消化道微生态与胰腺疾病

消化道微生态参与人体多种生理及病理过程,是消化领域的研究热点。消化道微生态可能与急慢性胰腺炎和胰腺癌等胰腺疾病关系密切,但学术界很少关注。慢性胰腺炎患者存在肠道菌群结构失衡,并易伴发小肠细菌过度生长。肠道菌群可能与自身免疫性胰腺炎等IgG4相关性疾病关系密切。急性胰腺炎患者存在肠道菌群结构变化,肠道屏障功能受损和细菌移位在急性胰腺炎疾病进展中起重要作用,但不同类型和疾病程度的急性胰腺炎患者肠道菌群结构和功能特征仍不清楚。牙周疾病和口腔微生态失衡会增加罹患胰腺癌的风险,但胰腺癌时肠道菌群的具体变化及作用仍不明确。本文就各类胰腺疾病背景下的消化道微生态研究现状及未来可能的研究方向进行阐述     

胰腺微环境外泌体miRNA参与胰腺炎症和纤维化的发病机制研究进展

慢性胰腺炎(chronic pancreatitis, CP)发病率逐年上升，目前尚无明确根治性治疗方法且后期有进展为胰腺癌的风险。CP的典型病理学特征是胰腺慢性炎症和纤维化，CP进展与胰腺微环境中三种主要细胞(腺泡细胞、巨噬细胞以及胰腺星状细胞)间的相互作用密切相关，然而它们具体是如何进行细胞间联系的目前尚不清楚。新近研究表明外泌体作为细胞间重要的通讯介质，其携带的miRNA可通过调控主要细胞内基因表达和信号通路等影响CP的发生发展。本文围绕胰腺微环境中外泌体来源miRNA与三种主要细胞相互作用的机制，对其最新研究进展进行归纳和总结分析，以期为CP发病机制的深入认识提供参考。     

胰腺星状细胞活化相关的信号转导通路

胰腺纤维化是慢性胰腺炎（chronic pancreatitis,CP）和胰腺癌主要的病理学特征,活化的胰腺星状细胞（pancreatic stellate cells,PSCs）是公认的致胰腺纤维化的主要效应细胞。PSCs的活化涉及到几个重要的信号转导通路：有丝分裂原活化蛋白激酶（mitogen-activated protein kinases,MAPK）、磷酯酰肌醇3激酶（phosphatidylinositol 3-kinase,PI3K）=、Smad信号转导蛋白、过氧化物酶体增生物激活受体-γ（PPAR-γ）、Rho-ROCK等细胞内信号途径。探讨这些信号通路在胰腺纤维化中所起的作用对慢性胰腺炎、胰腺癌及糖尿病的治疗有重要意义。现就与PSCs激活有关的信号通路的研究结合最新进展作一综述。     

Toll样受体在急性胰腺炎及其相关器官损伤中的作用

急性胰腺炎(acute pancreatitis,AP),尤其重型急性胰腺炎(severe acute pancreatitis,SAP)是临床常见的急腹症,其发病机制复杂,治疗效果迄今仍不令人满意。Toll样受体(Toll-like receptors,TLRs)属于模式识别受体(pattern recognition receptors,PRRs),在多种疾病中都起着关键性作用。TLRs参与AP相关炎症反应的发生发展,并且作为AP潜在的治疗靶点广为研究。本文就国内外TLRs在AP及其相关器官损伤的作用研究予以综述。     

慢性胰腺炎动物模型的比较与选择

慢性胰腺炎(chronic pancreatitis, CP)是一种慢性消化系统疾病,主要病理表现为胰腺的慢性炎症,最终以纤维化替代胰腺的正常组织,导致胰腺的内、外分泌功能损伤。近年来,为了深入研究CP的发病机制,研究人员开展了大量动物实验研究,涉及多种动物模型。选择合适的动物模型对开展后续的实验研究具有重要的意义。现从造模的方式入手,比较多种常用的CP动物模型,为CP研究过程中模型的选择提供依据。     

慢性胰腺炎胰腺纤维化发病机制研究新进展

慢性胰腺炎(chronic pancreatitis, CP)是由多种因素引起的胰腺内外分泌功能紊乱,可导致胰腺结构和功能发生不可逆性损伤,是临床常见的消化系统疾病。CP的病理特点是腺泡细胞损伤导致巨噬细胞等多种炎症细胞浸润,从而分泌大量促炎细胞因子,在胰腺组织微环境中引起胰腺星状细胞活化,进而产生大量的细胞外基质,表现为胰腺纤维化。而新近的研究提示:胰腺纤维化是一种动态病理现象,需要由多种自分泌和旁分泌的细胞因子组成复杂的网络,作用于相应的信号通路,最终导致纤维化形成。现以CP胰腺组织微环境中出现的主要细胞,如胰腺星状细胞、巨噬细胞、腺泡细胞及其在CP胰腺纤维化进展中的变化和作用为切入点,对CP胰腺纤维化的发病机制研究进展做一综述。     

