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A prophage competition element protects Salmonella from lysis 噬菌体竞争元件保护沙门氏菌不被溶解
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-11-07 DOI: 10.1016/j.chom.2024.10.012
Molly R. Sargen, Sophie Helaine
Most bacteria are polylysogens that carry multiple prophages integrated into the chromosome. These prophages confer advantages to their bacterial host, yet also pose a lethal threat as they can reactivate and enter a lytic cycle. DNA damage of the bacterial host is a common trigger of prophage lytic cycles. Because DNA damage is frequently experienced by bacterial pathogens exposed to host immune defenses, prophage activation may be common during infection. Investigating the consequences of prophage induction in Salmonella, we discover a prophage competition element in the Gifsy-1 prophage that we name ribonuclease effector module with ATPase, inhibitor, and nuclease (RemAIN) because it blocks the lytic cycles and release of viral particles of co-resident prophages. Intramacrophage Salmonella persisters, a subpopulation that incurs DNA damage, experience prophage reactivation and subsequent RemAIN activation, which influences Salmonella persisters and macrophage response to infection. Our findings reveal a multi-layered host-pathogen arms race in which prophage-prophage competition influences bacterial persistence and the mammalian immune response.
大多数细菌都是多聚原生体,其染色体上集成有多个噬菌体。这些噬菌体给细菌宿主带来优势,但也构成致命威胁,因为它们可以重新激活并进入溶菌循环。细菌宿主的 DNA 受损是噬菌体溶菌循环的常见触发因素。由于细菌病原体经常受到宿主免疫防御系统的 DNA 损伤,因此噬菌体在感染过程中可能会被激活。在研究沙门氏菌噬菌体诱导的后果时,我们在 Gifsy-1 噬菌体中发现了一种噬菌体竞争元件,我们将其命名为具有 ATP 酶、抑制剂和核酸酶的核糖核酸酶效应模块(REMAIN),因为它能阻止共驻噬菌体的溶解循环和病毒颗粒的释放。巨噬细胞内的沙门氏菌宿主是造成 DNA 损伤的亚群,它们会经历噬菌体再激活和随后的 RemAIN 激活,这影响了沙门氏菌宿主和巨噬细胞对感染的反应。我们的研究结果揭示了宿主与病原体之间的多层次军备竞赛,其中噬菌体与巨噬细胞之间的竞争影响了细菌的持久性和哺乳动物的免疫反应。
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引用次数: 0
Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients 抗 PD-1 治疗期间肠道微生物群的纵向分析揭示了黑色素瘤患者反应的稳定微生物特征
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-30 DOI: 10.1016/j.chom.2024.10.006
Angeli D.G. Macandog, Carlotta Catozzi, Mariaelena Capone, Amir Nabinejad, Padma P. Nanaware, Shujing Liu, Smita Vinjamuri, Johanna A. Stunnenberg, Serena Galiè, Maria Giovanna Jodice, Francesca Montani, Federica Armanini, Ester Cassano, Gabriele Madonna, Domenico Mallardo, Benedetta Mazzi, Salvatore Pece, Maria Tagliamonte, Vito Vanella, Massimo Barberis, Luigi Nezi
Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8+ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides.
