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Lysosomal physiology and pancreatic lysosomal stress in diabetes mellitus. 糖尿病的溶酶体生理学和胰腺溶酶体应激。
Pub Date : 2024-10-01 Epub Date: 2024-08-29 DOI: 10.1136/egastro-2024-100096
Meihua Hao, Sara C Sebag, Qingwen Qian, Ling Yang

Endocrine and exocrine functions of the pancreas control nutritional absorption, utilisation and systemic metabolic homeostasis. Under basal conditions, the lysosome is pivotal in regulating intracellular organelles and metabolite turnover. In response to acute or chronic stress, the lysosome senses metabolic flux and inflammatory challenges, thereby initiating the adaptive programme to re-establish cellular homeostasis. A growing body of evidence has demonstrated the pathophysiological relevance of the lysosomal stress response in metabolic diseases in diverse sets of tissues/organs, such as the liver and the heart. In this review, we discuss the pathological relevance of pancreatic lysosome stress in diabetes mellitus. We begin by summarising lysosomal biology, followed by exploring the immune and metabolic functions of lysosomes and finally discussing the interplay between lysosomal stress and the pathogenesis of pancreatic diseases. Ultimately, our review aims to enhance our understanding of lysosomal stress in disease pathogenesis, which could potentially lead to the discovery of innovative treatment methods for these conditions.

胰腺的内分泌和外分泌功能控制着营养的吸收、利用和全身代谢平衡。在基础条件下,溶酶体在调节细胞内细胞器和代谢物周转方面起着关键作用。在应对急性或慢性压力时,溶酶体会感知代谢通量和炎症挑战,从而启动适应程序重建细胞平衡。越来越多的证据表明,溶酶体应激反应与肝脏和心脏等不同组织/器官的代谢性疾病具有病理生理学相关性。在本综述中,我们将讨论胰腺溶酶体应激与糖尿病的病理相关性。我们首先概述溶酶体生物学,然后探讨溶酶体的免疫和代谢功能,最后讨论溶酶体应激与胰腺疾病发病机制之间的相互作用。最后,我们的综述旨在加深我们对溶酶体应激在疾病发病机制中的作用的理解,从而有可能发现治疗这些疾病的创新方法。
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引用次数: 0
New therapeutic target for alcohol-associated hepatitis (AH): AH-associated IL-8+ neutrophils. 酒精相关性肝炎(AH)的新治疗靶点:AH相关IL-8+中性粒细胞
Pub Date : 2024-10-01 Epub Date: 2024-12-21 DOI: 10.1136/egastro-2024-100166
Yukun Guan, Dechun Feng, Luca Maccioni, Yang Wang, Bin Gao
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引用次数: 0
Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease. 酒精相关性肝病发病机制中的细胞间和器官间串联。
Pub Date : 2024-10-01 Epub Date: 2024-12-09 DOI: 10.1136/egastro-2024-100104
Hui Gao, Yanchao Jiang, Ge Zeng, Nazmul Huda, Themis Thoudam, Zhihong Yang, Suthat Liangpunsakul, Jing Ma

Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence and severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation is a well-established key factor, recent evidence highlights the critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced liver injury. This review provides a comprehensive analysis of the complex interactions within the hepatic microenvironment in ALD. It examines the contributions of both parenchymal cells, like hepatocytes, and non-parenchymal cells, such as hepatic stellate cells, Kupffer cells, neutrophils, and liver sinusoidal endothelial cells, in driving the progression of the disease. Additionally, we explored the involvement of key mediators, including cytokines, chemokines and inflammasomes, which regulate inflammatory responses and promote liver injury and fibrosis. A particular focus has been placed on extracellular vesicles (EVs) as essential mediators of intercellular communication both within and beyond the liver. These vesicles facilitate the transfer of signalling molecules, such as microRNAs and proteins, which modulate immune responses, fibrogenesis and lipid metabolism, thereby influencing disease progression. Moreover, we underscore the importance of organ-to-organ crosstalk, particularly in the gut-liver axis, where dysbiosis and increased intestinal permeability lead to microbial translocation, exacerbating hepatic inflammation. The adipose-liver axis is also highlighted, particularly the impact of adipokines and free fatty acids from adipose tissue on hepatic steatosis and inflammation in the context of alcohol consumption.

