 Pilar is the head of genomics and in Fisabio, a research center in Valencia. His talk is entitled, from gut to health, the role of the gut microbiome in non-communicable diseases and microbiome targeted dietary intervention. Thank you very much, Pilar. Thank you. Thank you. Let's see, how do I move the slide? How do I change slides? Yeah, well it was pretty obvious. Sorry about that. Okay, so since this is going to be the first talk about the microbiome, I'm going to introduce a little bit the subject in general. And I like to start broad, so in the sense of realizing that microbiomes actually have co-evolved with pretty much all of living organisms on earth. So we don't have to think about it as something special of the human context, but it's a very common and actually completely widespread in nature. And humans are not the exception. We have quite complex microbiomes that inhabit in different parts of our body. And the gut microbiome is the most complex of all of these microbiomes that live with us. It achieves the highest cell densities recorded for actually any ecosystem on earth, so 10 to the 11th to 10 to the 12th cells per gram of luminal content in the colon. We actually have in our body slightly more cells of bacterial origin than cells of human origin. And it's composed by hundreds of different bacterial species as well as archaea, eukaryotic microbes and viruses. And one of the things that is very interesting and relevant about the microbiome is that it displays a very large variability among individuals. And we do not really understand well yet how to explain this variability. We know that someone is based on age, diet, health, et cetera, but there's still much to learn about it. Most of the bacteria of the gut microbiome inhabit intestinal lumens, so they're separated by a barrier of mucous from the actual epithelial barrier, but some can actually be in relatively close contact to the epithelial mucosa. The reason we're all here and we're so interested in the microbiome is because they're not just there going along with the right with us, but they're actually very important in our physiology. They actually perform a range of complex functions that are beneficial for us. As you would expect intuitively, many have to do with nutrition and metabolism in the sense, well, among other things that they help us digest complex polysaccharides, that otherwise we wouldn't be able to utilize because we don't have the enzymes for it. And so bacteria are capable of breaking these bonds here and transform these into simpler sugars that then we can use and further transform these simple sugars into things like short chain fatty acids, et cetera, that then have actually very important roles in our physiology. But they're also important in many other things. They also offer protection against pathogens. The fact that they're there at these high numbers protects us from pathogens coming in and installing themselves in our gut. They're capable of regulating the development of the tissues in the gut. And very important, they're very, very involved in the modulation of the immune system. The microbiota produces a large variety of molecules that have to do with gut function and actually not only with gut function, but with gut communication with other organs. So as with the famous gut brain axis or in communication, metabolic communication with the adipose tissue, which would be very relevant for obesity and other related topics. And just as a quick summary, I mentioned here some of these important metabolites could be short chain fatty acids, very relevant in a large number of physiological processes. They're provisioned energy to the cells of our epithelium. They're the main source of energy for the epithelial cells. Important role in modulating immunity and inflammatory tone. Other very important products of the gut microbiota are secondary bile acids. Gut microbiota transformed the primary bile acids that our body produced into the secondary bile acids that again have to do then with a lot of different functions. Indals, hormones and neurotransmitters, etc. These are micro-associated molecular patterns, which are some mostly external molecules in the cell walls of the bacteria that are what the immune system is going to recognize. And then there will be lots of responses to that. So as you can see, there's a lot of interactions with many important factors and that can be quite overlapping. So it's a very complex issue that we're dealing with in trying to separate all of these potential influences of the gut microbiota. Another important consequence of this is that of course, if we disturb this community with something like antibiotics for instance, we're going to affect a lot of different things. We're going to increase our susceptibility to infections because we're going to be disrupting this barrier to infection. We're going to disrupt the immune balance. So this can result in lots of different types of immune related diseases. And we're going to also affect many physiological processes that can result in deregulated metabolism and then eventually in obesity, metabolic syndrome, etc. And the problem is that actually our modern lifestyle does indeed affect the composition of the gut microbiome in numerous ways. We've already mentioned use of antibiotics, but that's by no means the only one. As we've heard, many of us have a poor diet. We have in general decreased microbial exposure compared to ancestors because of many reasons, lifestyle reasons especially in childhood. And it's been seen in the last decades that as one Western