铁死亡在急性胰腺炎中的研究进展

铁死亡是一种铁依赖性的新型细胞程序性死亡方式,已被证明与急性胰腺炎(acute pancreatitis,AP)的发生发展密切相关。通过调控铁离子代谢、活性氧堆积、谷胱甘肽过氧化物酶4以及核转录因子2/血红素氧合酶1与晚期糖基化终产物特异性受体/核转录因子-κB通路的表达,可抑制铁死亡发生,从而预防改善AP。AP是一种常见的消化系统急性病症,10%~20%可发展为重症急性胰腺炎(severe acute pancreatitis,SAP),SAP常合并其他器官(肠黏膜、肝、肺、肾等)损伤。目前,AP尚无明确的发病机制,缺乏有效的治疗方案。本文归纳出铁死亡在AP中的作用机制,及其对SAP引发相关器官(肝、肺、肾、肠黏膜)损伤的影响,以期为疾病的发生机制和预防治疗提供新见解。     

急性胰腺炎1796例病因及治疗效果分析

目的：分析我院急性胰腺炎（AP）的主要病因及治疗效果,为临床诊疗工作提供参考。方法：回顾性分析2008年1月至2012年12月于我院住院治疗的1796例AP患者的临床资料,统计其病因及治疗效果,对其病因及预后进行分析总结。结果：在1796例患者中,重症急性胰腺炎（SAP）522例,轻症急性胰腺炎（MAP）1274例。胆源性AP1025例,高脂血症性AP209例,酒精性AP200例。高脂血疰性AP中,SAP占49．8％,高于胆道疾病及酒精因素引起的SAP的比例（P〈0．05）。33例患者死亡,总病死率1．8％。结论：胆道疾病、酒精、高脂血症是我国AP主要病因,随着医疗水平的提高,AP的病死率有所下降。     

基于基因敲除技术综述AP腺泡细胞损伤的相关分子机制

急性胰腺炎(AP)是临床多发的危重消化系统疾病,胰腺腺泡细胞损伤是急性胰腺炎发生发展的重要病理机制之一。Ca²⁺超载、氧化应激、自噬受损、内质网应激等途径被认为是胰腺腺泡细胞损伤的关键途径,但此过程中具体基因、蛋白和信号通路发挥作用的相关机制并不完全明确。基因敲除技术是揭示基因功能以及验证生物学信号转导途径最有效的方法,为进一步明确急性胰腺炎胰腺腺泡细胞损伤的分子机制提供了新的技术手段。该文基于基因敲除技术系统综述了AP腺泡细胞损伤的相关分子机制,以期进一步明确急性胰腺炎腺泡细胞损伤相关病理生理机制,促进临床特效药物开发,提高急性胰腺炎临床疗效并改善患者预后。     

肠道微生物群在人类健康衰老中的作用机制研究进展北大核心

衰老的特征是组织器官的功能衰退以及衰老相关疾病风险的增加,这给维护和促进健康长寿带来一系列新的挑战。尽管进行了广泛的衰老相关研究,但进展有限。人们越来越意识到肠道微生物群的结构和功能积极参与了衰老过程。肠道微生物群紊乱表现为许多与年龄相关的肠外器官轴的衰老。肠道微生物群可以被调节,这暗示了通过肠道微生物群抗衰老是一个可以实现的重要目标。本综述总结了肠道微生物群在不同年龄段中的动态演替,这种动态的肠道微生物群从胎儿到出生和婴儿期开始迅速发展,从断奶期到幼儿期迅速变化,然后建立稳定的成年人菌群,直到随着年龄增长最后发生衰退;肠道微生物群与肠外器官轴(大脑、心脏、肝脏、胰腺、肌肉、皮肤和骨骼)衰老相关疾病,以及通过饮食、粪菌移植和微生态制剂调节肠道微生物群靶向抗衰老的研究进展,以期为调控肠道微生物群抗衰老研究提供参考。     

Preclinical insights into the gut‐skeletal muscle axis in chronic gastrointestinal diseases

