Lachnospiraceae in the gut microbiome and their role in disease

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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.