countries have been able to successfully control many infectious diseases at the same time there's been a very significant rise in other types of diseases such as the non-communicable diseases that we're talking about here. So all types of autoimmune diseases, atopic related diseases, inflammation related diseases have been steadily augmenting in the last decades and these are very likely related phenomena. And so many of these diseases have actually been linked to alterations in the gut microbiome. This does not mean that we know exactly how the alterations in the gut microbiome result in these diseases, but in some cases we do have some clues, but in most cases this is at the state of correlations right now. But there are studies that link alterations in the microbiome to various psychological disorders, to development of cancers, clearly to all types of allergies, cardiovascular disease, obviously obesity and metabolic syndrome, all kinds of autoimmune diseases and inflammatory diseases, NAFLD, liver disease, asthma, etc. In particular this is also very relevant if we look at early childhood because we know that there's factors such as cesarean sections and formula feeding that are have also augmented in Western countries that are very relevant for the actual development of the microbiome and if babies develop an unbalanced microbiome then that can have lifelong influences in the risk of all these kinds of diseases that we've already mentioned. So it is very important in the future to learn to work in ways that are much safer for the microbiome that are not as aggressive to the microbiome so basically learning to use less and better antibiotics and also learning how to modulate the microbiome with strategies that might include diet and probiotics, so foods and food supplements that promote the growth of beneficial bacteria and especially apply these as early as possible because the windows of opportunity for microbiome modulation clearly are going to be best employed in as early as gestation but also during the early years of life. Obviously diet is going to be a very important factor in all of these it's been shown that diet has a very strong influence for instance in risk of allergies in particular the Mediterranean diet in children has been linked with a lower risk of food allergies asthma and atopy and this is thought to be likely related to the high content of fruit cereals in legumes in this diet which are things that have a high content of fiber which one fermented by intestinal bacteria produces butyrate and other short chain fatty acids which as I mentioned are very important products of the gut microbiome for our physiology. Then on the contrary the western diet has been linked with a higher incidence of allergic disease likely as a result of a reduction in the levels of fiber and therefore butyrate. So there are many studies that we could go through here but I would like to focus on what we've been doing here in the project in stands for health. So one of our approaches has been an in vitro approach to trying to understand the effects of food on on gut microbiome so this is something that allows us to look at the effect of specific foods which would be very difficult to disentangle from intervention studies and so what we've done is a very large series of in vitro and the digestion and fermentation experiments using 55 different foods cooked in different ways because one of our main interests has also been related to the effect of cooking methods so up to 159 combinations of foods and different cooking methods and we looked at this with three different individuals each so this actually for for adults and then an even more complex set of experiments for for children and this has allowed us to actually identify some specific bacteria that are modulated by specific foods bacteria that augment or decrease with some specific foods this is a summary of our results one result that is really standing out is that the effect of plant-based foods and the effect of animal-based foods even in vitro is very remarkably different in particular for a particular class of or family rather of bacteria called the lactose piracy which are a very important component of the gut microbiome we see that the effects of animal and plant-based foods are very different so here for instance three main examples where vegetable and animal fats fish and cheese clearly augment this type of bacteria versus vegetables fruits and cereal based foods we've also been able to use this data to try to predict microbial metabolites produce urine food fermentation this is the work of the group of francis that he will be talking about later but we've been able in the project to develop a metabolic network model that predicts the metabolites produced by a person's individual gut microbiota and the nutrients of the nutrients of its specific food and here I'm showing you for instance that in the group of children that we've been analyzing we had children with different health conditions and with this metabolic network model we've been able to detect metabolites that are produced differently by the different groups of children so taking into account their gut composition with in this case with the same nutrients they're clearly producing different series of metabolites so this is the type of information that we need for developing more and more personalized nutrition programs another as I was saying another important aim of our experiments was to try to understand the impact of cooking methods on the effect of foods and the gut microbiome so what we detected