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ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis

《医学前沿（英文）》页码 972-992 doi: 10.1007/s11684-023-0990-1

摘要： Owing to the increasing incidence and prevalence of inflammatory bowel disease (IBD) worldwide, effective and safe treatments for IBD are urgently needed. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter and plays an important role in inflammation. To date, H₂S-releasing agents are viewed as potential anti-inflammatory drugs. The slow-releasing H₂S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), known as a potent therapeutic with chemopreventive and cytoprotective properties, has received attention recently. Here, we reported its anti-inflammatory effects on dextran sodium sulfate (DSS)-induced acute (7 days) and chronic (30 days) colitis. We found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon length. Moreover, ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B pathway. In vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression levels. In addition, ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter, Mucispirillum, Parasutterella, and Desulfovibrio. Transplanting ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory cytokines. Collectively, ADT-OH is safe without any short-term (5 days) or long-term (30 days) toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.

关键词： inflammatory bowel disease ADT-OH intestinal permeability gut microbiota

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Gut microbiota and its implications in small bowel transplantation

null

《医学前沿（英文）》 2018年第12卷第3期页码 239-248 doi: 10.1007/s11684-018-0617-0

摘要：

The gut microbiota is mainly composed of a diverse population of commensal bacterial species and plays a pivotal role in the maintenance of intestinal homeostasis, immune modulation and metabolism. The influence of the gut microbiota on solid organ transplantation has recently been recognized. In fact, several studies indicated that acute and chronic allograft rejection in small bowel transplantation (SBT) is closely associated with the alterations in microbial patterns in the gut. In this review, we focused on the recent findings regarding alterations in the microbiota following SBT and the potential roles of these alterations in the development of acute and chronic allograft rejection. We also reviewed important advances with respect to the interplays between the microbiota and host immune systems in SBT. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or therapeutic target for the predication and intervention of allograft rejection and chronic dysfunction. Given that current research on the gut microbiota has become increasingly sophisticated and comprehensive, large cohort studies employing metagenomic analysis and multivariate linkage should be designed for the characterization of host–microbe interaction and causality between microbiota alterations and clinical outcomes in SBT. The findings are expected to provide valuable insights into the role of gut microbiota in the development of allograft rejection and other transplant-related complications and introduce novel therapeutic targets and treatment approaches in clinical practice.

关键词： gut microbiota small bowel transplantation acute rejection chronic rejection mucosal immunity biomarker microbiota-targeted therapy

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Pien Tze Huang Protects Against Non-Alcoholic Steatohepatitis by Modulating the Gut Microbiota and Metabolites

Xianyi Zeng,Xiang Zhang,Hao Su,Hongyan Gou,Harry Cheuk-Hay Lau,Xiaoxu Hu,Ziheng Huang,Yan Li,Jun Yu,

《工程（英文）》 doi: 10.1016/j.eng.2022.10.010

摘要： Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease without effective treatment. The traditional Chinese medicine formulation Pien Tze Huang (PTH) can suppress inflammatory diseases. Here, we evaluate the effects of PTH on the evolution of NASH and its underlying mechanisms. We found that PTH prevented the development of steatohepatitis induced by various dietary models, including a high-fat high-cholesterol (HFHC) diet, choline-deficient high-fat diet (CD-HFD), and methionine- and choline-deficient (MCD) diet, along with significant suppression of liver injury, hepatic triglyceride, and lipid peroxidation. Moreover, ten days of PTH treatment after the onset of NASH significantly ameliorated MCD diet-induced steatosis and liver injury in mice. Through the metagenomic sequencing of stool samples, we found that PTH administration restored the gut microbiota with enrichment of probiotics including Lactobacillus acidophilus (L. acidophilus), Lactobacillus plantarum, Lactococcus lactis, and Bacillus subtilis. The enriched L. acidophilus prevented MCD diet-induced steatohepatitis. In addition, PTH restored the gut barrier function in mice with steatohepatitis, as evidenced by reduced intestinal permeability, decreased serum lipopolysaccharides (LPS) level, and increased epithelial tight-junction protein E-cadherin expression. Our metabolomic analysis via liquid chromatography-mass spectrometry profiling identified the alteration in the metabolism of bile acids in the portal vein of PTH-treated mice. We further confirmed that an intact gut microbiota is necessary for PTH to exhibit anti-steatohepatitis effects. In conclusion, PTH protects against steatohepatitis development by modulating the gut microbiota and metabolites. PTH is a potential promising prophylactic and therapeutic option for patients with NASH.

