Defining the role of S1p and myeloid cells during enterotoxigenic B. fragilis infection

定义 S1p 和骨髓细胞在产肠毒素脆弱拟杆菌感染过程中的作用

• 批准号: 10493352
• 负责人: Zhong-Bin Deng
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493352
• 关键词: Acetyl Coenzyme A; Acute Diarrhea; Anaerobic Bacteria; ApcMin/+ mice; Bacteroides fragilis; Cell Proliferation; Cell physiology; Cells; Cellular Metabolic Process; Ceramidase; Ceramides; Colitis; Colon; Colonic inflammation; Colorectal Cancer; Data; Development; Diet; Dinoprostone; Disease; Environment; Enzymes; Epithelial; Epithelial Cells; Fatty Acids; General Population; Genes; Histone Acetylation; Human; ITGAM gene; Immune; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Interleukin-17; Intestines; Lead; Link; Lipids; Liver; Lymphocyte Function; Metabolic; Metabolism; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Nuclear; PPAR gamma; PTGS2 gene; Pathogenesis; Pathway interactions; Phosphorylation; Production; Property; Proteins; Reaction; Regulation; Role; Shapes; Signal Transduction; Sphingolipids; Sphingosine; Steroids; Testing; Therapeutic; Toxin; Translating; blood glucose regulation; cell motility; colon tumorigenesis; dietary sphingolipids; extracellular; gene induction; granulocyte; gut bacteria; gut dysbiosis; gut inflammation; histone modification; intestinal epithelium; lipid metabolism; microbial; migration; monocyte; new therapeutic target; polarized cell; promoter; recruit; response; sphingosine 1-phosphate; sphingosine kinase; tumorigenesis

Enterotoxigenic Bacteroides fragilis (ETBF) has been associated with acute diarrheal, inflammatory bowel disease, and colorectal cancer (CRC). ETBF oncogenesis requires the coordinated action of its toxin, BFT, and an inflammatory response to orchestrate the recruitment of myeloid cells, but how ETBF recruits colonic myeloid cells remains poorly understood. S1p acts as bioactive sphingolipid messengers, influencing the myeloid cells migration and regulating colonic inflammation. However, whether ETBF integrates sphingolipid metabolites to determine the metabolism of colonic myeloid cells needs to be explored. Recent evidence indicates that remodeling of myeloid cells metabolism is central to the induction of innate immune response. We found ETBF infection alters the activity of sphingosine kinase, which is linked to metabolic remodeling, histone acetylation and PGE2 production in myeloid cells. Two integrated specific aims are proposed to test: Aim 1 will determine how ETBF infection regulates inflammatory myeloid cells accumulation in the colon. Aim 2 will determine if ETBF alteration of acetyl-CoA contributes to metabolic remodeling in myeloid cells via PPARγ activation. Deeper understanding of the proper role of sphingolipids and their enzymes in controlling the intestinal immune properties and in promoting the pathogenesis and progression of colitis will generate new perspectives in the development of “sphingolipid-centered” therapeutic strategies that control the onset and perpetuation of the ETBF-induced gut inflammation.

产肠毒素脆弱类杆菌（ETBF）与急性腹泻有关， 炎症性肠病和结肠直肠癌（CRC）。ETBF肿瘤发生需要 其毒素BFT和炎症反应的协调作用，以协调招募 但是ETBF如何募集结肠髓样细胞仍然知之甚少。S1p行为 作为生物活性的鞘脂信使，影响骨髓细胞的迁移和调节 结肠炎然而，ETBF是否整合了鞘脂代谢产物来确定 结肠髓样细胞的代谢需要探索。最近的证据表明， 髓样细胞代谢的重塑是诱导先天免疫应答的关键。 我们发现ETBF感染改变了鞘氨醇激酶的活性，这与代谢有关。 骨髓细胞中的重塑、组蛋白乙酰化和PGE2产生。两个综合具体 目的1将确定ETBF感染如何调节炎症 骨髓细胞在结肠中积聚。目的2将确定乙酰辅酶A的ETBF改变是否 通过PPARγ活化促进髓样细胞的代谢重塑。更深刻的认识 鞘脂及其酶在控制肠道免疫中的适当作用 性质和促进结肠炎的发病和进展将产生新的 “以鞘脂为中心”的治疗策略，控制 ETBF诱导的肠道炎症的发作和持续。