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.

项目总结/摘要 近年来，随着高脂肪膳食消费的增加，肥胖症的发病率持续上升， 导致代谢疾病的风险和发病率显著增加，包括糖尿病和心血管疾病 疾病目前的肥胖/糖尿病管理策略并不是最佳的，减肥手术是治疗肥胖的最佳方法。 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症中的应用 个体因此，开发新的治疗方法，可以模拟减肥的代谢益处， 外科手术是非常理想的。我们早期的研究表明，1b族磷脂酶A2的失活 （PLA 2g 1b）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 抵抗高脂饮食（HFD）诱导的肥胖，改善葡萄糖耐量以减轻高血糖症，和 对HFD诱导的血脂异常的抵抗力。进一步的研究表明，Pla 2g 1b-/-小鼠的肠道微生物群 也类似于垂直袖状胃切除术（VSG）的小鼠中存在的那些， 抑制HFD诱导的肠道微生物群中厚壁菌门/拟杆菌门比率的增加。有趣的是，我们也 观察到PLA 2g 1b脂解产物、溶血磷脂（LPC）和溶血磷脂酸显著减少 (LPA)/胆碱，血浆和沿着肠道的VSG手术后的小鼠。这些结果表明 PLA 2g 1b失活和VSG手术彼此表型相似，两种手术均降低LPC/LPA/胆碱 水平和改变肠道微生物群以赋予代谢益处。这些数据有力地支持了 前提是PLA 2g 1b抑制可能是一种新的治疗策略，以概括代谢的好处， 减肥手术该项目的总体目标是：（一）确定相互间的机制， PLA 2g 1b失活和减肥手术在调节肠道微生物群中的关系， 代谢性疾病的风险，和（ii）测试的假设，药理学PLA 2g 1b抑制是一个可行的策略， 代谢性疾病干预。目的1将检验以下假设： 管腔磷脂的PLA 2g 1b水解是响应于HFD改变肠道微生物群的原因。 该目的将确定LPC、LPA和/或胆碱在支配肠道微生物群中的具体影响， 代谢性疾病风险。目标2将确定VSG持续代谢益处的机制 手术这一目的将检验VSG手术提高LPC再表达的肠表达的假设。 酯化酶LPCAT 3降低肠LPC/LPA/胆碱水平，伴随代谢 效益目的3将检验PLA 2g 1b抑制重新编程肠道微生物群以逆转和抑制细胞增殖的假设。 改善肥胖和糖尿病。将使用8个遗传多样性近交系小鼠品系的分离组， 评估PLA 2g 1b抑制对遗传多样性肥胖/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 微生物群以及如何调节消化道中的营养加工可以赋予代谢益处。