关键词： Pien Tze Huang Non-alcoholic steatohepatitis Gut barrier function Gut microbiota

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Mechanistic and therapeutic advances in non-alcoholic fatty liver disease by targeting the gut microbiota

Ruiting Han, Junli Ma, Houkai Li

《医学前沿（英文）》 2018年第12卷第6期页码 645-657 doi: 10.1007/s11684-018-0645-9

摘要： Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases currently in the context of obesity worldwide, which contains a spectrum of chronic liver diseases, including hepatic steatosis, non-alcoholic steatohepatitis and hepatic carcinoma. In addition to the classical “Two-hit” theory, NAFLD has been recognized as a typical gut microbiota-related disease because of the intricate role of gut microbiota in maintaining human health and disease formation. Moreover, gut microbiota is even regarded as a “metabolic organ” that play complementary roles to that of liver in many aspects. The mechanisms underlying gut microbiota-mediated development of NAFLD include modulation of host energy metabolism, insulin sensitivity, and bile acid and choline metabolism. As a result, gut microbiota have been emerging as a novel therapeutic target for NAFLD by manipulating it in various ways, including probiotics, prebiotics, synbiotics, antibiotics, fecal microbiota transplantation, and herbal components. In this review, we summarized the most recent advances in gut microbiota-mediated mechanisms, as well as gut microbiota-targeted therapies on NAFLD.

关键词： gut microbiota NAFLD obesity insulin resistance bile acids probiotic

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Calorie restriction and its impact on gut microbial composition and global metabolism

Xiaojiao Zheng, Shouli Wang, Wei Jia

《医学前沿（英文）》 2018年第12卷第6期页码 634-644 doi: 10.1007/s11684-018-0670-8

摘要：

Calorie restriction (CR) is a dietary regimen that reduces calorie intake without incurring malnutrition or a reduction in essential nutrients. It has long been recognized as a natural strategy for promoting health, extending longevity, and prevents the development of metabolic and age-related diseases. In the present review, we focus on the general effect of CR on gut microbiota composition and global metabolism. We also propose mechanisms for its beneficial effect. Results showed that probiotic and butyrate-producing microbes increased their relative abundance, whereas proinflammatory strains exhibited suppressed relative abundance following CR. Analyses of the gut microbial and host metabolisms revealed that most host microbial co-metabolites were changed due to CR. Examples of dramatic CR-induced changes in host metabolism included a decrease in the rate of lipid biosynthesis and an increase in the rates of fatty acid catabolism, β-oxidation, glycogenolysis, and gluconeogenesis. The observed phenotypes and the further verification of the direct link between gut microbiota and metabolome may benefit patients that are at risk for developing metabolic disease. Thus, improved gut microbiota composition and metabolome are potential biomarkers for determining the effectiveness of dietary interventions for age-related and metabolic diseases.

关键词： caloric restriction gut microbiota metabolome

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通过调控肠道菌群治疗慢性疾病

洪斌, 蒋建东

《工程（英文）》 2022年第18卷第11期页码 17-20 doi: 10.1016/j.eng.2021.08.015

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Altered intestinal microbiota associated with colorectal cancer

Hong Zhang, Ying Chang, Qingqing Zheng, Rong Zhang, Cheng Hu, Weiping Jia

《医学前沿（英文）》 2019年第13卷第4期页码 461-470 doi: 10.1007/s11684-019-0695-7

摘要： The gut microbiota plays an important role in the development and progression of colorectal cancer (CRC). To learn more about the dysbiosis of carcinogenesis, we assessed alterations in gut microbiota in patients with CRC. A total of 23 subjects were enrolled in this study: 9 had CRC (CRC group) and 14 had normal colons (normal group). The microbiome of the mucosal–luminal interface of each subject was sampled and analyzed using 16S rRNA gene amplicon sequencing. We also used Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) to predict microbial functional profiles. The microbial composition of the mucosal lumen differed between the groups, and the presence of specific bacteria may serve as a potential biomarker for colorectal carcinogenesis. We identified a significant reduction in which is a butyrate-producing genera of bacteria, and a significant increase in in the gut microbiota of CRC patients. Different levels of gut microflora in healthy and CRC samples were identiﬁed. The observed abundance of bacterial species belonging to and may serve as a promising biomarker for the early detection of CRC.

