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

 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（由申请人提供）：艰难梭菌是一种革兰氏阳性、产芽孢细菌，可引起多种胃肠道疾病。在过去的十年中，与艰难梭菌感染 (CDI) 相关的发病率、严重程度和费用有所增加。传统抗生素治疗感染的困难、复发性感染率的增加以及高毒力菌株的出现强调了研究新治疗策略的必要性。肠道的破坏促进了 CDI 的启动 微生物群，最常见的是广谱抗菌治疗，这使得艰难梭菌定植和生长。然而，非抗生素相关的 CDI 病例的发生率有据可查，并且在稳步上升，这表明存在多种未探索的因素。可能影响 CDI 的易感性 在本提案中，我们将探讨营养金属锌 (Zn) 对 CDI 的影响。在感染过程中，营养金属的获取会对细菌的复制和传播产生深远的影响。为了利用这一点，宿主产生毒力因子。 钙卫蛋白 (CP) 是一种通过结合锌和锰 (Mn) 的能力介导的蛋白质因子，可产生限制金属利用率的因子。 CP 介导的锌缺乏可能会影响感染期间锌的利用率，但饮食中锌水平的改变与免疫系统功能下降和对各种感染的易感性增加有关。缺乏相关数据 此外，饮食中的锌对 CDI 易感性的影响尚未明确，(i) 膳食金属水平的改变会深刻影响肠道微生物组的组成，而这种重塑会影响肠道微生物组。对艰难梭菌的易感性，(ii) 钙卫蛋白 (CP) 介导的金属螯合对于限制艰难梭菌的生长、发病机制和持久性至关重要，以及 (iii) 艰难梭菌通过表达涉及金属吸收、代谢和解毒的专用基因系统来适应营养金属水平的变化我们计划通过一系列综合的具体目标来测试这三个假设。水平影响小鼠肠道微生物组和 CDI 易感性（目标 1），接下来我们将确定 CP 介导的金属饥饿在 CDI 中的作用（目标 2）。在高或低 n 条件下生长和毒力所需的产物（目标 3）。这些实验将阐明改变膳食锌水平对肠道微生物组和 CDI 的影响。体内平衡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体内获取营养，该提案的结果将为开发新的治疗策略奠定基础。 C.D.I.