Endogenous and Dietary Sphingolipids as Modulators in Inflammatory Bowel Disease

内源性和膳食鞘脂作为炎症性肠病的调节剂

基本信息

批准号：
10222659
负责人：
JULIE D SABA
金额：
$ 36.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222659
关键词：
Address Affect Anabolism Anti-Inflammatory Agents Antibodies Antioxidants Biochemical Catabolism Cell physiology Cell surface Cells Chemicals Chemopreventive Agent Chronic Citrobacter rodentium Coculture Techniques Colitis Colon Colon Carcinoma Computing Methodologies Crohn&apos s disease Development Disease Enterocytes Enzymes Epithelial Exhibits Food Future Genetic Glutathione Goals Human Resources Human body Immune Immune response Immunity Incidence Infection Inflammation Inflammatory Inflammatory Bowel Diseases Injury Interleukin-10 Intestines Knock-out Knockout Mice Lead Leukocytes Lipids Lyase Measures Mediating Medical Metabolic Metabolism Modeling Monitor Mus Organ Pathogenesis Pathway interactions Piroxicam Plants Platelet Activating Factor Platelet Activating Factor Activation Population Process Production Property Proteins Reactive Oxygen Species Risk Role SPHK1 enzyme STAT3 gene Sampling Signal Pathway Signal Transduction Source Sphingolipids Sphingosine-1-Phosphate Receptor Stimulus Stress Symptoms T cell differentiation T cell therapy T-Cell Proliferation T-Lymphocyte Testing Tight Junctions Time Tissues Ulcerative Colitis base carcinogenesis carcinogenicity colon cancer risk comparative cytokine dietary sphingolipids experience experimental study gastrointestinal epithelium gastrointestinal symptom gut homeostasis gut microbiome immune activation immune function in vitro Assay in vivo inflammatory disease of the intestine inhibitor/antagonist liquid chromatography mass spectrometry lymphocyte trafficking metabolic profile metabolome metabolomics microbial microbiome analysis microbiome composition microbiota novel oxidant stress platelet activating factor receptor prevent receptor recruit response site-1 protease sphingadienes sphingosine 1-phosphate sphingosine-1-phosphate lyase tissue injury tool development trafficking

项目摘要

Inflammatory bowel disease (IBD) is a chronic condition caused by disruption of innate and adaptive immune mechanisms that normally maintain gut homeostasis. IBD also predisposes to the development of colitis- associated colon cancer (CAC). Elucidating mechanisms underlying the development and persistence of IBD could lead to new medical strategies to treat IBD and prevent CAC. Metabolism of sphingolipids is a major activity of gut epithelium that becomes dysregulated in inflamed tissues and is implicated in the pathogenesis of both IBD and CAC. Nonetheless, how sphingolipids mechanistically contribute to IBD development is poorly understood. Within enterocytes, sphingosine kinase 1 (SK1) can metabolize endogenous sphingolipids as well as mammalian dietary sphingolipids, leading to the formation of the bioactive molecule sphingosine-1- phosphate (S1P). S1P regulates lymphocyte trafficking and promotes inflammation and carcinogenesis by signaling through its receptors (S1PR1-5) and by activating STAT3 and NFκB. S1P lyase (SPL), an essential enzyme that is highly expressed in healthy enterocytes, irreversibly degrades S1P, keeping gut S1P levels low. However, SK1 is upregulated during inflammation, and SPL activity is hampered by oxidant stress. These changes result in accumulation of S1P. We generated tissue-specific SPLGutKO mice lacking SPL only in enterocytes. SPLGutKO mice have high gut S1P levels and provide a model for investigating S1P's role in colitis. Using both chemical and infectious models of colitis, we found that SPL inactivation in gut epithelium promotes colitis/CAC. We provide additional evidence that SPLGutKO mice exhibit alterations in immune cell trafficking to the gut, breach of the gut epithelial barrier, and profound changes in the metabolic profiles of gut tissues in the absence of an inflammatory stimulus. Specifically, we observed high levels of platelet activating factor (PAF) and depletion of glutathione (GSH) in SPLGutKO mouse intestines. PAF promotes leukocyte recruitment, activation and reactive oxygen species (ROS) formation through activation of the PAF receptor (PAFR). GSH is the main intracellular antioxidant needed to protect gut epithelium against ROS-mediated injury. Thus, the two key metabolic changes we observed in SPLGutKO mice could enhance oxidant stress while rendering the gut defenseless against that stress. Based on our findings, we hypothesize that sphingolipids influence the development of colitis by perturbing PAF and GSH metabolism, thereby altering immune cell trafficking and epithelial barrier integrity. To test this central hypothesis, we propose three Specific Aims: 1) Establish how sphingolipids perturb the gut metabolome; 2) Determine how sphingolipids facilitate immune cell trafficking to the gut; 3) Elucidate how sphingolipids compromise gut epithelial barrier integrity. By determining how sphingolipids influence gut metabolism of PAF and GSH, and testing causal relationships between sphingolipids, PAF, GSH, gut immune cell trafficking, and gut epithelial barrier functions, we will clarify how sphingolipid metabolism promotes colitis and, alternatively, how this pathway can be targeted to treat IBD.