免疫检查点抑制剂(ICIs)可改善晚期黑色素瘤的治疗效果,但许多患者会出现难治性或复发。肠道微生物群调节抗肿瘤反应。然而,不一致的基线预测因素导致了反应的异质性和横断面数据的不足。我们对无法切除的黑色素瘤患者进行了基线和抗PD-1治疗期间的随访,收集粪便和血液样本,调查肠道微生物群和免疫标记物的变化。在 ICI 治疗期间,患者不同的反应与不同的肠道微生物群动态有关。我们通过稳定的微生物群功能筛选出完全应答者,并通过多个外部队列和实验进行验证。我们确定了主要组织相容性复合体 I 类(MHC I 类)限制肽,这些肽来源于拉赫诺斯皮拉科(Lachnospiraceae)鞭毛蛋白相关基因(FLach),是肿瘤相关抗原的结构同源物,在 ICI 治疗前检测到完全应答者中的 FLach 反应性 CD8+ T 细胞,并证明 FLach 肽能提高抗肿瘤免疫力。这些发现凸显了微生物功能的预后价值和仿肿瘤微生物肽的治疗潜力。
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引用次数: 0
Comprehensive analysis of Mycobacterium tuberculosis genomes reveals genetic variations in bacterial virulence 结核分枝杆菌基因组综合分析揭示了细菌毒力的遗传变异
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-28 DOI: 10.1016/j.chom.2024.10.004
Wittawin Worakitchanon, Hideki Yanai, Pundharika Piboonsiri, Reiko Miyahara, Supalert Nedsuwan, Worarat Imsanguan, Boonchai Chaiyasirinroje, Waritta Sawaengdee, Sukanya Wattanapokayakit, Nuanjan Wichukchinda, Yosuke Omae, Prasit Palittapongarnpim, Katsushi Tokunaga, Surakameth Mahasirimongkol, Akihiro Fujimoto
Tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), is a significant health problem worldwide. Here, we developed a method to detect large insertions and deletions (indels), which have been generally understudied. Leveraging this framework, we performed a comprehensive analysis of single nucleotide variants and small and large indels across 1,960 Mtb clinical isolates. Comparing the distribution of variants demonstrated that gene disruptive variants are underrepresented in genes essential for bacterial survival. An evolutionary analysis revealed that Mtb genomes are enriched in partially deleterious mutations. Genome-wide association studies identified small and large deletions in eccB2 significantly associated with patient prognosis. Additionally, we unveil significant associations with antibiotic resistance in 23 non-canonical genes. Among these, large indels are primarily found in genetic regions of Rv1216c, Rv1217c, fadD11, and ctpD. This study provides a comprehensive catalog of genetic variations and highlights their potential impact for the future treatment and risk prediction of tuberculosis.
结核病是由结核分枝杆菌(Mtb)引起的一种疾病,是世界性的重大健康问题。在这里,我们开发了一种检测大插入和大缺失(indels)的方法,但对这些问题的研究普遍不足。利用这一框架,我们对 1,960 株 Mtb 临床分离株中的单核苷酸变异和大小吲哚进行了全面分析。比较变异的分布情况表明,基因破坏性变异在细菌生存所必需的基因中所占比例较低。进化分析表明,Mtb基因组富含部分有害变异。全基因组关联研究发现,eccB2的小缺失和大缺失与患者的预后密切相关。此外,我们还揭示了 23 个非经典基因与抗生素耐药性的重要关联。其中,大缺失主要出现在 Rv1216c、Rv1217c、fadD11 和 ctpD 的基因区域。这项研究提供了一个全面的基因变异目录,并强调了它们对结核病未来治疗和风险预测的潜在影响。
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引用次数: 0
Metatranscriptomics-guided discovery and characterization of a polyphenol-metabolizing gut microbial enzyme 元转录组学指导下的多酚代谢肠道微生物酶的发现与表征
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-28 DOI: 10.1016/j.chom.2024.10.002
Minwoo Bae, Chi Le, Raaj S. Mehta, Xueyang Dong, Lindsey M. Pieper, Lorenzo Ramirez, Margaret Alexander, Sina Kiamehr, Peter J. Turnbaugh, Curtis Huttenhower, Andrew T. Chan, Emily P. Balskus
Gut microbial catechol dehydroxylases are a largely uncharacterized family of metalloenzymes that potentially impact human health by metabolizing dietary polyphenols. Here, we use metatranscriptomics (MTX) to identify highly transcribed catechol-dehydroxylase-encoding genes in human gut microbiomes. We discover a prevalent, previously uncharacterized catechol dehydroxylase (Gp Hcdh) from Gordonibacter pamelaeae that dehydroxylates hydrocaffeic acid (HCA), an anti-inflammatory gut microbial metabolite derived from plant-based foods. Further analyses suggest that the activity of Gp Hcdh may reduce anti-inflammatory benefits of polyphenol-rich foods. Together, these results show the utility of combining MTX analysis and biochemical characterization for gut microbial enzyme discovery and reveal a potential link between host inflammation and a specific polyphenol-metabolizing gut microbial enzyme.
