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

• 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
• 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' 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

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功能紊乱引起的慢性疾病， 正常情况下维持肠道内稳态的机制。IBD也容易导致结肠炎的发展- 相关结肠癌（CAC）。阐明IBD发展和持续的潜在机制 可能导致治疗IBD和预防CAC的新医学策略。鞘脂的代谢是 肠道上皮细胞的活性在发炎组织中变得失调，并与发病机制有关 IBD和CAC。尽管如此，鞘脂如何在机制上促进IBD的发展还不清楚。 明白在肠上皮细胞内，鞘氨醇激酶1（SK 1）也可以代谢内源性鞘脂 作为哺乳动物的饮食鞘脂，导致生物活性分子鞘氨醇-1- 磷酸盐（S1 P）。S1 P调节淋巴细胞运输并促进炎症和癌变， 通过其受体（S1 PR 1 -5）和激活STAT 3和NFκB进行信号传导。S1 P裂解酶（SPL），一种必需的 在健康肠细胞中高度表达的酶，不可逆地降解S1 P，使肠道S1 P水平保持在低水平。 然而，SK 1在炎症过程中上调，SPL活性受到氧化应激的阻碍。这些 变化导致S1 P的积累。我们产生了组织特异性SPLGutKO小鼠，仅在 肠细胞SPLGutKO小鼠具有高肠道S1 P水平，并为研究S1 P在结肠炎中的作用提供了模型。 使用化学和感染性结肠炎模型，我们发现肠上皮细胞中SPL失活促进了结肠炎的发生。 结肠炎/CAC。我们提供了额外的证据，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， 没有炎症刺激。具体来说，我们观察到高水平的血小板活化因子（PAF） 以及SPLGutKO小鼠肠中谷胱甘肽（GSH）的消耗。PAF促进白细胞募集， 通过激活PAF受体（PAFR）激活和活性氧（ROS）形成。GSH 是保护肠上皮细胞免受ROS介导的损伤所需的主要细胞内抗氧化剂。因此 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 对压力毫无抵抗力基于我们的研究结果，我们假设鞘脂影响 通过干扰PAF和GSH代谢，从而改变免疫细胞， 运输和上皮屏障完整性。为了验证这一核心假设，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 3）阐明鞘脂如何损害肠上皮屏障完整性。通过确定 鞘脂如何影响PAF和GSH的肠道代谢，并测试它们之间的因果关系 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 鞘脂代谢促进结肠炎，以及该途径如何靶向治疗IBD。

项目成果

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

• DOI: 10.1002/jimd.12238
• 发表时间: 2020-09
• 期刊: Journal of inherited metabolic disease
• 影响因子: 4.2
• 作者: Zhao P;Liu ID;Hodgin JB;Benke PI;Selva J;Torta F;Wenk MR;Endrizzi JA;West O;Ou W;Tang E;Goh DL;Tay SK;Yap HK;Loh A;Weaver N;Sullivan B;Larson A;Cooper MA;Alhasan K;Alangari AA;Salim S;Gumus E;Chen K;Zenker M;Hildebrandt F;Saba JD
• 通讯作者: Saba JD

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

• DOI: 10.3390/ijms221910617
• 发表时间: 2021-09-30
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Spohner AK;Jakobi K;Trautmann S;Thomas D;Schumacher F;Kleuser B;Lütjohann D;El-Hindi K;Grösch S;Pfeilschifter J;Saba JD;Meyer Zu Heringdorf D
• 通讯作者: Meyer Zu Heringdorf D

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

• DOI: 10.1016/j.jbior.2018.09.004
• 发表时间: 2019-01
• 期刊: Advances in biological regulation
• 作者: Choi YJ;Saba JD
• 通讯作者: Saba JD