 So our research question is, how much does the genetic makeup of a person determine the composition of the gut microbiome? And this is important because we know that the gut microbiome influences various disease states and paramount amongst those is metabolic disease and obesity. And if we can understand how the microbiome is shaped, it gives us a novel therapeutic target in addressing these chronic inflammatory diseases such as metabolic syndrome, type 2 diabetes and obesity and associated diseases. So when we think about what determines the composition of the gut microbiome, we know that environmental influences and these include diet and lifestyle are very very important. But we knew almost nothing about the genetic composition of the individual and how that affects the microbiome and that is what we were interested in finding out. How much does host genetics influence the microbiome and which specific components of the microbiome respond to differences in the genetic composition between individuals? Our approach was to use as a classical genetics approach, which is to study human twins and you can use the fact that identical twins which are of course born at the same time share the same genome comparing those to fraternal twins born at the same time which share only half of a genome because they're more like normal brothers and sisters. So we teamed up with the Twins UK Registry, which is run out of Kings College London and they have a population of 15,000 twins that they work with and they asked their participants if they were interested in working with us on this particular study and if they were to provide us with a stool sample. So we received stool samples from over a thousand twin pairs. Some of them provided several stool samples so we could actually look at stability over time. And what we do then is take the stool sample, extract the DNA and sequence the 16S ribosomal RNA gene diversity in that sample. What this gene is is the gene that's contained on the bacterial or a kale chromosome and you can think of it as a barcode that tells you what kind of bacterium that is. So for each sample we generate on the order of 80,000 of these sequences and when we look through the sequences it's a big mix of sequences of different variations and you can tell what types of bacteria were there and in what relative proportion. So now for each of the several thousand stool samples belonging to these twins we have what type of bacteria there and in what proportion and that's the information that we use to compare the microbiomes of the twins. So the first finding was a list of the microbes in the gut that are heritable, meaning when you look in the identical twins you get more similar levels than when you look in the fraternal twins. That means there's a genetic component to their abundances. So there's something in the human genome that is setting the levels of these particular taxa now that are in this list. Now the very top of the list is a family of bacteria called the chrysosine liaceae and if you look at the other members of the list what we found is they co-occur together and the family chrysosine liaceae and the members of that family are at the set there the key players there at the center of this group of bacteria. So that was also very interesting to us that the things that are genetically determined by the host also tend to co-occur. The third finding was we found that if you look at the lean versus obese individuals in our study the lean individuals on average had more of this consortium. So they had more of the chrysosine liaceae family and the things that it co-occur is with. And finally we looked in previously published data sets and looked to see where these taxa had been seen before where these bacteria had been seen before in other studies and what we're finding is that it's a general theme that there's more of these in lean people. So it wasn't just in our population but if you look in other studies, other populations chrysosine liaceae and the things that it co-occurs with are generally more abundant in lean people than obese people. So here we have this association between chrysosine liaceae the things that co-occurs with this nice consortium and a lean phenotype in the humans and we want to ask if this is a causal relationship or not. So we turn to using germ-free animals to test this. Now germ-free mice is what we use are born and raised aseptically in bubbles in the laboratory. So everything that they experience is sterilized. The air is sterilized, the water is sterilized, the food is sterilized, the bedding is sterilized and amazingly enough they can live this way without any microbes whatsoever. And this gives us an opportunity to now inoculate them with the microbes that we want in order to see what happens to the physiology of the animal. And what we did was we took a fecal sample from an obese donor that lacked the chrysosine liaceae and we gave that to a number of mice. And then we took the exact same fecal samples and we added a cultured member of the family. We added chrysosine laminuta that we grew in the laboratory. We added that to the the fecal sample from the obese donor and we gave that to mice. So you have mice that just get fecal material from the obese donor and then mice that have chrysosine laminuta added to it. Those that got chrysosine laminuta added to it are thinner than those that don't get the chrysosine laminuta supplement. So now this is showing us that just by adding this bacterium in we can see a change in the adiposity or the body composition of the animals. And that tells us that there's a direct causal relationship between the presence of the chrysosinella and the body fat content of the host that has that in its gut. So we started out this research asking how do human genes influence the composition of the microbiome. And what we ended up was finding that the genes influence the composition of the microbiome which then influence phenotype. In this case body complex body fat composition and what what it means for us I think is that instead of thinking that genes influence body composition maybe directly that they're working through the microbiome. And the microbiome is something that's easy to get at and it's might be it's certainly much easier to alter than the human genome itself. And so if you're an individual that has a genotype that gives you a low level of chrysosinella for instance it might be very easy to just take chrysosinella as an oral supplement in order to make you look like someone that's genetically with a higher level of chrysosinella and that might help you maintain or promote or a lean phenotype it might it might perhaps help with weight maintenance weight loss we don't know yet these attests we still have to maybe try to carry out in humans. So for us to follow up on this work there's a couple of different ways we're following up. Of course the scientists we'd like to understand the mechanism. So we're conducting studies in mice to understand how chrysosinella leads to a leaner phenotype in the in the mouse model. Of course we're very interested in whether or not this could be useful in humans for an aid in weight loss or weight maintenance and so we are planning to try to perhaps give chrysosinella as a probiotic in people and starting with safety trials and so on and moving this into translational research and perhaps human health in the end and using developing this bacterium as a probiotic which might be simple maybe you just take it or it might need its partners and so we need to understand which of its partners in the consortium might need to go with it and how to support them once they're given to an individual.