肠道微生物儿茶酚脱羟化酶是一个基本未定性的金属酶家族,它通过代谢膳食中的多酚而对人体健康产生潜在影响。在这里,我们使用元转录组学(MTX)来识别人类肠道微生物组中高度转录的儿茶酚脱羟酶编码基因。我们发现了一种普遍存在的、以前未定性的儿茶酚脱羟基酶(Gp Hcdh),它来自于 Gordonibacter pamelaeae,能脱羟基化氢咖啡酸(HCA),这是一种从植物性食物中提取的抗炎性肠道微生物代谢物。进一步的分析表明,Gp Hcdh 的活性可能会降低富含多酚食物的抗炎功效。总之,这些结果表明了将 MTX 分析和生化表征结合起来发现肠道微生物酶的实用性,并揭示了宿主炎症与特定多酚代谢肠道微生物酶之间的潜在联系。
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引用次数: 0
Exclusive enteral nutrition initiates individual protective microbiome changes to induce remission in pediatric Crohn’s disease 纯肠内营养启动个体保护性微生物组变化,诱导小儿克罗恩病病情缓解
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-25 DOI: 10.1016/j.chom.2024.10.001
Deborah Häcker, Kolja Siebert, Byron J. Smith, Nikolai Köhler, Alessandra Riva, Aritra Mahapatra, Helena Heimes, Jiatong Nie, Amira Metwaly, Hannes Hölz, Quirin Manz, Federica De Zen, Jeannine Heetmeyer, Katharina Socas, Giang Le Thi, Chen Meng, Karin Kleigrewe, Josch K. Pauling, Klaus Neuhaus, Markus List, Dirk Haller
Exclusive enteral nutrition (EEN) is a first-line therapy for pediatric Crohn’s disease (CD), but protective mechanisms remain unknown. We established a prospective pediatric cohort to characterize the function of fecal microbiota and metabolite changes of treatment-naive CD patients in response to EEN (German Clinical Trials DRKS00013306). Integrated multi-omics analysis identified network clusters from individually variable microbiome profiles, with Lachnospiraceae and medium-chain fatty acids as protective features. Bioorthogonal non-canonical amino acid tagging selectively identified bacterial species in response to medium-chain fatty acids. Metagenomic analysis identified high strain-level dynamics in response to EEN. Functional changes in diet-exposed fecal microbiota were further validated using gut chemostat cultures and microbiota transfer into germ-free Il10-deficient mice. Dietary model conditions induced individual patient-specific strain signatures to prevent or cause inflammatory bowel disease (IBD)-like inflammation in gnotobiotic mice. Hence, we provide evidence that EEN therapy operates through explicit functional changes of temporally and individually variable microbiome profiles.
纯肠内营养(EEN)是治疗小儿克罗恩病(CD)的一线疗法,但其保护机制尚不清楚。我们建立了一个前瞻性儿科队列,以描述对 EEN(德国临床试验 DRKS00013306)无效的 CD 患者粪便微生物群的功能和代谢物变化。综合多组学分析从个体可变的微生物组图谱中发现了网络集群,Lachnospiraceae 和中链脂肪酸是保护性特征。生物正交非规范氨基酸标记可选择性地识别对中链脂肪酸有反应的细菌物种。元基因组分析确定了对 EEN 反应的高菌株动态。通过肠道恒温培养和将微生物群转移到无菌的Il10缺陷小鼠体内,进一步验证了饮食暴露粪便微生物群的功能变化。饮食模型条件诱导了患者特异性菌株特征,以预防或导致非生物小鼠发生类似炎症性肠病(IBD)的炎症。因此,我们提供的证据表明,EEN疗法是通过明确改变时间和个体可变的微生物组特征来发挥作用的。
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引用次数: 0
Vaginal lactobacilli produce anti-inflammatory β-carboline compounds 阴道乳酸菌产生抗炎的β-咔啉化合物
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-17 DOI: 10.1016/j.chom.2024.09.014
Virginia J. Glick, Cecilia A. Webber, Lauren E. Simmons, Morgan C. Martin, Maryam Ahmad, Cecilia H. Kim, Amanda N.D. Adams, Sunghee Bang, Michael C. Chao, Nicole C. Howard, Sarah M. Fortune, Manasvi Verma, Marco Jost, Lalit K. Beura, Michael J. James, Seo Yoon Lee, Caroline M. Mitchell, Jon Clardy, Ki Hyun Kim, Smita Gopinath
The optimal vaginal microbiome is a Lactobacillus-dominant community. Apart from Lactobacillus iners, the presence of Lactobacillus species is associated with reduced vaginal inflammation and reduced levels of pro-inflammatory cytokines. Loss of Lactobacillus-dominance is associated with inflammatory conditions, such as bacterial vaginosis (BV). We have identified that Lactobacillus crispatus, a key vaginal bacterial species, produces a family of β-carboline compounds with anti-inflammatory activity. These compounds suppress nuclear factor κB (NF-κB) and interferon (IFN) signaling downstream of multiple pattern recognition receptors in primary human cells and significantly dampen type I IFN receptor (IFNAR) activation in monocytes. Topical application of an anti-inflammatory β-carboline compound, perlolyrine, was sufficient to significantly reduce vaginal inflammation in a mouse model of genital herpes infection. These compounds are enriched in cervicovaginal lavage (CVL) of healthy people compared with people with BV. This study identifies a family of compounds by which vaginal lactobacilli mediate host immune homeostasis and highlights a potential therapeutic avenue for vaginal inflammation.
