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.

锌缺乏症已成为一个日益严重的公共卫生问题。事实上，估计占全球的17%