in this case is that we got very different results for the three individuals that we that we analyzed so it seems that the effects of cooking methods are going to be highly personalized and this is going to need much more much more research in the future but we clearly were able to find some effects of the different types of cooking methods on the bacteria that were being favored with specific foods so in case I'm just showing a couple of examples for meat we saw that fried meat versus boiled and grilled was favoring different types of bacteria sometimes or actually in all cases we all we only saw this effect in a particular individual here the same for certain tubers we could see effects of a specific type of cooking method fried versus boiled and roasted but these were only detected in one individual so this is likely as I said very personalized very depending on the type of food and also on the individual microbiota so this is going to need a lot of further work this is a bit of a summary of all of our general results so here we're presenting for the three individuals that the most different cooking methods in every case so for instance if we look at meat in the an individual three the largest difference were between boiled meat and roasted meat and these were the bacteria that were differentially abundant in each of these cases so this is the type of data that that we've been gathering and that will be will help refine personalized nutrition programs so in general the main conclusions of this work I would say would be that the composition of the gut microbiota can definitely be altered using specific foods despite degrading their individual variability we saw trends that we definitely could recover in all of the individuals analyzed plant and animal based foods favor very different gut bacteria in particular one of the strongest effects that we saw was an animal fats favors some beneficial bacteria but also some disease associated ones so it's not all good or bad that's why it's going to be very important to learn to modulate how we use specific foods and cooking methods clearly we could see important effects but these were highly individualized another aspect that we are investigating and that while many groups are investigating is the effects of dietary supplements and in particular instance for health one thing that we've focused on is the effect of tannins with a particular kind of polyphenols supplied by our colleagues and so we've done several studies now looking at the effect of tannins both looking at foods enriched with tannins and tannin extracts by themselves and we've seen that indeed tannins have beneficial effects in the gut microbiota um we see that they produce an increase in beneficial bacteria in this case agarmancia for instance this is something we observe with all food matrices and also this resulted in a booster effect on short chain fatty acid production and in the case of the tannin extracts we were also able to look at the correlation between tannins and short chain fatty acid production and specific bacteria so the bacteria that we actually saw increasing were actually correlated both with short chain fatty acid production and actually also with antioxidant activity obviously we're not the only people looking at this kind of things there's many studies also that utilize animal models so in our case our work was based on in vitro fermentations but there are many studies that use animal models that have also been able to demonstrate the importance of different types of of probiotic substances on the for modulating the gut microbiome and this is related symptoms for instance this is a an early work by the group of Kani and Elzen here in Belgium actually where they were able to to show that there have been oxalan in in obese mice in a model of obese mice could modulate bacteria and that this correlated with several kinds of beneficial aspects on the host adipose tissue and on the host metabolic parameters another example of this would be a work in which I was involved recently in another European project where we looked at the effect of mastija which is a resin produced by a Greek tree that has been used since antiquity and also in mice we could show that it had an important effect on gut microbiota diversity and in this case in the symptoms of non-alcoholic liver disease obviously very important for all of these are studies that utilize human interventions and we're going to hear a little bit about the ones in our project now but a lot of different groups are working on this also for instance with mastija we also did a human intervention and with tanins as I mentioned we also did a human intervention actually as part that stands for health and we showed similar results to those that we had in in vitro so just to conclude future directions that we can talk a little bit more about now in the in the discussion session it's going to be very important to understand better the individual variation in how the microbiome behaves and how it responds to foods some of these may have to do of course with interactions with genetics but also we need to understand interactions between bacteria themselves and although I think we've done a lot of progress in our project but we need to further improve predictions on metabolic output further improve how we actually include this into personalized diet programs and you know keep improving the translation of all of this research so thanks to my group and to the stands for health colleagues and I don't know if they're saying for a few questions thank you very much billar