The impact of dietary metals on the gut microbiome and Clostridium difficile infection

膳食金属对肠道微生物组和艰难梭菌感染的影响

• 批准号: 8979956
• 负责人: Joseph Paul Zackular
• 金额: $ 4.1万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979956
• 关键词: Acinetobacter baumannii; Activities of Daily Living; Affect; Antibiotics; Bacteria; Binding; Cessation of life; Clostridium difficile; Complex; Data; Development; Diarrhea; Diet; Diet Modification; Dietary Zinc; Disease; Drug Metabolic Detoxication; Elderly; Future; Gastric Acid; Gastrointestinal Diseases; Gastrointestinal tract structure; Genes; Growth; Healthcare; Homeostasis; Hospitalization; Immune system; Immunity; Incidence; Infection; Infection Control; Leukocyte L1 Antigen Complex; Manganese; Mediating; Metabolism; Metals; Microbe; Modeling; Molecular; Mus; Nutrient; Nutritional; Nutritional status; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Predisposition; Process; Production; Property; Proteins; Recurrence; Reproduction spores; Resistance; Risk Factors; Role; Series; Severities; Staphylococcus aureus; Starvation; Stomach Diseases; Structure; System; Testing; Toxic Megacolon; Variant; Vertebrates; Virulence; Virulence Factors; Virulent; Work; Zinc; Zinc deficiency; antimicrobial; base; chelation; combat; community setting; cost; environmental change; factor C; feeding; immune function; microbial; microbial community; microbiome; mutant; novel therapeutics; pathogen; public health relevance; research study; treatment strategy; uptake; Acinetobacter baumannii; Activities of Daily Living; Affect; Antibiotics; Bacteria; Binding; Cessation of life; Clostridium difficile; Complex; Data; Development; Diarrhea; Diet; Diet Modification; Dietary Zinc; Disease; Drug Metabolic Detoxication; Elderly; Future; Gastric Acid; Gastrointestinal Diseases; Gastrointestinal tract structure; Genes; Growth; Healthcare; Homeostasis; Hospitalization; Immune system; Immunity; Incidence; Infection; Infection Control; Leukocyte L1 Antigen Complex; Manganese; Mediating; Metabolism; Metals; Microbe; Modeling; Molecular; Mus; Nutrient; Nutritional; Nutritional status; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Predisposition; Process; Production; Property; Proteins; Recurrence; Reproduction spores; Resistance; Risk Factors; Role; Series; Severities; Staphylococcus aureus; Starvation; Stomach Diseases; Structure; System; Testing; Toxic Megacolon; Variant; Vertebrates; Virulence; Virulence Factors; Virulent; Work; Zinc; Zinc deficiency; antimicrobial; base; chelation; combat; community setting; cost; environmental change; factor C; feeding; immune function; microbial; microbial community; microbiome; mutant; novel therapeutics; pathogen; public health relevance; research study; treatment strategy; uptake

