Diet driven evolution of epidemic ribotypes of Clostridium difficile

饮食驱动艰难梭菌流行性核糖型的进化

基本信息

批准号：
10291417
负责人：
ROBERT A BRITTON
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-17 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291417
关键词：
Acids Address Affinity Amino Acid Substitution Animal Feed Animals Antibiotics Attenuated Back Biochemistry Centers for Disease Control and Prevention (U.S.)Cessation of life Clostridium difficile Communities Complex Data Diet Disaccharides Disease Disease Outbreaks Disease Outcome Enzymes Epidemic Europe Evolution Family suidae Food Food Additives Food Supplements Food Supply Genes Genetic Genome Glucose Grant Growth Health Care Costs High Prevalence Hospitals Human Ice Cream Infection Intestines Inulin Invaded Journals Knock-out Label Laboratories Link Livestock Medicine Metabolism Modeling Morbidity - disease rate Nature New England Nosocomial Infections Operon Pathogenesis Phosphotransferases Phylogenetic Analysis Physiology Polysaccharides Production Property Proteins Public Health Regulation Reporting Research Ribotypes Role Severity of illness Shellfish Single Nucleotide Polymorphism Starch Sucrose Toxin Trehalose United States Work antibiotic-associated diarrhea arabinogalactan base beef cost dietary emerging pathogen enteric infection fitness fluoroquinolone resistance improved innovation microbiota mortality mouse model mutant pathogen sugar transmission process

项目摘要

The emergence of pathogens that cause increased morbidity and mortality is a major public health concern. Clostridium difficile is a major cause of hospital acquired infection and is the leading cause of antibiotic-associated diarrhea. In the past decade, two epidemic ribotypes (RT027 and RT078) of C. difficile have emerged as major ribotypes in hospital outbreaks around the world despite not being observed at significant levels prior to the year 2000. These ribotypes are associated with increased morbidity and mortality and have been classified as hypervirulent. However, the mechanistic basis for why these strains began to emerge in the early 2000s is unclear. We have found that RT027 and RT078 strains have acquired the ability to grow on the disaccharide trehalose more efficiently than other ribotypes of C. difficile. Our preliminary data shows that the mechanistic bases for the improved growth in these two ribotypes are genetically and mechanistically distinct, suggesting convergent evolution of improved trehalose metabolism in these phylogenetically distinct ribotypes. In addition, we have found that disrupting the ability of a RT027 strain to utilize trehalose dramatically attenuates disease severity, suggesting that trehalose metabolism contributes to the hypervirulent nature of RT027 and RT078 strains. Trehalose, a disaccharide of glucose, became a widely used food supplement after being granted GRAS status approval by the FDA in 2000 and EFSA in Europe in 2001. Trehalose has a number of desirable properties as a sugar additive due to the alpha, alpha 1-1 linkage that is heat and acid stable, which renders it 45% less sweet than sucrose. Normally found in foods such as mushrooms and shellfish, trehalose is now added to numerous food and drink products ranging from ground beef to ice cream. The addition of trehalose to the worldwide food supply coincides with the first reports of RT027 and RT078 strains in the early 2000s, even though these ribotypes were present in hospitals as far back as 1985. We propose that addition of increased levels of trehalose to the food supply has selected for RT027 and RT078 strains due to their ability to more efficiently metabolize trehalose and has contributed to hospital epidemics. We will use two recently developed models in our laboratory, human fecal minibioreactor array model of C. difficile invasion and a humanized microbiota mouse model of C. difficile infection, to study the impact of trehalose and improved trehalose metabolism on the ability of RT027 and RT078 strains to cause C. difficile infection. We will also investigate the mechanistic bases for improved trehalose metabolism of RT027 and RT078 strains. Finally, we will assess what impact improved trehalose metabolism has on colonization dynamics, disease severity and carriage in animals of these hypervirulent C. difficile ribotypes. The following specific aims are proposed: Aim 1. Investigate the mechanism of how trehalose metabolism by C. difficile increases disease severity. Aim 2. Understand the mechanistic basis for improved trehalose metabolism in RT027 C. difficile. Aim 3. Understand the role of the acquired trehalose operon on RT078 fitness and animal carriage. We expect this work will establish a link between the recent addition of trehalose in the human diet and the emergence of epidemic C. difficile ribotypes. This will provide the first direct evidence of the alteration of the human diet directly impacting the pathogenesis of an enteric infection.