最佳的阴道微生物群落是以乳酸杆菌为主的群落。除乳酸杆菌茵外,乳酸杆菌的存在还与阴道炎症的减少和促炎症细胞因子水平的降低有关。乳酸杆菌优势的丧失与炎症有关,如细菌性阴道病(BV)。我们发现,脆片乳杆菌是一种重要的阴道细菌,它能产生一系列具有抗炎活性的β-咔啉化合物。这些化合物能抑制原代人体细胞中多种模式识别受体下游的核因子κB(NF-κB)和干扰素(IFN)信号传导,并能显著抑制单核细胞中 IFN 受体(IFNAR)的活化。在生殖器疱疹感染的小鼠模型中,局部应用抗炎的β-咔啉化合物perlolyrine足以显著减轻阴道炎症。与 BV 患者相比,健康人的宫颈阴道灌洗液(CVL)中富含这些化合物。这项研究确定了阴道乳酸杆菌介导宿主免疫平衡的化合物家族,并强调了治疗阴道炎症的潜在途径。
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引用次数: 0
Gut symbiont-derived anandamide promotes reward learning in honeybees by activating the endocannabinoid pathway 源自肠道共生菌的安乃近通过激活内源性大麻素途径促进蜜蜂的奖赏学习
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-16 DOI: 10.1016/j.chom.2024.09.013
Zhaopeng Zhong, Xiaohuan Mu, Haoyu Lang, Yueyi Wang, Yanling Jiang, Yuwen Liu, Qian Zeng, Siyuan Xia, Baotong Zhang, Zilong Wang, Xiaofei Wang, Hao Zheng
Polyunsaturated fatty acids (PUFAs) are dietary components participating in neurotransmission and cell signaling. Pollen is a source of PUFAs for honeybees, and disruptions in dietary PUFAs reduce the cognitive performance of honeybees. We reveal that gut bacteria of honeybees contribute to fatty acid metabolism, impacting reward learning. Gut bacteria possess Δ-6 desaturases that mediate fatty acid elongation and compensate for the absence of honeybee factors required for fatty acid metabolism. Colonization with Gilliamella apicola, but not a mutant lacking the Δ-6 desaturase FADS2, increases the production of anandamide (AEA), a ligand of the endocannabinoid system, and alters learning and memory. AEA activates the Hymenoptera-specific transient receptor AmHsTRPA in astrocytes, which induces Ca2+ influx and regulates glutamate re-uptake of glial cells to enhance reward learning. These findings illuminate the roles of gut symbionts in host fatty acid metabolism and the impacts of endocannabinoid signaling on the reward system of social insects.