 DESCRIPTION (provided by applicant): Clostridium difficile is a gram-positive, spore-forming bacterium that causes a wide range of gastrointestinal disorders. Over the past decade, incidence, severity, and costs associated with C. difficile infection (CDI) have increased significantly. Difficulties in treating infections with conventional antibiotics, increasing rates f recurrent infection, and the emergence of hyper-virulent strains underscore the need for investigating new therapeutic strategies. Initiation of CDI is facilitated by disruption of the gut microbiome, most commonly mediated by broad-spectrum antimicrobial treatment, which enables C. difficile colonization and outgrowth. However, the rate of non-antibiotic associated CDI cases are well documented and steadily on the rise. This suggests that a wide range of unexplored factors likely influence susceptibility to CDI. In this proposal, we will explore the impact of the nutrient metal, Zinc (Zn), on CDI. During infection, access to nutrient metals profoundly impacts bacterial replication and virulence factor production. To exploit this, the host produces factors that limit metal availability in a process termed nutritional immunity. One such protein factor, calprotectin (CP), has strong antimicrobial properties mediated by its ability to bind Zn and manganese (Mn). Surprisingly, little work has been done to characterize the contribution of CP-mediated Zn starvation in CDI. Another factor likely impacting Zn availability during infection is diet. Altered dietary Zn levels are associated with decrease immune system function and increased susceptibility to various infections; however, there is a paucity of data on how altered dietary metal levels affect the gut microbiome. Furthermore, the impact of dietary Zn on susceptibility to CDI has yet to be defined. We hypothesize that (i) alterations in dietary metal levels profoundly impact the composition of the gut microbiome and this remodeling affects the susceptibility to C. difficile, (ii) calprotectin (CP) mediated metal sequestration is essential for limiting growth, pathogenesis, and persistence of C. difficile, and (iii) C. difficil adapts to variations in nutrient metal levels through the expression of dedicated gene systems involved in metal uptake, metabolism, and detoxification. We plan to test these three hypotheses through a series of integrated Specific Aims. First, we will define how dietary alterations in nutrient metal levels affect the murine gut microbiome and susceptibility CDI (Aim 1). We will next determine the role for CP-mediated metal starvation in CDI (Aim 2). Finally, we will identify C. difficile gene products that are required for growth and virulence in high or low n conditions (Aim 3). These experiments will elucidate the impact of altered dietary Zn levels on the gut microbiome and CDI. Furthermore, characterization of C. difficile gene products involved in nutrient metal homeostasis will lay the groundwork for future studies focused on understanding how C. difficile acquires nutrients within the host. Together, results from this proposal will lay the groundwork for the development of novel therapeutics strategies for treatment of CDI.

 描述（由适用提供）：艰难梭菌是一种革兰氏阳性，散射形成的细菌，会引起广泛的胃肠道疾病。在过去的十年中，与艰难梭菌感染（CDI）相关的事件，严重程度和成本已大大增加。治疗传统抗生素感染的困难，增加了复发性感染的发生率以及高病毒菌株的出现强调了研究新的治疗策略的需求。 CDI的启动是通过肠道破坏来制备的 微生物组，最常见的是通过广谱抗菌治疗介导的，这可以实现艰难梭菌定植和产物。但是，非抗生素相关的CDI病例的速率已充分记录并悄悄地上升。这表明广泛的意外因素可能会影响对CDI的敏感性。在此提案中，我们将探讨营养金属锌（Zn）对CDI的影响。在感染过程中，获得营养金属会深刻影响细菌复制和病毒因子的产生。为了利用这一点，主机 在称为营养免疫学过程中限制金属可用性的因素。一种这样的蛋白质因子，即钙卫蛋白（CP），具有结合锌和锰（MN）的能力介导的强抗菌特性。令人惊讶的是，几乎没有做过表征CP介导的Zn饥饿的贡献的工作。感染过程中可能影响Zn供应的另一个因素是饮食。饮食锌水平改变与免疫系统功能降低有关，并增加对各种感染的敏感性；但是，关于数据的数据很少 饮食金属水平改变如何影响肠道微生物组。此外，饮食Zn对CDI敏感性的影响尚未定义。 We hypothesize that (i) alterations in dietary metal levels profoundly impact the composition of the gut microbiome and this remodeling affects the susceptibility to C. difficile, (iii) calprotectin (CP) mediated metal sequestration is essential for limiting growth, pathogenesis, and persistence of C. difficile, and (iii) C. difficult adapts to variations in nutrient metal levels through the expression of dedicated gene systems involved in金属摄取，代谢和排毒。我们计划通过一系列集成的特定目标来检验这三个假设。首先，我们将定义营养金属水平的饮食改变如何影响鼠肠道微生物组和敏感性CDI（AIM 1）。接下来，我们将确定CP介导的金属饥饿在CDI中的作用（AIM 2）。最后，我们将确定在高或低条件下生长和病毒所需的艰难梭菌基因产物（AIM 3）。这些实验将阐明饮食锌水平改变对肠道微生物组和CDI的影响。此外，参与营养金属稳态的艰难梭菌基因产物的表征将为未来的研究奠定基础，重点是了解艰难梭菌如何在宿主中获得营养。总之，该提案的结果将为开发用于治疗CDI的新疗法策略的基础。