Lachnospiraceae in the gut microbiome and their role in disease

肠道微生物组中的毛螺菌科及其在疾病中的作用

• 批准号: BB/V001876/1
• 负责人: Daniel Wall
• 金额: $ 56.73万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV001876%2F1
• 关键词: Lachnospiraceae; gut; microbiome; their; role

Despite the gut microbiome being linked to numerous diseases, fundamental questions remain regarding how it influences mammalian physiology. Many studies show correlation between gut bacteria and specific diseases, but with little indication of the mechanism by which they may affect disease initiation or progression. Applying the BBSRC approach of Integrative Microbiome Research we have generated exceptional preliminary data by carrying out research that combines the skills, methodologies and expertise from a range of disciplines from within the biosciences and beyond. This has enabled us to begin to understand a unique mechanism by which the gut microbiome can directly influence mammalian health. Our recent work shows how a unique family of bacteria within the mammalian gut, the Lachnospiraceae, produce two molecules (3M-4-TMAB and 4-TMAP) that were unknown until our recent discovery. These molecules were found in every organ in a mouse, even crossing into white matter. Their significance however lies in their structural mimicry of carnitine, a molecule critical to mammalian energy production. Carnitine acts as a carrier molecule, transporting fatty acids into mitochondria where they are burned for energy. However the bacterial molecules we discovered inhibit this process, reducing the amount of energy cells can produce when they are present. This is incredibly significant as the process of energy production in the mitochondria is known to be affected in a number of human diseases including type 2 diabetes and regressive/non-syndromic autism. While we propose an unprecedented input for the gut microbiome into mammalian disease, our recent breakthrough work (in press at Science Advances) and the preliminary data we present here, provide solid evidence for both the systemic presence and inhibitory potential of these molecules. Also the presence of the Lachnospiraceae bacteria that produce these molecules at significantly increased levels in both type 2 diabetes patients and those with regressive autism is well known. We even determined that others have identified the presence of 3M-4-TMAB and 4-TMAP in prior studies of type 2 diabetes and autism, although at the time they were unaware of what these molecules were or their significance. Given our findings we believe that understanding the role of these molecules in mammalian physiology is imperative. We intend in this proposal to;- Firstly, elucidate the means by which these molecules interfere with energy production in the mitochondriaThis will entail detailed studies of their interactions with enzymes linked to this process as well as wider effects these molecules may have on mammalian physiology. We will also check to see if, when they are produced in the intestine, they lead to a reduction in carnitine levels as it may act as a precursor molecule for making 3M-4-TMAB and 4-TMAP. Such a reduction in carnitine levels (as seen in T2D and ASD) would further contribute to a drop in energy production by mammalian cells. We will also test inhibitors against the bacteria to see if we can stop production of 3M-4-TMAB and 4-TMAP, an approach that could lead to future therapeutic interventions in these diseases. - Secondly,we will determine the effects of these molecules on health and disease in mammalian cells and animal modelsWe will use specific cells to see if presence of these molecules induces specific signs of disease. For type 2 diabetes this would be any indication cells are no longer responding to insulin, leading to glucose build up in the blood. In obesity, we would see fat build up in cells as energy generation is blocked, while in regressive ASD stem cells in the brain that require fatty acid breakdown to generate energy would now begin to proliferate rapidly. Our work will then use animals, some lacking a gut microbiome, to test the ability of these molecules to alter mammalian physiology with respect to each disease.

尽管肠道微生物组与许多疾病有关，但关于它如何影响哺乳动物生理学的基本问题仍然存在。许多研究表明肠道细菌与特定疾病之间存在相关性，但很少表明它们可能影响疾病发生或进展的机制。应用 BBSRC 综合微生物组研究方法，我们通过结合生物科学内外一系列学科的技能、方法和专业知识进行研究，生成了出色的初步数据。这使我们能够开始了解肠道微生物组可以直接影响哺乳动物健康的独特机制。我们最近的工作展示了哺乳动物肠道内的一个独特的细菌家族——毛螺菌科——如何产生两种分子（3M-4-TMAB 和 4-TMAP），这两种分子在我们最近的发现之前是未知的。这些分子存在于小鼠的每个器官中，甚至进入白质。然而，它们的重要性在于它们对肉碱的结构模仿，肉碱是一种对哺乳动物能量产生至关重要的分子。肉碱充当载体分子，将脂肪酸运输到线粒体中，在那里脂肪酸被燃烧以获取能量。然而，我们发现的细菌分子会抑制这一过程，从而减少细胞存在时产生的能量。这是非常重要的，因为众所周知，线粒体中的能量产生过程会受到许多人类疾病的影响，包括 2 型糖尿病和退行性/非综合征性自闭症。虽然我们提出肠道微生物组对哺乳动物疾病的影响是前所未有的，但我们最近的突破性工作（在《科学进展》上发表）和我们在此提供的初步数据为这些分子的系统存在和抑制潜力提供了坚实的证据。此外，众所周知，毛螺菌科细菌在 2 型糖尿病患者和患有退行性自闭症患者中产生的这些分子水平显着增加。我们甚至确定其他人在之前的 2 型糖尿病和自闭症研究中已经鉴定出 3M-4-TMAB 和 4-TMAP 的存在，尽管当时他们不知道这些分子是什么或其重要性。鉴于我们的发现，我们相信了解这些分子在哺乳动物生理学中的作用势在必行。我们打算在这项提案中：-首先，阐明这些分子干扰线粒体能量产生的方式，这将需要详细研究它们与与此过程相关的酶的相互作用，以及这些分子可能对哺乳动物生理学产生的更广泛影响。我们还将检查当它们在肠道中产生时是否会导致肉碱水平降低，因为它可能充当制造 3M-4-TMAB 和 4-TMAP 的前体分子。肉碱水平的降低（如 T2D 和 ASD 中所见）将进一步导致哺乳动物细胞能量产生的下降。我们还将测试针对细菌的抑制剂，看看是否可以停止 3M-4-TMAB 和 4-TMAP 的生产，这种方法可能会导致未来对这些疾病的治疗干预。 - 其次，我们将确定这些分子对哺乳动物细胞和动物模型的健康和疾病的影响我们将使用特定的细胞来观察这些分子的存在是否会诱发特定的疾病迹象。对于 2 型糖尿病，这意味着细胞不再对胰岛素做出反应，从而导致血液中葡萄糖积聚。在肥胖症中，我们会看到细胞中脂肪堆积，因为能量产生受到阻碍，而在退行性自闭症谱系障碍中，大脑中需要分解脂肪酸才能产生能量的干细胞现在开始迅速增殖。然后，我们的工作将使用动物（其中一些缺乏肠道微生物组）来测试这些分子改变哺乳动物针对每种疾病的生理机能的能力。