, Colin J Rees
{"title":"Need for standardised approaches to human microbiome research using the example of colorectal neoplasia research.","authors":"Sarah Manning, Rashmi Sinha, Colin J Rees","doi":"10.1136/gutjnl-2024-333765","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333765","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1136/gutjnl-2024-333827
Jiashu Han, Dan Shan
{"title":"Environmental and healthcare trade-offs between single-use and reusable gastroscopes.","authors":"Jiashu Han, Dan Shan","doi":"10.1136/gutjnl-2024-333827","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333827","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Enterically transmitted hepatitis viruses, such as hepatitis A virus (HAV) and hepatitis E virus (HEV), remain notable threats to public health. However, stable and reliable animal models of HAV and HEV infection are lacking. Objective This study aimed to establish HAV and HEV infections in multiple small animals by intravenously injecting lipid nanoparticle (LNP)-encapsulated full-length viral RNAs (LNP-vRNA). Design In vitro transcribed and capped full-length HAV RNA was encapsulated into LNP and was intravenously inoculated to Ifnar −/− mice, and HEV RNA to rabbits and gerbils. Virological parameters were determined by RT-qPCR, ELISA and immunohistochemistry. Liver histopathological changes were analysed by H&E staining. Antiviral drug and vaccine efficacy were further evaluated by using the LNP-vRNA-based animal model. Results On intravenous injection of LNP-vRNA, stable viral shedding was detected in the faeces and infectious HAV or HEV was recovered from the livers of the inoculated animals. Liver damage was observed in LNP-vRNA (HAV)-injected mice and LNP-vRNA (HEV)-injected rabbits. Mongolian gerbils were also susceptible to LNP-vRNA (HEV) injections. Finally, the antiviral countermeasures and in vivo function of HEV genome deletions were validated in the LNP-vRNA-based animal model. Conclusion This stable and standardised LNP-vRNA-based animal model provides a powerful platform to investigate the pathogenesis and evaluate countermeasures for enterically transmitted hepatitis viruses and can be further expanded to other viruses that are not easily cultured in vitro or in vivo. All data relevant to the study are included in the article or uploaded as online supplemental information.
{"title":"Establishment of enterically transmitted hepatitis virus animal models using lipid nanoparticle-based full-length viral genome RNA delivery system","authors":"Tianxu Liu, Jian Li, Xin Yin, Fengmin Lu, Hui Zhao, Lin Wang, Cheng-Feng Qin","doi":"10.1136/gutjnl-2024-332784","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332784","url":null,"abstract":"Background Enterically transmitted hepatitis viruses, such as hepatitis A virus (HAV) and hepatitis E virus (HEV), remain notable threats to public health. However, stable and reliable animal models of HAV and HEV infection are lacking. Objective This study aimed to establish HAV and HEV infections in multiple small animals by intravenously injecting lipid nanoparticle (LNP)-encapsulated full-length viral RNAs (LNP-vRNA). Design In vitro transcribed and capped full-length HAV RNA was encapsulated into LNP and was intravenously inoculated to Ifnar −/− mice, and HEV RNA to rabbits and gerbils. Virological parameters were determined by RT-qPCR, ELISA and immunohistochemistry. Liver histopathological changes were analysed by H&E staining. Antiviral drug and vaccine efficacy were further evaluated by using the LNP-vRNA-based animal model. Results On intravenous injection of LNP-vRNA, stable viral shedding was detected in the faeces and infectious HAV or HEV was recovered from the livers of the inoculated animals. Liver damage was observed in LNP-vRNA (HAV)-injected mice and LNP-vRNA (HEV)-injected rabbits. Mongolian gerbils were also susceptible to LNP-vRNA (HEV) injections. Finally, the antiviral countermeasures and in vivo function of HEV genome deletions were validated in the LNP-vRNA-based animal model. Conclusion This stable and standardised LNP-vRNA-based animal model provides a powerful platform to investigate the pathogenesis and evaluate countermeasures for enterically transmitted hepatitis viruses and can be further expanded to other viruses that are not easily cultured in vitro or in vivo. All data relevant to the study are included in the article or uploaded as online supplemental information.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"28 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}