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

锌（Zn）缺乏已成为日益严重的公共卫生问题。事实上，据估计， 人口不足。动物研究表明，即使是微量锌缺乏也会导致 严重损害生理功能。这是特别真实的肠道锌是需要维持 肠内稳态锌缺乏介导的肠道稳态丧失和微生物生态失调， 最近被认为是炎症性肠病发展和严重程度的主要机制途径 疾病（IBD）。具体而言，锌缺乏症在IBD患者中很常见，患病率为15%至20%。 40%，可能是由于饮食不足和肠道损失增加。此外，一种常见的遗传变异的锌 转运蛋白ZIP8（rs13107325; A391T）与克罗恩病风险增加相关。在 在胃肠道健康的背景下，还值得注意的是，锌也是细菌的必需营养素。因此，在本发明中， 寄生虫必须从宿主那里竞争和吸收锌，这可能会进一步影响宿主的能力， 获得足够的锌水平。细菌利用多种策略来获取金属，例如分泌 称为金属载体的小分子（即，铁载体和锌载体）。致病菌的过度生长， 表达高水平的金属载体，被假设为微生物群贡献的一种机制。 IBD的发病机制。在这个应用中，我们提出了一个新的范例，其中细菌金属载体的生产 是导致IBD疾病严重程度/炎症加速的关键机制途径。我们特别 假设IBD疾病状态与微生物金属载体独特亚群相关，并进一步 假设IBD相关金属载体加重疾病严重程度。四个关键发现支持这一点 假设：首先，携带A391 T等位基因的人IBD患病率增加，并且与携带A391 T等位基因的人IBD患病率显著相关。 改变肠道微生物群落。第二，Zip8 393T-KI小鼠对化学药物的敏感性增加， 诱发结肠炎。第三，微生物金属载体与粘附-侵袭性的发展相关， 大肠杆菌（AIEC）介导的结肠炎。第四，产生了一类新的锌转运蛋白（锌载体 广泛的已知胃肠道细菌物种，其中许多在IBD生态失调中过度代表。 为了验证我们的假设，即细菌锌载体的产生是导致增加的关键机制途径， IBD疾病的严重程度，我们提出了三个研究目标：目标1将建立宿主遗传学之间的串扰， 肠道微生物组成、细菌金属载体和饮食锌水平与IBD严重程度的关系。目标2将 确定和表征细菌金属载体对肠上皮健康的影响。目标3将寻求 使用充分表征的IBD生物库验证细菌金属载体与IBD疾病的关联。

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.