关键词： colorectal cancer (CRC) gut microbiota intestinal Eubacterium Devosia

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肠道菌群与肿瘤发生及肝病

吕桂帅, 程宁涛, 王红阳

《工程（英文）》 2017年第3卷第1期页码 110-114 doi: 10.1016/J.ENG.2017.01.017

摘要：

一个多世纪以前，科学家们就首次发现了肿瘤区域中细菌的存在。但是，微生物在肿瘤发生中的作用近年来才被认识到。近几十年来，与肠道菌群失调相关的疾病代表了全世界最严重的一些公共卫生问题。大量的流行病学研究表明，肠道菌群与某些常见肿瘤密切相关。然而，肠道菌群与肿瘤相关联的具体分子机制仍不明确。研究表明，肠道菌群的改变有助于确定肝癌、酒精相关肝病、非酒精性脂肪肝和肝硬化的发生和发展。鉴于益生菌是一种可通过调节免疫系统促进人类健康的药物，其可能会为肝细胞癌(HCC) 和非酒精性脂肪肝的治疗提供新方向。本文总结了肠道菌群在肿瘤及肝病中的研究进展，综述了肠道菌群与肿瘤和肝病之间的关系。此外，考虑到细菌内稳态的重要性，我们也对益生菌进行了概述，旨在为相关疾病的治疗提供指导。

关键词：肠道菌群稳态失调肿瘤发生肝细胞癌非酒精性脂肪性肝病

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Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy

《医学前沿（英文）》 2022年第16卷第3期页码 307-321 doi: 10.1007/s11684-022-0927-0

摘要： The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.

关键词： tumor immunotherapy immune checkpoint inhibitor antibiotics gut microbiota drug–drug interaction

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鱼类肠道菌群研究进展及潜在应用 Review

栾银银, 黎明, 周伟, 药园园, 杨雅麟, 张震, Einar Ringø, Rolf Erik Olsen, Jihong Liu Clarke, 解绶启, 麦康森, 冉超, 周志刚

《工程（英文）》 2023年第29卷第10期页码 137-146 doi: 10.1016/j.eng.2022.12.011

摘要：

肠道菌群在宿主健康和疾病中起着重要作用。我们对鱼类菌群的理解远落后于人类和其他哺乳动物。尽管如此，现有研究也强调了微生物对鱼类的健康、生长性能和各种生理功能中的重要性。目前，模式动物、经济鱼类和野生鱼类中都展开了微生物的研究。鱼类菌群的组成取决于宿主选择、饮食和环境等因素。肠道菌群可以影响鱼类宿主的营养代谢、免疫和抗病能力，而宿主则通过免疫和非免疫因素以鱼菌互作的方式调节肠道菌群的稳态。目前已经开发出的无菌鱼类模型，对于研究鱼类与微生物互作的机理研究有着重要意义。在本篇综述中，我们讨论了鱼类微生物研究的最新进展，描述了包括鱼类微生物多样性，以及宿主-菌群交互作用的研究结果。同时，还讨论了鱼类菌群对鱼类健康及行业可持续发展的潜在作用。

关键词：肠道菌群鱼宿主-菌群交互作用水产养殖

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肠道菌群调节在肝细胞癌和肝移植中的应用 Review

向泽, 吴健, 李佳芮, 郑树森, 魏绪勇, 徐骁

《工程（英文）》 2023年第29卷第10期页码 59-72 doi: 10.1016/j.eng.2022.12.012

摘要：

肝细胞癌（HCC）是最常见的肝脏恶性肿瘤，严重危害公众健康。肝移植（LT）是治疗HCC的有效方法，但缺血再灌注（I/R）损伤、移植排斥反应及各类并发症会大大降低其疗效。近年来，作为外科学、肿瘤学、免疫学及其他相关学科交叉融合而形成的一门综合性学科，移植肿瘤学应运而生。肠道菌群作为一个新兴的研究领域，是移植肿瘤学的重要部分。肠道菌群通过微生物群-肠道-肝脏轴对HCC的发生、发展以及LT疗效产生影响。本文综述了肠道菌群与慢性肝病的双向相互作用及其影响HCC的机制，并且概括了肠道菌群在HCC中的诊断和预后价值。此外，我们还回顾了LT后肠道菌群的变化，并讨论了肠道菌群与肝脏I/R损伤、免疫抑制药物疗效以及LT后并发症之间的关系。在移植肿瘤学时代，肠道菌群在HCC和LT中的作用应得到重视，这可以为临床瓶颈难题的解决提供新的见解。