酒精相关性肝病(ALD)是一个日益严重的全球健康问题,其患病率和严重程度正在稳步上升。虽然细菌内毒素易位进入门静脉循环是一个公认的关键因素,但最近的证据强调了由多种刺激引发的无菌炎症在酒精性肝损伤中的关键作用。本文综述全面分析了ALD中肝脏微环境中复杂的相互作用。它检查了实质细胞(如肝细胞)和非实质细胞(如肝星状细胞、库普弗细胞、中性粒细胞和肝窦内皮细胞)在推动疾病进展中的作用。此外,我们探索了关键介质的参与,包括细胞因子、趋化因子和炎症小体,它们调节炎症反应并促进肝损伤和纤维化。特别关注的是细胞外囊泡(EVs)作为肝脏内外细胞间通讯的重要介质。这些囊泡促进信号分子(如microrna和蛋白质)的转移,从而调节免疫反应、纤维形成和脂质代谢,从而影响疾病进展。此外,我们强调了器官间串扰的重要性,特别是在肠-肝轴,那里的生态失调和肠道通透性增加导致微生物易位,加剧肝脏炎症。脂肪-肝轴也被强调,特别是脂肪因子和脂肪组织的游离脂肪酸对酒精摄入情况下肝脏脂肪变性和炎症的影响。
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引用次数: 0
Goblet cells: guardians of gut immunity and their role in gastrointestinal diseases. 鹅口疮细胞:肠道免疫力的守护者及其在胃肠道疾病中的作用。
Pub Date : 2024-10-01 DOI: 10.1136/egastro-2024-100098
Fernanda Raya Tonetti, Alvaro Eguileor, Cristina Llorente

Goblet cells (GCs) are specialised guardians lining the intestine. They play a critical role in gut defence and immune regulation. GCs continuously secrete mucus creating a physical barrier to protect from pathogens while harbouring symbiotic gut bacteria adapted to live within the mucus. GCs also form specialised GC-associated passages in a dynamic and regulated manner to deliver luminal antigens to immune cells, promoting gut tolerance and preventing inflammation. The composition of gut bacteria directly influences GC function, highlighting the intricate interplay between these components of a healthy gut. Indeed, imbalances in the gut microbiome can disrupt GC function, contributing to various gastrointestinal diseases like colorectal cancer, inflammatory bowel disease, cystic fibrosis, pathogen infections and liver diseases. This review explores the interplay between GCs and the immune system. We delve into the underlying mechanisms by which GC dysfunction contributes to the development and progression of gastrointestinal diseases. Finally, we examine current and potential treatments that target GCs and represent promising avenues for further investigation.

鹅口疮细胞(GC)是肠道内壁的特殊守护者。它们在肠道防御和免疫调节中发挥着关键作用。鹅口疮细胞不断分泌粘液,形成一道物理屏障,保护肠道免受病原体的侵袭,同时滋养适应在粘液中生活的共生肠道细菌。肠道黏液还以动态调节的方式形成专门的肠道黏液相关通道,向免疫细胞输送腔内抗原,促进肠道耐受性并防止炎症。肠道细菌的组成直接影响 GC 的功能,凸显了健康肠道这些组成部分之间错综复杂的相互作用。事实上,肠道微生物群的失衡会破坏肠道菌群的功能,导致各种胃肠道疾病,如结直肠癌、炎症性肠病、囊性纤维化、病原体感染和肝脏疾病。本综述探讨了胃肠道激素与免疫系统之间的相互作用。我们将深入探讨 GC 功能障碍导致胃肠道疾病发生和发展的潜在机制。最后,我们研究了针对 GCs 的现有和潜在治疗方法,这些方法代表了有希望开展进一步研究的途径。
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引用次数: 0
Rare cause of recurrent acute pancreatitis in teenage man.
Pub Date : 2024-09-11 eCollection Date: 2024-09-01 DOI: 10.1136/egastro-2024-100105
Yamin Lai, Jiachun Pan, Kaixin Peng, Dong Wu, Li Wen
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引用次数: 0
Causal role of the gut microbiome in certain human diseases: a narrative review.
Pub Date : 2024-09-10 eCollection Date: 2024-09-01 DOI: 10.1136/egastro-2024-100086
Connor Prosty, Khaled Katergi, Jesse Papenburg, Alexander Lawandi, Todd C Lee, Hao Shi, Philip Burnham, Lee Swem, Bertrand Routy, Cedric P Yansouni, Matthew P Cheng