多不饱和脂肪酸(PUFA)是参与神经传递和细胞信号传导的膳食成分。花粉是蜜蜂的多不饱和脂肪酸来源之一,而膳食中的多不饱和脂肪酸会降低蜜蜂的认知能力。我们发现,蜜蜂的肠道细菌有助于脂肪酸代谢,从而影响奖励学习。肠道细菌拥有介导脂肪酸伸长的Δ-6去饱和酶,可弥补蜜蜂脂肪酸代谢所需因子的缺失。蜜蜂定殖 Gilliamella apicola(但不是缺乏 Δ-6 去饱和酶 FADS2 的突变体)会增加内源性大麻素系统的配体--anandamide(AEA)的产生,并改变学习和记忆。AEA能激活星形胶质细胞中的蝶呤特异性瞬时受体AmHsTRPA,从而诱导Ca2+流入并调节胶质细胞对谷氨酸的再摄取,从而提高奖赏学习能力。这些发现阐明了肠道共生体在宿主脂肪酸代谢中的作用以及内源性大麻素信号对社会性昆虫奖赏系统的影响。
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引用次数: 0
SINE RNA of the imprinted miRNA clusters mediates constitutive type III interferon expression and antiviral protection in hemochorial placentas 印迹 miRNA 簇的 SINE RNA 在血胎中介导组成型 III 型干扰素的表达和抗病毒保护
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-12 DOI: 10.1016/j.chom.2024.10.003
Ishani Wickramage, Jeffrey VanWye, Klaas Max, John H. Lockhart, Ismet Hortu, Ezinne F. Mong, John Canfield, Hiran M. Lamabadu Warnakulasuriya Patabendige, Ozlem Guzeloglu-Kayisli, Kimiko Inoue, Atsuo Ogura, Charles J. Lockwood, Kemal M. Akat, Thomas Tuschl, Umit A. Kayisli, Hana Totary-Jain
(Cell Host & Microbe 31, 1185–1199.e1–e10; July 12, 2023)
(Cell Host & Microbe 31, 1185-1199.e1-e10; July 12, 2023)。
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引用次数: 0
Hospitalization throws the preterm gut microbiome off-key 住院治疗使早产儿肠道微生物群失调
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.chom.2024.09.009
Jing Qian, Emily N. Yeo, Matthew R. Olm
Environmental exposures substantially influence the infant gut microbiome. In this issue of Cell Host & Microbe, Thänert et al.1 characterize how medical interventions in the neonatal intensive care unit (NICU) shape gut microbiome dynamics in the first months of life by analyzing over 2,500 fecal samples with metagenomics and metatranscriptomics.
环境暴露会对婴儿肠道微生物组产生重大影响。在本期《细胞宿主与amp; 微生物》(Cell Host & Microbe)杂志上,Thänert 等人1 通过元基因组学和元转录组学分析了 2500 多份粪便样本,描述了新生儿重症监护室(NICU)的医疗干预措施如何影响婴儿出生后最初几个月的肠道微生物组动态。
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引用次数: 0
Gut microbiome and bladder cancer: A new link through nitrosamine metabolism 肠道微生物群与膀胱癌:亚硝胺代谢的新联系
IF 30.3 1区 医学 Q1 MICROBIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.chom.2024.09.003
Sridhar Mani
A recent Nature paper1 reveals that gut microbes metabolize N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) into the bladder carcinogen N-n-butyl-N-(3-carboxypropyl)-nitrosamine (BCPN) in the intestines, establishing a direct link between gut microbial activity and the development of bladder cancer.
最近的一篇《自然》(Nature)论文1 揭示,肠道微生物会在肠道中将 N-丁基-N-(4-羟基丁基)-亚硝胺(BBN)代谢为膀胱致癌物 N-丁基-N-(3-羧基丙基)-亚硝胺(BCPN),从而建立了肠道微生物活动与膀胱癌发病之间的直接联系。
{"title":"Gut microbiome and bladder cancer: A new link through nitrosamine metabolism","authors":"Sridhar Mani","doi":"10.1016/j.chom.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.chom.2024.09.003","url":null,"abstract":"A recent <em>Nature</em> paper<span><span><sup>1</sup></span></span> reveals that gut microbes metabolize N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) into the bladder carcinogen N-<em>n</em>-butyl-N-(3-carboxypropyl)-nitrosamine (BCPN) in the intestines, establishing a direct link between gut microbial activity and the development of bladder cancer.","PeriodicalId":9693,"journal":{"name":"Cell host & microbe","volume":null,"pages":null},"PeriodicalIF":30.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385766","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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