Lachnospiraceae in the gut microbiome and their role in disease

尽管肠道微生物群与许多疾病有关，但关于它如何影响哺乳动物生理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，但几乎没有迹象表明它们可能通过什么机制影响疾病的发生或发展。应用BBSRC的整合微生物组研究方法，我们通过开展研究，结合了生物科学内外一系列学科的技能、方法和专业知识，产生了特殊的初步数据。这使我们能够开始了解肠道微生物群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中一个独特的细菌家族--Lachnospiraceae--是如何产生两个分子(3M-4-TMAB和4-TMAP)的，这两个分子在我们最近的发现之前是未知的。这些分子在小鼠的每个器官中都有发现，甚至进入了白质。然而，它们的意义在于它们对肉碱的结构模仿，肉碱是一种对哺乳动物能量生产至关重要的分子。肉碱充当载体分子，将脂肪酸输送到线粒体中，在那里它们被燃烧成能量。然而，我们发现的细菌分子抑制了这一过程，减少了细胞在存在时可以产生的能量。这一点非常重要，因为已知线粒体中的能量产生过程在许多人类疾病中受到影响，包括2型糖尿病和退行性/非综合征性自闭症。虽然我们提出了肠道微生物组对哺乳动物疾病的前所未有的输入，但我们最近的突破性工作(在《科学进展》上)和我们在这里提供的初步数据，为这些分子的系统性存在和抑制潜力提供了坚实的证据。此外，在2型糖尿病患者和退化性自闭症患者中，产生这些分子水平显着增加的拉赫诺斯菌科细菌的存在也是众所周知的。我们甚至确定，在之前的2型糖尿病和自闭症研究中，其他人已经确定了3M-4-TMAB和4-TMAP的存在，尽管当时他们并不知道这些分子是什么或它们的意义。鉴于我们的发现，我们认为了解这些分子在哺乳动物生理学中的作用是当务之急。在这项建议中，我们打算；-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这一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产生的更广泛的影响。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的降低，因为它可能作为制造3M-4-TMAB和4-TMAP的前体分子。肉碱水平的这种降低(如在T2D和ASD中所见)将进一步导致哺乳动物细胞的能量产生的下降。我们还将测试针对细菌的抑制剂，看看我们是否可以停止3M-4-TMAB和4-TMAP的生产，这一方法可能导致未来对这些疾病的治疗干预。-其次，我们将在哺乳动物细胞和动物模型中确定这些分子对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导致特定的疾病迹象。对于2型糖尿病来说，这可能是细胞对胰岛素不再有反应的任何迹象，导致血糖在血液中积聚。在肥胖症中，我们会看到脂肪在细胞中积聚，因为能量产生被阻止，而在退化的ASD中，大脑中需要脂肪酸分解才能产生能量的干细胞现在会开始快速增殖。然后，我们的工作将使用动物，其中一些缺乏肠道微生物组，以测试这些分子针对每种疾病改变哺乳动物生理的能力。

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.