Intestinal LPC/LPA modulation of gut microbiota and metabolic disease

肠道 LPC/LPA 对肠道微生物群和代谢疾病的调节

• 批准号: 9354489
• 负责人: David Yiu-Kwan Hui
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9354489
• 关键词: Ablation; Adult; Adverse effects; Atherosclerosis; Bacteroidetes; Cardiovascular Diseases; Cardiovascular system; Child; Choline; Chronic; Clinical; Clinical Data; Consequentialism; Consumption; Data; Development; Diabetes Mellitus; Diet; Dyslipidemias; Effectiveness; Enzymes; Esterification; Fatty Liver; Fatty acid glycerol esters; Gastrectomy; Gastrointestinal tract structure; Genes; Genetic Variation; Goals; High Fat Diet; Hydrolysis; Hyperglycemia; Hyperlipidemia; Inbred Strains Mice; Incidence; Individual; Intervention; Intestines; Knowledge; Lipids; Lipolysis; Liver diseases; Lysophosphatidylcholines; Lysophospholipids; Mediating; Metabolic; Metabolic Diseases; Morbid Obesity; Mus; Nutrient; Obesity; Operative Surgical Procedures; Pancreas; Pharmacology; Phenocopy; Phospholipase A2; Phospholipid Metabolism; Phospholipids; Plasma; Population Heterogeneity; Prevalence; Procedures; Production; Reporting; Resistance; Risk; Role; Testing; Therapeutic; United States; Work; Youth; bariatric surgery; base; diabetes management; disorder risk; experimental study; feeding; glucose tolerance; gut microbiota; improved; lysophosphatidic acid; microbiome; microbiota; mouse model; novel; novel strategies; novel therapeutics; pandemic disease; pre-clinical; public health relevance; response; therapeutic target

PROJECT SUMMARY/ABSTRACT Incidence of obesity continues to escalate in recent years with increasing consumption of high fat meals, leading to significant increase in risk and incidence of metabolic diseases including diabetes and cardiovascular disease. The current strategy for obesity/diabetes management is not optimal with bariatric surgery being the most effective. However, the potential risk of surgical procedures has limited its use to clinically severe obese individuals. Therefore, the development of novel therapeutics that can mimic the metabolic benefits of bariatric surgery is highly desirable. Our earlier studies revealed that inactivation of the group 1b phospholipase A2 (PLA2g1b) gene in mice resulted in metabolic benefits similar to that observed with bariatric surgery, including resistance to high fat diet (HFD)-induced obesity, improved glucose tolerance to alleviate hyperglycemia, and resistance to HFD-induced dyslipidemia. Additional studies revealed that the gut microbiota of Pla2g1b-/- mice also resembled those present in mice with vertical sleeve gastrectomy (VSG) surgery, with both procedures suppressing HFD-induced increase of Firmicutes/Bacteroidetes ratio in the gut microbiota. Interestingly, we also observed significant reduction of PLA2g1b lipolytic products, lysophospholipids (LPC) and lysophosphatidic acid (LPA)/choline, in plasma and along the intestinal tract of mice after VSG surgery. These results indicated that PLA2g1b inactivation and VSG surgery phenocopy each other , with both procedures reducing LPC/LPA/choline levels and altering the gut microbiota to confer metabolic benefits. These data provided strong support for the premise that PLA2g1b inhibition may be a novel therapeutic strategy to recapitulate the metabolic benefits of bariatric surgery. The overall goals of this project are: (i) to identify the mechanism underlying the inter- relationship between PLA2g1b inactivation and bariatric surgery in modulation of the gut microbiota and metabolic disease risk, and (ii) test the hypothesis that pharmacologic PLA2g1b inhibition is a viable strategy for metabolic disease intervention. Aim 1 will test the hypothesis that lipid nutrient metabolites generated by PLA2g1b hydrolysis of luminal phospholipids are responsible for the altered gut microbiota in response to HFD. This aim will identify the specific influence of LPC, LPA, and/or choline in dictating the gut microbiota and metabolic disease risk. Aim 2 will identify the mechanism underlying the sustained metabolic benefits of VSG surgery. This aim will test the hypothesis that VSG surgery elevates intestinal expression of the LPC re- esterification enzyme LPCAT3 to reduce intestinal LPC/LPA/choline levels with the accompanying metabolic benefits. Aim 3 will test the hypothesis that PLA2g1b inhibition reprograms the gut microbiota to reverse and improve obesity and diabetes. A segregating panel of 8 genetically diverse inbred mouse strains will be used to evaluate the effectiveness of PLA2g1b inhibition for obesity/diabetes intervention in a genetically diverse population. Completion of this study will fill a knowledge gap regarding how dietary nutrients modulate the gut microbiota and how modulating nutrient processing in the digestive tract may confer metabolic benefits.

项目概要/摘要 近年来，随着高脂肪饮食的增加，肥胖发生率持续上升， 导致糖尿病和心血管等代谢疾病的风险和发病率显着增加 疾病。当前的肥胖/糖尿病管理策略并非最佳，减肥手术是最佳选择 最有效。然而，外科手术的潜在风险限制了其在临床严重肥胖者中的应用 个人。因此，开发可以模仿减肥的代谢益处的新疗法 手术是非常可取的。我们早期的研究表明，1b 组磷脂酶 A2 失活 (PLA2g1b) 基因在小鼠中产生的代谢益处与减肥手术中观察到的相似，包括 抵抗高脂肪饮食（HFD）引起的肥胖，改善葡萄糖耐量以缓解高血糖，以及 抵抗 HFD 引起的血脂异常。其他研究表明 Pla2g1b-/- 小鼠的肠道微生物群 也类似于接受垂直袖状胃切除术（VSG）手术的小鼠中出现的结果，两种手术 抑制 HFD 诱导的肠道微生物群中厚壁菌门/拟杆菌门比例的增加。有趣的是，我们还 观察到 PLA2g1b 脂肪分解产物、溶血磷脂 (LPC) 和溶血磷脂酸显着减少 VSG 手术后小鼠血浆中和肠道中的 (LPA)/胆碱。这些结果表明 PLA2g1b 失活和 VSG 手术表型相互复制，两种手术都会减少 LPC/LPA/胆碱 水平并改变肠道微生物群以带来代谢益处。这些数据为 前提是 PLA2g1b 抑制可能是一种新的治疗策略，可以概括代谢益处 减肥手术。该项目的总体目标是：（i）确定交互作用背后的机制。 PLA2g1b 失活与减肥手术调节肠道微生物群之间的关系 代谢疾病风险，以及 (ii) 检验药物 PLA2g1b 抑制是一种可行策略的假设 代谢性疾病干预。目标 1 将检验以下假设：脂质营养代谢物由 PLA2g1b 管腔磷脂的水解是 HFD 导致肠道微生物群发生改变的原因。 该目标将确定 LPC、LPA 和/或胆碱在决定肠道微生物群和 代谢性疾病风险。目标 2 将确定 VSG 持续代谢益处的机制 外科手术。这一目标将检验 VSG 手术提高肠道 LPC 表达的假设。 酯化酶 LPCAT3 可降低肠道 LPC/LPA/胆碱水平以及伴随的代谢 好处。目标 3 将检验这样的假设：PLA2g1b 抑制会重新编程肠道微生物群以逆转和 改善肥胖和糖尿病。由 8 种遗传多样性近交小鼠品系组成的分离小组将用于 评估 PLA2g1b 抑制对遗传多样性的肥胖/糖尿病干预的有效性 人口。这项研究的完成将填补有关膳食营养素如何调节肠道的知识空白 微生物群以及调节消化道中的营养处理如何带来代谢益处。