关键词：肠道菌群肝细胞癌（HCC）肝移植（LT）临床价值介导机制

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病理状态下肠道微生态的调节

王玉兰, 王保红, 吴俊芳, 江向洋, 唐惠儒, Ole H. Nielsen

《工程（英文）》 2017年第3卷第1期页码 83-89 doi: 10.1016/J.ENG.2017.01.013

摘要：

人类微生态是寄居在人体中的微生物聚集体，且主要存在于胃肠道(GIT) 中。肠道微生态随着人体发育而演化，并在人类健康和疾病中起着重要作用。近年来，由于微生态会影响宿主代谢、生理学和免疫系统发育，而且微生态紊乱可能导致许多疾病，其越来越受到人们的关注。肠道微生态可能与恶性肿瘤有一定联系，如胃癌和结直肠癌；也可能与其他一些疾病有关，如非酒精性脂肪肝(NAFLD)、被称为工业化世界“生活方式疾病”的肥胖和糖尿病、冠心病以及中枢神经系统紊乱。虽然分子技术革命为我们更准确地研究肠道微生态提供了必要的工具，但是我们需要更精确地阐明其与某些人类疾病病理变化的关系，明确微生态在不同疾病中的作用是新的治疗策略发展的基础。本文概述了肠道微生态对人类健康的重要影响以及调整肠道菌群结构的潜在用途，如菌群移植用于治疗耐药艰难梭菌(C. difficile) 的感染。通过微生态干预调整肠道区域以改善人类健康的概念虽刚刚兴起，但其治疗意义显著。因此，抑制有害菌、促进有益菌可能会保护人类健康，并且这些努力将为探索发展更加合理的治疗方案打下基础。

关键词：肠道菌群疾病菌群调节

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肠道菌群是调节神经系统功能紊乱的潜在靶点 Review

武万强, 孔庆敏, 田培郡, 翟齐啸, 王刚, 刘小鸣, 赵建新, 张灏, Yuan Kun Lee, 陈卫

《工程（英文）》 2020年第6卷第4期页码 415-423 doi: 10.1016/j.eng.2019.07.026

摘要：

众所周知，肠道菌群在调节宿主生理功能方面具有重要作用，如调节免疫和代谢平衡。近年来，越来越多证据表明肠道菌群能够通过肠-脑轴调节中枢神经系统功能，这为研究肠道和大脑间的相互作用关系开辟了一条新路径。本文首先介绍了肠道菌群与大脑相互作用的肠–脑轴分子机制，以及肠道菌群失调引发的神经系统功能紊乱；然后介绍了调节肠道菌群失衡是干预神经系统功能紊乱的潜在策略，如益生菌、益生元、合生元以及饮食等干预措施。目前关于肠道菌群–肠–脑轴方面的研究尚处在起步阶段，但继续深入阐明肠道菌群调节神经系统功能的分子机制不仅能揭示神经系统功能紊乱的新型病理机制，而且能够为神经系统功能紊乱提供潜在的诊断标志物和干预策略。

