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Gut microbiota signatures of vulnerability to food addiction in mice and humans. 小鼠和人类易受食物成瘾影响的肠道微生物群特征。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-07 DOI: 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.

目的:食物成瘾是一种多因素疾病,其特征是对食物摄入失去控制,这可能会促进肥胖并改变肠道微生物群的组成。我们研究了肠道微生物群在食物成瘾机制中的潜在参与:设计:我们使用耶鲁食物成瘾量表(YFAS)2.0标准对小鼠和人类亚群的极端食物成瘾进行分类,以确定与易患这种疾病有关的肠道微生物群特征:结果:在与食物成瘾相关的肠道微生物群特征方面,动物和人类队列都显示出重要的相似性。这些特征表明,在人类和小鼠队列中,属于变形菌门的细菌可能会对食物成瘾的发生产生无益影响,而放线菌则可能具有保护作用。在上瘾的人体内观察到 Blautia wexlerae 的相对丰度降低,在上瘾的小鼠体内观察到 Blautia 属的相对丰度降低。已知乳糖和鼠李糖等非消化性碳水化合物有利于布劳菌的生长,给这些碳水化合物后,小鼠粪便中布劳菌的相对数量增加,同时食物成瘾的情况也显著改善。在口服布劳菌作为有益微生物后,情况也得到了类似的改善:通过了解这种行为改变与肠道微生物群之间的相互关系,这些发现为未来治疗食物成瘾和相关饮食失调迈出了一步。
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引用次数: 0
Untargeted faecal metabolomics for the discovery of biomarkers and treatment targets for inflammatory bowel diseases. 非靶向粪便代谢组学用于发现炎症性肠病的生物标记物和治疗靶点。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-07 DOI: 10.1136/gutjnl-2023-329969
Arnau Vich Vila, Jingwan Zhang, Moting Liu, Klaas Nico Faber, Rinse K Weersma

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.

肠道微生物组已被认为是炎症性肠病(IBD)发病机制中的一个关键组成部分,肠道细菌产生的多种代谢物是人类微生物组与宿主免疫或宿主新陈代谢相互作用的一个重要机制。目前,高通量代谢组学分析和新型计算方法可对包括粪便样本在内的各种生物材料中的数千种代谢物进行全面评估。包括短链脂肪酸、色氨酸代谢物和胆汁酸在内的几组代谢物与 IBD 相关。在这篇 "最新进展 "文章中,我们介绍了代谢组学研究对 IBD 领域的贡献,重点是粪便代谢组学。我们讨论了这些代谢物对 IBD 预后和治疗干预意义的最新发现,并对代谢组学研究的未来方向提出了见解。
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引用次数: 0
Drug targets for haemorrhoidal disease: proteome-wide Mendelian randomisation and colocalisation analyses. 痔疮疾病的药物靶点:全蛋白质组孟德尔随机化和共定位分析。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-07 DOI: 10.1136/gutjnl-2023-330967
Shifang Li, Meijiao Gong
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引用次数: 0
Neutrophil extracellular traps activate hepatic stellate cells and monocytes via NLRP3 sensing in alcohol-induced acceleration of MASH fibrosis. 在酒精诱导的 MASH 纤维化加速过程中,中性粒细胞胞外捕获器通过 NLRP3 传感激活肝星状细胞和单核细胞。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-07 DOI: 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。
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引用次数: 0
When alcohol and fat meet, neutrophil traps form to promote liver injury. 当酒精和脂肪相遇时,就会形成中性粒细胞陷阱,促进肝脏损伤。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-07 DOI: 10.1136/gutjnl-2024-332514
Gavin E Arteel, Bin Gao
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引用次数: 0
Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates. 在非人灵长类动物中开发的一种新型急性间歇性卟啉症临床相关模型中,全身信使核糖核酸替代疗法是有效的。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-04 DOI: 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.