Muscle wasting represents a constant pathological feature of common chronic gastrointestinal diseases, including liver cirrhosis (LC), inflammatory bowel diseases (IBD), chronic pancreatitis (CP) and pancreatic cancer (PC), and is associated with increased morbidity and mortality. Recent clinical and experimental studies point to the existence of a gut‐skeletal muscle axis that is constituted by specific gut‐derived mediators which activate pro‐ and anti‐sarcopenic signalling pathways in skeletal muscle cells. A pathophysiological link between both organs is also provided by low‐grade systemic inflammation. Animal models of LC, IBD, CP and PC represent an important resource for mechanistic and preclinical studies on disease‐associated muscle wasting. They are also required to test and validate specific anti‐sarcopenic therapies prior to clinical application. In this article, we review frequently used rodent models of muscle wasting in the context of chronic gastrointestinal diseases, survey their specific advantages and limitations and discuss possibilities for further research activities in the field. We conclude that animal models of LC‐, IBD‐ and PC‐associated sarcopenia are an essential supplement to clinical studies because they may provide additional mechanistic insights and help to identify molecular targets for therapeutic interventions in humans.     

Recovery of human gut microbiota genomes with third-generation sequencing

Human gut microbiota modulates normal physiological functions, such as maintenance of barrier homeostasis and modulation of metabolism, as well as various chronic diseases including type 2 diabetes and gastrointestinal cancer. Despite decades of research, the composition of the gut microbiota remains poorly understood. Here, we established an effective extraction method to obtain high quality gut microbiota genomes, and analyzed them with third-generation sequencing technology. We acquired a large quantity of data from each sample and assembled large numbers of reliable contigs. With this approach, we constructed tens of completed bacterial genomes in which there were several new bacteria species. We also identified a new conditional pathogen, Enterococcus tongjius, which is a member of Enterococci. This work provided a novel and reliable approach to recover gut microbiota genomes, facilitating the discovery of new bacteria species and furthering our understanding of the microbiome that underlies human health and diseases.Subject terms: DNA sequencing, Mechanisms of disease     

Quantitative proteomics analysis reveals that proteins differentially expressed in chronic pancreatitis are also frequently involved in pancreatic cancer

The effective treatment of pancreatic cancer relies on the diagnosis of the disease at an early stage, a difficult challenge. One major obstacle in the development of diagnostic biomarkers of early pancreatic cancer has been the dual expression of potential biomarkers in both chronic pancreatitis and cancer. To better understand the limitations of potential protein biomarkers, we used ICAT technology and tandem mass spectrometry-based proteomics to systematically study protein expression in chronic pancreatitis. Among the 116 differentially expressed proteins identified in chronic pancreatitis, most biological processes were responses to wounding and inflammation, a finding consistent with the underlining inflammation and tissue repair associated with chronic pancreatitis. Furthermore 40% of the differentially expressed proteins identified in chronic pancreatitis have been implicated previously in pancreatic cancer, suggesting some commonality in protein expression between these two diseases. Biological network analysis further identified c-MYC as a common prominent regulatory protein in pancreatic cancer and chronic pancreatitis. Lastly five proteins were selected for validation by Western blot and immunohistochemistry. Annexin A2 and insulin-like growth factor-binding protein 2 were overexpressed in cancer but not in chronic pancreatitis, making them promising biomarker candidates for pancreatic cancer. In addition, our study validated that cathepsin D, integrin beta1, and plasminogen were overexpressed in both pancreatic cancer and chronic pancreatitis. The positive involvement of these proteins in chronic pancreatitis and pancreatic cancer will potentially lower the specificity of these proteins as biomarker candidates for pancreatic cancer. Altogether our study provides some insights into the molecular events in chronic pancreatitis that may lead to diverse strategies for diagnosis and treatment of these diseases.     

宿主遗传因素对肠道菌群的影响

随着高通量测序技术的发展,人们逐渐认识到肠道菌群与人类的健康和疾病密切相关,并发现肠道菌群受很多因素的影响。除了研究传统饮食和药物对肠道菌群的改变外,近年来,科学家也开始注重遗传因素在塑造肠道菌群中的作用。遗传因素可决定宿主的饮食偏好、肠道的生理结构、肠道屏障功能和免疫功能等,而这些都直接与肠道菌群相互作用,参与肠道微生态平衡的构建和稳定。因此,在研究肠道菌群与疾病发生相关性的过程中也需要考虑遗传因素的重要性。随着基因敲除、无菌小鼠和菌群移植等实验技术的革新,以及主成分分析、数量性状基因座和全基因组关联性分析等大数据分析手段的提高,科学家能够深入研究宿主遗传基因与肠道菌群之间的关联性,从而证明宿主遗传基因在塑造肠道微生态的过程中具有重要作用。本文将首先简述肠道菌群与疾病发生之间可能存在的联系,然后从多方面综述遗传因素对肠道菌群的影响及主要的研究进展,从而为今后该领域的深入研究提供重要的指导,也为今后预防和治疗疾病提供新思路和新方法。     