炎症性肠病 (IBD) 是一种由先天性和适应性免疫系统破坏引起的慢性疾病通常维持肠道稳态的机制也容易导致结肠炎的发生。相关结肠癌 (CAC) 的发展和持续存在的机制。鞘脂代谢是治疗 IBD 和预防 CAC 的新医学策略。肠道上皮细胞的活性在发炎组织中失调并与发病机制有关然而，对于 IBD 和 CAC 的研究，鞘脂如何促进 IBD 发展尚不清楚。据了解，在肠细胞内，鞘氨醇激酶 1 (SK1) 也可以代谢内源性鞘脂。作为哺乳动物膳食鞘脂，导致生物活性分子 sphingosine-1- 的形成磷酸盐 (S1P) 通过调节淋巴细胞运输并促进炎症和癌变。通过其受体 (S1PR1-5) 并通过激活 STAT3 和 NFκB（SPL）（一种重要的物质）来传递信号。这种酶在健康肠细胞中高表达，不可逆地降解 S1P，使肠道 S1P 水平保持较低水平。然而，SK1 在炎症过程中上调，并且 SPL 活性受到氧化应激的阻碍。我们生成了仅在缺乏 SPL 的组织特异性 SPLGutKO 小鼠中。 SPLGutKO 小鼠肠道 S1P 水平较高，为研究 S1P 在结肠炎中的作用提供了模型。使用结肠炎的化学和感染模型，我们发现肠道上皮中的 SPL 失活促进我们提供了额外的证据表明 SPLGutKO 小鼠表现出免疫细胞运输的改变。肠道、肠道上皮屏障的破坏以及肠道组织代谢谱的深刻变化具体来说，我们观察到高水平的血小板活化因子（PAF）。 SPLGutKO 小鼠肠道中谷胱甘肽 (GSH) 的消耗促进白细胞募集，通过激活 PAF 受体 (PAFR) 来激活和形成活性氧 (ROS)。是保护肠上皮免受 ROS 介导的损伤所需的主要细胞内抗氧化剂。我们在 SPLGutKO 小鼠中观察到的两个关键代谢变化可以增强氧化应激，同时使根据我们的研究结果，我们的肠道对这种压力毫无抵抗力，我们发现鞘脂会影响这种压力。通过扰乱 PAF 和 GSH 代谢从而改变免疫细胞来发展结肠炎为了检验这一中心假设，我们提出了三个具体目标：1) 确定鞘脂如何扰乱肠道代谢组 2) 确定鞘脂如何促进免疫细胞转运至肠道；3) 通过测定阐明鞘脂如何损害肠道上皮屏障完整性。鞘脂如何影响 PAF 和 GSH 的肠道代谢，并测试两者之间的因果关系鞘脂、PAF、GSH、肠道免疫细胞运输和肠道上皮屏障功能，我们将阐明如何鞘脂代谢会促进结肠炎，以及如何靶向该途径来治疗 IBD。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fifty years of lyase and a moment of truth: sphingosine phosphate lyase from discovery to disease.

裂解酶的五十年历史和关键时刻：磷酸鞘氨醇裂解酶从发现到疾病。

DOI：
发表时间：
2019-03
期刊：
影响因子：
6.5
作者：
Saba; Julie D
通讯作者：
Julie D

MRI Spectrum of Brain Involvement in Sphingosine-1-Phosphate Lyase Insufficiency Syndrome.

1-磷酸鞘氨醇裂解酶不足综合征脑部参与的 MRI 谱。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Martin, K W;Weaver, N;Alhasan, K;Gumus, E;Sullivan, B R;Zenker, M;Hildebrandt, F;Saba, J D
通讯作者：
Saba, J D

Mouse Liver Compensates Loss of Sgpl1 by Secretion of Sphingolipids into Blood and Bile.

小鼠肝脏通过将鞘脂分泌到血液和胆汁中来补偿 Sgpl1 的损失。

DOI：
发表时间：
2021-09-30
期刊：
影响因子：
5.6
作者：
Spohner, Anna Katharina;Jakobi, Katja;Trautmann, Sandra;Thomas, Dominique;Schumacher, Fabian;Kleuser, Burkhard;Lütjohann, Dieter;El;Grösch, Sabine;Pfeilschifter, Josef;Saba, Julie D;Meyer Zu Heringdorf, Dagmar
通讯作者：
Meyer Zu Heringdorf, Dagmar

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation.

磷酸鞘氨醇裂解酶不足综合征对补充维生素 B6 辅因子的反应。

DOI：
发表时间：
2020-09
期刊：
影响因子：
4.2
作者：
Zhao, Piming;Liu, Isaac D;Hodgin, Jeffrey B;Benke, Peter I;Selva, Jeremy;Torta, Federico;Wenk, Markus R;Endrizzi, James A;West, Olivia;Ou, Weixing;Tang, Emily;Goh, Denise Li;Tay, Stacey Kiat;Yap, Hui;Loh, Alwin;Weaver, Nicole
通讯作者：
Weaver, Nicole

Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism.

磷酸鞘氨醇裂解酶不足综合征（SPLIS）：一种新的鞘脂代谢先天性错误。