Intestinal LPC/LPA modulation of gut microbiota and metabolic disease

项目摘要/摘要 近年来，随着高脂肪饮食的消费增加，肥胖症的发病率持续上升， 导致包括糖尿病和心血管在内的代谢性疾病的风险和发病率显著增加 疾病。目前的肥胖/糖尿病管理策略并不是最优的，因为减肥手术是 最有效的。然而，外科手术的潜在风险使其仅限于临床上严重的肥胖症。 个人。因此，能够模拟减肥的代谢益处的新疗法的开发 手术是非常可取的。我们早期的研究表明，1b组磷脂酶A2的失活 (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 抵抗高脂饮食(HFD)诱导的肥胖，改善葡萄糖耐量以缓解高血糖，以及 对高脂血症的抵抗力。进一步的研究表明，Pla2g1b-/-小鼠的肠道微生物区系 也类似于接受垂直袖状胃切除(VSG)手术的小鼠，这两种手术都是 抑制HFD引起的肠道微生物区系中Firmicuts/类杆菌比例的增加。有趣的是，我们还 观察到PLA2g1b脂解产物、溶血磷脂(LPC)和溶血磷脂酸显著减少 (LPA)/胆碱，在VSG术后小鼠的血浆和肠道中。这些结果表明， PLA2g1b失活和VSG手术表型相互作用，两种方法都降低了LPC/LPA/胆碱 水平和改变肠道微生物区系以赋予新陈代谢益处。这些数据为经济增长提供了有力支持。 假设PLA2g1b抑制可能是一种新的治疗策略，概括了 减肥手术。这一项目的总体目标是：(1)确定相互关系的基础机制 PLA2g1b失活与减肥手术对肠道微生物区系调控的关系 代谢性疾病风险，以及(Ii)检验药物抑制PLA2g1b是一种可行的策略的假设 代谢性疾病干预。目标1将检验这样一种假设，即由 腔磷脂PLA2g1b的水解是HFD引起肠道微生物区系改变的原因。 这一目标将确定LPC、LPA和/或胆碱在决定肠道微生物区系和 代谢性疾病风险。目标2将确定VSG持续代谢益处的潜在机制 做手术。这一目标将检验这样的假设，即VSG手术提高了肠道LPC Re-1的表达。 酯化酶LPCAT3降低肠道LPC/LPA/胆碱水平及其代谢 福利。目标3将测试假设，PLA2g1b抑制重新编程肠道微生物区系，以逆转和 改善肥胖和糖尿病。一个由8个遗传不同的近交系小鼠品系组成的分离小组将用于 评价PLA2g1b抑制对肥胖/糖尿病干预的遗传多样性的有效性 人口。这项研究的完成将填补关于饮食营养如何调节肠道的知识空白。 微生物区系，以及如何调节消化道中的营养处理可以赋予新陈代谢益处。

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.