Composed of an elaborate ecosystem of bacteria, fungi, viruses and protozoa residing in the human digestive tract, the gut microbiome influences metabolism, immune modulation, bile acid homeostasis and host defence. Through observational and preclinical data, the gut microbiome has been implicated in the pathogenesis of a spectrum of chronic diseases ranging from psychiatric to gastrointestinal in nature. Until recently, the lack of unequivocal evidence supporting a causal link between gut microbiome and human health outcomes incited controversy regarding its significance. However, recent randomised controlled trial (RCT) evidence in conditions, such as Clostridioides difficile infection, cancer immunotherapy and ulcerative colitis, has supported a causal relationship and has underscored the potential of the microbiome as a therapeutic target. This review delineates the RCT evidence substantiating the potential for a causal relationship between the gut microbiome and human health outcomes, the seminal observational evidence that preceded these RCTs and the remaining knowledge gaps.

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引用次数: 0
Pancreatic incidentaloma: incidental findings from history towards the era of liquid biopsy.
Pub Date : 2024-09-09 eCollection Date: 2024-09-01 DOI: 10.1136/egastro-2024-100082
J-Matthias Löhr, Miroslav Vujasinovic, Nikolaos Kartalis, Philipp Osten

This report provides an overview of the most common diagnostic methods that bring to light incidental findings of pancreatic cancer. It reviews the impact of medical imaging and genetic assessment on the definitions of incidental findings and incidentaloma of the pancreas. For different diagnostic approaches (eg, MRI and CT) and for different affections (cysts/intraductal papillary mucinous neoplasia, solid lesions), specific guidelines have been proposed and some are established. Based on this, we summarise the differences between the traditional methods with those applied in the PANCAID project. Biomarkers, genetic predispositions, mutations and circulating tumour cells give rise to different levels of concern. The final part of the report discusses the risks and the opportunities associated with further diagnostic procedures and surgical interventions. From the ethical perspective, the most urging question is, can a screening based on liquid biopsy and blood samples open a gateway for the prevention of pancreatic cancer-even if morbidity and lethality of today's surgical interventions is still very high?

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引用次数: 0
Artificial intelligence-enabled advanced endoscopic imaging to assess deep healing in inflammatory bowel disease.
Pub Date : 2024-08-01 eCollection Date: 2024-09-01 DOI: 10.1136/egastro-2024-100090
Yasuharu Maeda, Ilaria Ditonno, Miguel Puga-Tejada, Irene Zammarchi, Giovanni Santacroce, Subrata Ghosh, Marietta Iacucci

Endoscopic remission is the primary long-term therapeutic goal in inflammatory bowel disease (IBD). The assessment of this therapeutic target typically relies on white light endoscopy (WLE) combined with histological sampling. Nonetheless, distinguishing between endoscopic mild, patchy inflammation and quiescent disease can be challenging, and discrepancies have been observed between endoscopic and histological disease activity, mainly when using WLE. Recent advances in endoscopic technologies are gradually transforming clinical practice. Dye-based chromoendoscopy and virtual chromoendoscopy are currently available in the endoscopist armamentarium, enhancing the assessment of mucosal architecture and vascular patterns, improving the visualisation of patchy inflammation and helping detect subtle dysplastic colonic lesions. Moreover, novel advanced tools, including probe-based confocal laser endomicroscopy and endocytoscopy, offer the remarkable ability to investigate the deep aspect of the gastrointestinal tract in real time, including the structure and function of the intestinal barrier and inflammatory-related alterations. Thus, these techniques can bridge the gap between endoscopy and histology, enabling the integration of novel treat-to-target strategies associated with more favourable outcomes. Artificial intelligence (AI) represents a further step forward in overcoming the limitations associated with endoscopy, including subjectivity and the requirement for expertise. Their implementation in clinical practice may enable standardised, accurate and rapid disease assessment. Moreover, AI can aid in accurately predicting responses to therapy and disease outcomes by stratifying patients' risks, thereby advancing us towards patient-centred personalised medicine. This narrative review summarises the available advanced endoscopic technologies and their integration with AI to assess IBD activity, define promising therapeutic targets and predict long-term outcomes.