关键词：肠道菌群肠-脑轴神经系统功能紊乱干预策略

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肠道菌群与冠状动脉疾病的发生风险 Article

胡嘉禄, 姚志峰, 唐敏娜, 唐春, 赵晓璠, 苏曦, 卢淡泊, 李秋荣, 王张生, 颜彦, 王则能

《工程（英文）》 2021年第7卷第12期页码 1715-1724 doi: 10.1016/j.eng.2020.05.025

摘要：

在过去的几年中，小规模队列研究发现肠道菌群随冠状动脉疾病出现而改变。既往研究中所发现的冠状动脉疾病患者肠道中富集或减少的微生物群，在其他冠状动脉疾病队列中是否具有可重复性，有待进一步研究和验证。本研究共纳入78 名受试者，其中19 例受试者无冠状动脉狭窄（Ctrl 组），14 例受试者冠状动脉狭窄程度小于50%（LT50 组），45 例受试者冠状动脉狭窄程度大于50%（GT50 组）。采集受试者粪便标本，并提取DNA 进行16S 核糖体RNA 基因测序。对可执行的分类操作单位（operational taxonomic units, OTU）进行分析以确定不同类群的分类单元，采用多变量logistic 回归分析检验所定义的分类单元是否能独立预测冠状动脉疾病风险。结果显示，δ-变形杆菌纲、梭杆菌属、嗜胆菌属、放线菌属和梭菌XIX属在Ctrl 组中富集；普雷沃氏菌科、副拟杆菌属和芽孢杆菌属在LT50 组中富集；罗氏菌属和丁酸单胞菌属在GT50 组中富集。δ-变形杆菌纲、梭杆菌属、嗜胆菌属和脱硫弧菌科种群的增加与冠状动脉疾病风险降低相关。在相对丰度高于中位数的个体中，冠状动脉疾病风险分别降低为相对丰度低于中位数的个体的0.26 倍、0.21 倍、0.18 倍和0.26 倍（p < 0.05），而普雷沃氏菌科种群的增加与冠状动脉疾病风险增加相关，冠状动脉疾病风险增加5.63 倍（p < 0.01）。使用20 种微生物群联合诊断LT50组与Ctrl组、GT50组与Ctrl组、LT50组+GT50组与Ctrl组、GT50组与Ctrl组+LT50组，受试者工作特征
（ROC）曲线下的面积均高于0.88。然而，除拟杆菌属外，既往研究所报道的在冠状动脉疾病或健康对照组受试者中富集的肠道菌群在本队列并未观察到。总之，冠状动脉疾病与健康对照组受试者具有不同的菌群特征。不同队列研究所发现的冠状动脉疾病富集的肠道菌群特征不具有重复性，提示肠道菌群较难应用于冠状动脉疾病的早期诊断和预防。综合本研究与既往研究结果，只有拟杆菌属丰度减少是冠状动脉疾病进展的可靠标志物。

关键词：肠道菌群动脉粥样硬化冠状动脉疾病

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多组学联用揭示花粉过敏基于肠道菌的新机制 Article

韩珮, 李丽莎, 王子熹, 锡琳, 于航, 丛林, 张正威, 符洁, 彭冉, 潘利斌, 马殊荣, 王学艳, 王洪田, 王向东, 王琰, 孙劲旅, 蒋建东

《工程（英文）》 2022年第15卷第8期页码 115-125 doi: 10.1016/j.eng.2021.03.013

摘要：

由于过敏性疾病在世界范围内流行且尚无治愈方法，因此有必要探讨其病理生理机制。由于过敏性疾病与肠道菌群失调相关，本研究从宿主与微生物的分子层面，结合代谢组学和微生物组学，寻找可能的机制。本研究对SD大鼠注射青蒿花粉提取物以诱导其对花粉的过敏反应，这种过敏反应降低了血液中的缬氨酸、异亮氨酸、天门冬氨酸、谷氨酸、谷氨酰胺、吲哚丙酸和肌醇浓度，并减少了粪便中的短链脂肪酸（SCFA）。来自于瘤胃球菌科（Ruminococcaceae）、毛螺菌科（Lachnospiraceae）和梭状芽孢杆菌（Clostridiales）的几个有益菌属在模型组中表达减少，而幽门螺杆菌Helicobacter 和阿克曼氏菌Akkermansia 仅在模型组中表达。此外，模型组肠道claudin-3 和肝脏脂肪酸结合蛋白表达下调，与代谢变化和细菌有关。本文的研究结果表明，氨基酸及其衍生物（尤其是缬氨酸和色氨酸的还原产物吲哚丙酸）、短链脂肪酸和肠道微生物（特别是幽门螺杆菌Helicobacter 和阿克曼氏菌Akkermansia）的改变可能通过抑制claudin蛋白表达和影响黏液层而破坏肠道屏障功能，进而导致花粉过敏。

关键词：代谢组学肠道菌群花粉过敏过敏性疾病肠道屏障功能紊乱