目的:急性间歇性卟啉症(AIP)是一种罕见的代谢性疾病:急性间歇性卟啉症(AIP)是一种罕见的代谢性疾病,由肝脏卟啉原脱氨酶(PBGD)单倍体缺陷引起,PBGD是血红素生物合成的第三种酶。AIP患者的神经内脏发作与肝脏过量产生潜在神经毒性的血红素前体密切相关:设计:我们通过选择性敲除肝脏 PBGD 基因在非人灵长类(NHPs)中复制了 AIP,并评估了人 PBGD(hPBGD)mRNA 修复的安全性和疗效:结果:肝内注射含有针对内源性 PBGD mRNA 的短发夹 RNA 的重组腺相关病毒载体,可使肝组织中的 PBGD 活性持续受到抑制长达 7 个月。给 NHPs 注射致卟啉药物可诱导肝血红素合成、尿卟啉前体升高,并再现 AIP 患者的急性发作症状,包括疼痛、运动障碍和脑 GABA 能活动增强。该模型还再现了与 AIP 相关的功能异常,如脑灌注和脑葡萄糖摄取减少、肝脏 TCA 循环紊乱、一碳代谢、药物生物转化、脂质组学特征和线粒体呼吸链活性异常。此外,在这种 AIP NHP 模型中反复全身给药 hPBGD mRNA 可恢复肝脏 PBGD 水平和活性,从而成功地防止急性发作、肝脏代谢变化和中枢神经系统紊乱。这种方法比目前的AIP治疗标准具有更好的疗效:这一新型模型极大地拓展了我们对AIP在分子、生化和临床层面的认识,并证实了多次全身给药hPBGD mRNA作为一种潜在的AIP病因治疗方法的安全性和可转化性。
{"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}
引用次数: 0
Unravelling lipidomic disruptions across multiple tissues in Chd8 -mutant ASD mice through integration of lipidomics and single-cell transcriptomics. 通过整合脂质组学和单细胞转录组学,揭示 Chd8 突变 ASD 小鼠多个组织的脂质组学紊乱。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-02 DOI: 10.1136/gutjnl-2024-332972
You Yu, Bing Zhang, Ning Wang, Zhenqiang Zuo, Peifeng Ji, Fangqing Zhao
{"title":"<b>Unravelling lipidomic disruptions across multiple tissues in</b> <i><b>Chd8</b></i> -<b>mutant ASD mice through integration of lipidomics and single-cell transcriptomics</b>.","authors":"You Yu, Bing Zhang, Ning Wang, Zhenqiang Zuo, Peifeng Ji, Fangqing Zhao","doi":"10.1136/gutjnl-2024-332972","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332972","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":"142365059","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}
引用次数: 0
Need for standardised approaches to human microbiome research using the example of colorectal neoplasia research. 以结直肠肿瘤研究为例,人类微生物组研究需要标准化方法。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-02 DOI: 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}
引用次数: 0
Environmental and healthcare trade-offs between single-use and reusable gastroscopes. 一次性胃镜和可重复使用胃镜在环境和医疗保健方面的权衡。
IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-02 DOI: 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}
引用次数: 0
Establishment of enterically transmitted hepatitis virus animal models using lipid nanoparticle-based full-length viral genome RNA delivery system 利用基于脂质纳米粒子的全长病毒基因组 RNA 运送系统建立肠道传播的肝炎病毒动物模型
IF 24.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut
Pub Date : 2024-10-01 DOI: 10.1136/gutjnl-2024-332784
Tianxu Liu, Jian Li, Xin Yin, Fengmin Lu, Hui Zhao, Lin Wang, Cheng-Feng Qin
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.
背景经肠道传播的肝炎病毒,如甲型肝炎病毒(HAV)和戊型肝炎病毒(HEV),仍然是公共卫生的显著威胁。然而,目前还缺乏稳定可靠的 HAV 和 HEV 感染动物模型。本研究旨在通过静脉注射脂质纳米粒子(LNP)包裹的全长病毒 RNA(LNP-vRNA),在多种小型动物中建立 HAV 和 HEV 感染模型。设计 将体外转录和封端的全长 HAV RNA 封装到 LNP 中,静脉注射给 Ifnar -/- 小鼠,并将 HEV RNA 注射给兔子和沙鼠。病毒学参数通过 RT-qPCR、ELISA 和免疫组化进行测定。肝脏组织病理学变化通过 H&E 染色进行分析。利用基于 LNP-vRNA 的动物模型进一步评估了抗病毒药物和疫苗的疗效。结果 静脉注射 LNP-vRNA 后,在粪便中检测到稳定的病毒脱落,并从接种动物的肝脏中回收了感染性 HAV 或 HEV。在注射 LNP-vRNA(HAV)的小鼠和注射 LNP-vRNA(HEV)的兔子身上观察到肝损伤。蒙古沙鼠对注射 LNP-vRNA(HEV)也很敏感。最后,在基于 LNP-vRNA 的动物模型中验证了 HEV 基因组缺失的抗病毒对策和体内功能。结论 这种稳定和标准化的基于 LNP-vRNA 的动物模型为研究肠道传播的肝炎病毒的发病机制和评估对策提供了一个强大的平台,并可进一步扩展到体外或体内不易培养的其他病毒。与该研究相关的所有数据均包含在文章中或作为在线补充信息上传。
{"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}
引用次数: 0
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