Gut bacterial metallophores in the development and severity of inflammatory bowel disease

肠道细菌金属载体在炎症性肠病的发生和严重程度中的作用

• 批准号: 10411567
• 负责人: Derrick R Samuelson
• 金额: $ 69.33万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411567
• 关键词: Affect; Alleles; Animals; Attention; Bacteria; Biological Process; Cell division; Cell physiology; Cessation of life; Chronic; Clinical; Colitis; Crohn' s disease; DNA biosynthesis; Data; Development; Diet; Dietary Zinc; Dietary intake; Disease; Environmental Risk Factor; Enzymes; Epithelial; Epithelial Cells; Escherichia coli; Extracellular Matrix; Gastrointestinal tract structure; Gene Cluster; Genetic; Harvest; Health; Homeostasis; Human; Immunologic Factors; Impairment; Individual; Inflammation; Inflammatory Bowel Diseases; Intake; Intestinal Fibrosis; Intestines; Knock-in; Knock-in Mouse; Life; Linear Models; Link; Maintenance; Mammals; Mediating; Mediation; Metals; Modeling; Nature; Nutrient; Organoids; Pathogenesis; Pathway interactions; Patients; Permeability; Physiological; Population; Predisposition; Prevalence; Prevention strategy; Production; Protein Biosynthesis; Public Health; Recording of previous events; Regulation; Relapse; Research; Risk; Role; Severities; Severity of illness; Siderophores; Testing; Trace metal; Wild Type Mouse; Zinc; Zinc deficiency; biobank; chemically induced colitis; combat; comorbidity; curative treatments; deprivation; dysbiosis; gastrointestinal; genetic variant; genome sequencing; gut microbiota; immune function; innovation; intestinal epithelium; intestinal homeostasis; microbial; microbial community; microbial composition; microbiota; mouse model; novel; novel therapeutic intervention; pathobiont; public health relevance; role model; small molecule; whole genome; wound healing; yersiniabactin; zinc-binding protein

Zinc (Zn) deficiency has emerged as a growing public health problem. In fact, an estimated 17% of the global population is deficient. Animal studies have demonstrated that even marginal zinc deprivation leads to significantly impairs physiological functions. This is especially true in the gut where zinc is required to maintain intestinal homeostasis. Zn deficiency-mediated loss of intestinal homeostasis and microbial dysbiosis have recently been proposed as major mechanistic pathways for the development and severity of inflammatory bowel disease (IBD). Specifically, Zn deficiency is common in patients with IBD with a prevalence ranging from 15% to 40%, likely due to diet deficits and increased intestinal loss. In addition, a common genetic variant of the Zn transporter ZIP8 (rs13107325; A391T) has been associated with an increased risk of Crohn’s disease. In the context of gastrointestinal health, it is also notable that zinc is also an essential nutrient for bacteria. As such, commensals must compete for and scavenge zinc from their host, which likely further effects the host’s ability to acquire adequate levels of zinc. Bacteria utilize numerous strategies to acquire metal, such as the secretion of small molecules known as metallophores (i.e., siderophores and zincophores). Overgrowth of pathobionts, which express high levels of metallophores, is hypothesized to be one mechanism by which the microbiota contributes to IBD pathogenesis. In this application, we propose a new paradigm in which bacterial metallophore production is a key mechanistic pathway leading to accelerated IBD disease severity/inflammation. Specifically, we hypothesize that IBD disease status is associated with a unique subset of microbial metallophores and further hypothesize that IBD-associated metallophores exacerbate disease severity. Four key findings support this hypothesis: First, humans with the A391T allele have and increased prevalence of IBD and have significantly altered intestinal microbial communities. Second, Zip8 393T-KI mice have increased susceptibility to chemically induced colitis. Third, microbial metallophores are associated with the development of adherent-invasive Escherichia coli (AIEC)-mediated colitis. Fourth, a novel class of zinc transporters (zincophores) are produced by a wide-range of known gastrointestinal bacterial species many of which are over-represented in IBD dysbiosis. To test our hypothesis that bacterial zincophore production is a key mechanistic pathway leading to increased IBD disease severity, we propose three research Aims: Aim 1 will establish cross-talk between host genetics, gut microbial composition, bacterial metallophores, and dietary Zn levels as a link to IBD severity. Aim 2 will determine and characterize the effects of bacterial metallophores on intestinal epithelial health. Aim 3 will seek to validate the association of bacterial metallophores with IBD disease using a well characterized IBD biobank.

锌（Zn）缺乏症已成为日益增长的公共卫生问题。实际上，估计全球17％ 人口不足。动物研究表明，即使是边缘锌剥夺也导致 严重损害身体功能。在需要锌维护的肠道中尤其如此 肠内稳态。 Zn缺乏介导的肠内稳态和微生物营养不良的丧失已有 最近提出，作为炎症性肠发展和严重程度的主要机械途径 疾病（IBD）。特别是，IBD患者常见Zn缺乏症，患病率从15％到 40％，可能是由于饮食定义和肠道损失增加。另外，Zn的常见遗传变异 转运蛋白Zip8（RS13107325; A391T）与克罗恩病的风险增加有关。在 胃肠道健康的背景，还值得注意的是，锌也是细菌的必不可少的营养素。像这样， Cermensals必须竞争他们的主人的竞争并清除锌，这可能会进一步影响主机的能力 获得足够的锌水平。细菌利用许多策略来获取金属，例如分泌 小分子称为金属泳道（即铁载体和锌载体）。病原体的过度生长 表达高水平的金属流量，假设是一种机制 到IBD发病机理。在此应用中，我们提出了一种新的范式，其中细菌是金属球体产生的 是导致IBD疾病严重性/炎症加速的关键机械途径。具体来说，我们 假设IBD疾病状态与微生物金属粒子的独特子集有关 假设与IBD相关的金属泳剂加剧了疾病的严重程度。四个关键发现支持这一点 假设：首先，具有A391T等位基因的人具有IBD的患病率并增加了 肠道微生物群落改变。其次，Zip8 393T-KI小鼠对化学的敏感性提高了 诱发结肠炎。第三，微生物金属粒子与粘附侵入性的发展有关 大肠杆菌（AIEC）介导的结肠炎。第四，产生了一类新型的锌转运蛋白（Zincophores） 通过大量已知的胃肠道细菌种类，其中许多物种在IBD营养不良中代表过多。 为了测试我们的假设，即细菌锌酚产生是一种关键机械途径，导致增加 IBD疾病的严重程度，我们提出了三个研究目的：AIM 1将在宿主遗传学之间建立串扰， 肠道微生物组成，细菌金属粒子和饮食锌水平与IBD严重程度的联系。 AIM 2意志 确定并表征细菌金属粒子对肠上皮健康的影响。 AIM 3将寻求 使用具有良好特征的IBD生物库来验证细菌金属流团与IBD疾病的关联。