Gut Flora metabolism of dietary carnitine and cardiovascular disease

项目摘要 本申请是对标题为“膳食营养素的肠道植物群代谢”的2 R 01 HL 103866的管理补充 肉毒碱和心血管疾病”（关于阿尔茨海默氏症的管理补充剂的NOT-AG-20-034 用于NIH赠款，但不针对阿尔茨海默病）。总体建议的依据是： 认识到肠道微生物群有助于发展和不良后果相关的 心血管疾病（CVD），其他慢性炎症性疾病和TMAO升高的最新发现 阿尔茨海默病（AD）老年受试者以及轻度认知障碍受试者CSF中的水平 损害（MCI）。最近在AD小鼠模型中也报道了TMAO水平升高。一个直接的 肠道微生物群产生的TMAO在MCI或AD的易感性发展中的作用缺乏。肠道微生物- 三甲胺（TMA）的依赖性产生及其在宿主肝脏中转化为三甲胺N-氧化物 （TMAO）被认为在机制上和临床上与CVD的发展相关。在以前的工作中 我们鉴定了饮食胆碱和磷脂酰胆碱转化为TMA和TMAO的微生物参与者， TMAO导致CVD的机制，以及干预和抑制TMAO的方法 胆碱的生成。然而，这些研究的表现也表明，微生物TMA/TMAO 在某些受试者，特别是杂食动物中，肉毒碱的产生可能源于膳食肉毒碱。此外，微生物 和微生物酶机制参与肠道微生物群依赖的TMAO升高， 肉毒碱或富含红肉的饮食与胆碱/磷脂酰胆碱中的微生物参与者不同， 转化为TMA/TMAO。这一行政补充的首要目标是测试是否 饮食中的三甲胺和TMAO生成的肠道微生物代谢增加了MCI的风险， AD，以及TMAO生成途径的治疗干预是否有潜在的希望 对于AD。拟议的研究是多学科的，包括基础， 翻译和人类临床研究。在目标1中，我们将定义元生物的相关性 胆碱-γ-丁酰甜菜碱（gBB）-γ-丁酰甜菜碱-γ-丁酰甜菜碱（gBB）-γ-丁酰甜菜碱途径至MCI， AD通过临床关联研究。在目标2中，我们将探索一种治疗方法， AD动物模型中胆碱依赖性TMA和TMAO的产生以及相关的行为表型。 拟议研究的成功完成将进一步揭示肠道微生物TMAO的潜在作用 MCI和AD发展的途径。它们还将使诊断和 MCI和AD的治疗方法。

Project Summary This application is an Administrative Supplement to 2R01HL103866, entitled "Gut flora metabolism of dietary carnitine and cardiovascular disease" (NOT-AG-20-034 on Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease). The overall proposal is predicated upon the recognition that gut microbiota contribute to both the development and adverse consequences associated with Cardiovascular Disease (CVD), other chronic inflammatory diseases and the recent findings of elevated TMAO levels in the CSF of aging subjects with Alzheimer’s disease (AD), as well as those with mild cognitive impairment (MCI). Elevated TMAO levels have also recently been reported in mouse models of AD. Yet a direct role for gut microbiota-generated TMAO in susceptibility for development of MCI or AD is lacking. Gut microbe- dependent generation of trimethylamine (TMA), and its conversion in the host liver to trimethylamine N-oxide (TMAO), are recognized for being mechanistically and clinically linked to the development of CVD. In prior work we identified microbial participants in conversion of dietary choline and phosphatidylcholine into TMA and TMAO, mechanisms through which TMAO contributes to CVD, and approaches for intervening and suppressing TMAO generation from choline. However, performance of those studies also revealed that microbial TMA/TMAO generation in some subjects, particularly omnivores, can originate from dietary carnitine. Moreover, the microbes and microbial enzymatic machinery involved in gut microbiota-dependent TMAO elevation from either dietary carnitine, or a diet enriched in red meat, are distinct from the microbial participants in choline/phosphatidylcholine conversion into TMA/TMAO. The overarching goal of this administrative supplement is to test whether gut microbial metabolism of dietary trimethylamines and TMAO generation enhances risk for MCI and AD, and whether therapeutic interventions for the TMAO-generating pathway have potential promise for AD. The proposed research studies are multidisciplinary, and encompass a combination of basic, translational and human clinical investigations. In Aim 1 we will define the relevance of the metaorganismal choline  TMA  TMAO and carnitine  gamma-butyrobetaine (gBB)  TMA  TMAO pathway to MCI and AD through clinical association studies. In Aim 2, we will explore a therapeutic approach for inhibiting dietary choline-dependent TMA and TMAO generation, and relevant behavioral phenotypes in an animal model of AD. Successful completion of the proposed studies will further reveal a potential role for the gut microbial TMAO pathway in MCI and AD development. They also will enable potential advances in both diagnostics and therapeutic approaches for MCI and AD.