导致发病率和死亡率增加的病原体的出现是一个重大的公共卫生问题忧虑。艰难梭菌是医院获得性感染的主要原因，也是导致医院感染的主要原因抗生素相关性腹泻。在过去的十年中，艰难梭菌的两种流行核糖型（RT027和RT078）尽管没有在 2000 年之前的显着水平。这些核糖型与发病率和死亡率增加有关并被归类为高毒力。然而，这些菌株开始传播的机制基础 2000 年代初期出现的情况尚不清楚。我们发现RT027和RT078菌株已经获得了在二糖上生长的能力海藻糖比艰难梭菌的其他核糖型更有效。我们的初步数据表明，机械这两种核糖型改善生长的基础在遗传和机制上是不同的，表明这些系统发育上不同的核糖型中海藻糖代谢改善的趋同进化。此外，我们发现破坏 RT027 菌株利用海藻糖的能力可以显着减轻疾病严重程度，表明海藻糖代谢导致 RT027 和 RT078 的高毒力性质菌株。海藻糖是一种葡萄糖二糖，获得批准后成为广泛使用的食品补充剂 2000 年获得 FDA 批准，2001 年获得欧洲 EFSA 批准。海藻糖具有许多理想的特性由于 α、α 1-1 连接具有热和酸稳定性，因此具有作为糖添加剂的特性甜度比蔗糖低 45%。海藻糖通常存在于蘑菇和贝类等食物中，现在也被发现添加到从碎牛肉到冰淇淋等多种食品和饮料产品中。海藻糖添加到全球食品供应中与 RT027 和 RT027 的首次报告同时发生。 RT078 菌株早在 2000 年代初就已出现，尽管这些核糖体早在 1985 年就已在医院中出现。我们建议选择在食品供应中添加更高水平的海藻糖 RT027 和 RT078菌株由于能够更有效地代谢海藻糖而为医院做出了贡献流行病。我们将在我们的实验室使用两个最近开发的模型，人类粪便微型生物反应器阵列艰难梭菌入侵模型和艰难梭菌感染的人源化微生物群小鼠模型，以研究艰难梭菌感染海藻糖和改善的海藻糖代谢对 RT027 和 RT078 菌株引起艰难梭菌能力的影响。艰难梭菌感染。我们还将研究RT027改善海藻糖代谢的机制基础和RT078菌株。最后，我们将评估改善海藻糖代谢对定植有何影响这些高毒力艰难梭菌核糖型的动态、疾病严重程度和动物携带情况。下列提出了具体目标：目标 1. 研究 C. 代谢海藻糖的机制。艰难梭菌会增加疾病的严重程度。目标 2. 了解改良海藻糖的机制基础 RT027 艰难梭菌中的代谢。目标 3. 了解获得性海藻糖操纵子在 RT078 健身和动物运输车。我们预计这项工作将在最近添加的人类饮食中的海藻糖和流行性艰难梭菌核糖型的出现。这将提供第一个人类饮食改变直接影响肠道感染发病机制的直接证据。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The metabolic profile of Bifidobacterium dentium reflects its status as a human gut commensal.

DOI：
10.1186/s12866-021-02166-6
发表时间：
2021-05-24
期刊：
BMC microbiology
影响因子：
4.2
作者：
Engevik MA;Danhof HA;Hall A;Engevik KA;Horvath TD;Haidacher SJ;Hoch KM;Endres BT;Bajaj M;Garey KW;Britton RA;Spinler JK;Haag AM;Versalovic J
通讯作者：
Versalovic J