肠道、肺部菌群直接或通过肠—肺轴对呼吸系统慢性疾病的影响

人体寄生的微生物与人体为共生关系,数量庞大,并形成不同的微生态系统,影响人体免疫、代谢、内分泌等生理过程。菌群失衡导致微生态紊乱,从而导致相关疾病的发生发展。呼吸系统慢性疾病患者常有肠道菌群和肺部菌群的改变,肠道菌群通过肠—肺轴影响呼吸系统免疫及呼吸系统慢性疾病,肺部菌群的改变导致肺部疾病的同时亦会通过血流引起肠道菌群的变化。近年来随着高通量测序及生物信息学技术的发展,相关研究也越发被重视,本文着重对肠道菌群、肺部菌群通过肠—肺轴或直接在肺部免疫及呼吸系统慢性疾病中所起的作用进行综述。     

Extracellular vesicles and pancreatitis: mechanisms,status and perspectives

Comprehensive reviews and large population-based cohort studies have played an important role in the diagnosis and treatment of pancreatitis and its sequelae. The incidence and mortality of pancreatitis have been reduced significantly due to substantial advancements in the pathophysiological mechanisms and clinically effective treatments. The study of extracellular vesicles (EVs) has the potential to identify cell-to-cell communication in diseases such as pancreatitis. Exosomes are a subset of EVs with an average diameter of 50~150 nm. Their diverse and unique constituents include nucleic acids, proteins, and lipids, which can be transferred to trigger phenotypic changes of recipient cells. In recent years, many reports have indicated the role of EVs in pancreatitis, including acute pancreatitis, chronic pancreatitis and autoimmune pancreatitis, suggesting their potential influence on the development and progression of pancreatitis. Plasma exosomes of acute pancreatitis can effectively reach the alveolar cavity and activate alveolar macrophages to cause acute lung injury. Furthermore, upregulated exosomal miRNAs can be used as biomarkers for acute pancreatitis. Here, we summarized the current understanding of EVs in pancreatitis with an emphasis on their biological roles and their potential use as diagnostic biomarkers and therapeutic agents for this disease.     

Gut microbiome in gastrointestinal cancer: a friend or foe?

The impact of the gut microbiome on host health is becoming increasingly recognized. To date, there is growing evidence that the complex characteristics of the microbial community play key roles as potential biomarkers and predictors of responses in cancer therapy. Many studies have shown that altered commensal bacteria lead to cancer susceptibility and progression in diverse pathways. In this review, we critically assess the data for gut microbiota related to gastrointestinal cancer, including esophageal, gastric, pancreatic, colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma. Importantly, the underlying mechanisms of gut microbiota involved in cancer occurrence, prevention and treatment are elucidated. The purpose of this review is to provide novel insights for applying this understanding to the development of new therapeutic strategies in gastrointestinal cancer by targeting the microbial community.     

肠道菌群与乳腺疾病的相关性研究进展

肠道菌群作为人体内复杂微生态系统的组成部分, 其作用并不是局限于局部而是作用于全身, 通过影响宿主的代谢、免疫系统和炎症反应等, 在乳腺疾病如乳腺癌和乳腺炎的发生、发展及治疗中扮演了主要角色。随着研究的深入, 人们发现乳腺癌的发生机制与炎症及免疫等密切相关, 而肠道菌群通过改变宿主微生态, 直接参与机体的生理过程和免疫系统的发育。此外, 肠道菌群可通过改变肠黏膜通透性影响炎症发生。因此近年来肠道菌群与乳腺疾病的关系成为研究的热点。本文通过总结近3年的文献, 从中西医角度对肠道菌群与乳腺疾病之间的相互关系作一综述。

     

肠道菌群与乙型肝炎病毒感染相关肝病的研究进展

乙型肝炎病毒(hepatitis B virus, HBV)可引起人体急性或慢性感染,甚至导致肝硬化或肝癌,其作用机制目前仍未完全阐明。近年来,肠-肝轴受到广泛关注,肠道微生态的相关研究迅速发展,越来越多的实验结果表明,肠道菌群(gut microbiota, GM)与HBV相关肝病的发生和发展具有一定关联。GM可能是了解HBV感染发病机制的一个新视角,并为HBV相关疾病的治疗提供新靶点,这将对未来的治疗策略产生积极影响。本文就HBV感染者肠道菌群与乙型肝炎相关肝病的研究进展进行综述。