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引用次数: 0
Characterisation of HBV and co-infection with HDV and HIV through spatial transcriptomics 通过空间转录组学描述 HBV 以及与 HDV 和 HIV 合并感染的特征
Pub Date : 2024-07-01 DOI: 10.1136/egastro-2024-100067
Amy Cross, James M. Harris, Edward Arbe-Barnes, Colin Nixon, R. Dhairyawan, Andrew Hall, Alberto Quaglia, Fadi Issa, Patrick T F Kennedy, Jane A. McKeating, U. Gill, Dimitra Peppa
The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection.The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions.Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses. Shared features including ‘cytotoxicity’ and ‘B cell receptor signalling’ were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of γδT cells in the HDV/HBV sample, were observed within analysed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression.This proof-of-principle study shows the value of this platform in investigating the complex immune landscape, highlighting relevant host pathways to disease pathogenesis.
需要更好地了解与慢性乙型肝炎(CHB)相关的肝内过程,尤其是在乙型肝炎病毒(HDV)和艾滋病病毒(HIV)合并感染的情况下。空间转录组学可以为复杂的肝内生物过程提供新的见解,从而指导新的个性化治疗。我们采用 NanoString GeoMx 数字空间图谱分析平台评估了三名慢性乙型肝炎病毒(HBV)、HDV 或 HIV 合并感染的治疗前患者的福尔马林固定石蜡包埋(FFPE)活检样本中 HBV 表面抗原和 CD45 的表达。GeoMx 人类全转录组图谱分析对特定感兴趣区(ROIs)中富集基因的表达进行了量化。利用人类肝细胞图谱的训练矩阵对 ROI 内的细胞类型比例进行去卷积。加权基因相关网络分析评估了各采样区域的转录组特征。空间上离散的转录组特征和不同的生物通路与 HBV 感染/疾病状态和免疫反应有关。包括 "细胞毒性 "和 "B细胞受体信号传导 "在内的共同特征在不同患者之间是一致的,这表明除个体特征外还有共同的因素。HDV/HBV合并感染表现出与细胞凋亡和免疫细胞招募有关的基因上调,而HIV/HBV合并感染则表现出与干扰素反应调节有关的基因上调。在分析区域内观察到了不同的细胞特征和免疫细胞群,其中 HDV/HBV 样本中的γδT 细胞较多。肝细胞功能的转录差异表明,HDV/HBV 协同感染的新陈代谢过程紊乱可能会影响疾病的进展。这项原理验证研究显示了这一平台在研究复杂免疫环境方面的价值,突出了疾病发病机制的相关宿主途径。
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引用次数: 0
Mendelian randomisation analysis for intestinal disease: achievement and future. 肠道疾病的孟德尔随机分析:成就与未来。
Pub Date : 2024-06-17 eCollection Date: 2024-04-01 DOI: 10.1136/egastro-2023-100058
Xixian Ruan, Tianyi Che, Xuejie Chen, Yuhao Sun, Tian Fu, Shuai Yuan, Xue Li, Jie Chen, Xiaoyan Wang

Intestinal disease is a group of complex digestive system diseases imposing a significant burden globally. Identifying the risk factors and potential complications of intestinal disease is important for its prevention and treatment. However, traditional observational clinical studies are limited by confounding factors and reverse causation, making causal inference challenging. Mendelian randomisation (MR) method has been developed to effectively mitigate these constraints and assess the causal relationships. This review briefly introduces the MR method, summarises MR research on intestinal disease and delineates the prospective avenues for future research. Conventional risk factors, such as lifestyle behaviours (eg, physical activity, smoking and alcohol consumption), nutrients (eg, selenium), obesity markers (eg, body mass index and waist-to-hip ratio) and inflammatory biomarkers, have been validated in MR studies. Multiomics MR studies are becoming novel hotspots, which provide a theoretical foundation for the exploration of pathogenesis and the investigation of new drug targets. However, most of the recent studies are based on European individuals, and thus it is necessary to replicate the results in other ancestries. Moreover, triangulation integrating MR and other epidemiology methods is suggested as a validated paradigm for causal inference in future MR studies.

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引用次数: 0
期刊
eGastroenterology
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