[Music] thank you for this great opportunity I'm really pleased and honored to have you the chance to introduce the sessions here today as you understood from the nice presentation of Philip I will be telling you a lot on the human gut microbiota more so than the chicken and in my first slide I just will have the opportunity to emphasize I will be talking of humans and I will be talking of symbiosis interaction between the microbes and the host as a key aspect of the work on the bottom left what I show here is the contributions of the microbiota to physiology of the human and it deals with traffic and metabolic contributions for example it will provide the ability to degrade plant related material or plant fibers which also is important for the animals it will contribute vitamins B and K vitamins especially it will also contribute the barrier function or colonization prevention which is quite important also in animal breeding direct interaction with the microbes and also with the immune system and crosstalk with all the organs including muscles brain heart of the body and we become microbial at birth and we are micro tool for our whole life so even though I don't talk so much of chicken I will tell you about yourself actually and we we built or we developed our microbiota at the same time in early life as we develop our immune system and that leads to this unique situation where the microbiota is recognized as part of self by the immune system which is a key element of the maintenance of symbiosis and health and well-being there could be disruption when it comes with the ecological aspects then it's associated with loss of function and essentially barrier function or colonization prevention and when it's at the level of immunity then it comes with risk of immune related disorders like you know in inflammatory conditions so we want to build knowledge we want to understand we want to monitor and we want to be able to fine-tune the system so we are I am you are 100 trillion bacteria and this is just talking of bacteria there is even more Sage's for example there's yeast fungi protists sometimes that are present and they're present in in the body and on on the body on the skin also at every mucosal interface in the mouth or even in the lungs in New York in genital tract and it in the gut obviously where we have the most dense and diverse community and if we look at numbers just to start with facing 23,000 human genes we have on average 600,000 microbial genes so this contribution is massive in terms of potential functionality and that's where the science of the microbiome comes into play and were really happy to be able to evolve on that system now I have new concepts to bring so I will start giving you my views of symbiosis between humans and microbes and one of the reasons why there is such a big development is that in spite of the improvement in health conditions progress in medicine increasing longevity of the humans what we have been able to observe over the second half of the previous century is as we were controlling better and better infectious conditions and this is the slopes going down on the left-hand side for you at the same time the observation in terms of epidemiology was the rise in immune related conditions essentially the big chronic diseases that we see expanding on Earth today and well the World Health Organization tells us that one person in four will be concerned by one or the other of those chronic conditions so we need to think of prevention and there's really an urgent ease because we do not control that today just a snapshot on autism in the US the incidence has been going up exponentially like the contribution to this meeting but this is worrying actually one person in 50 that is born in the u.s. today we'll be concerned by autism in Europe it's more like one out of 150 so we do not control we have to understand what is going on here and in turn it may actually impact human longevity so what did we do wrong to get into this situation there's a few elements that we can think of when we think of why this is happening so I listed some of them at the top here we have changed a lot of things that concerned the microbiota and the interaction between the host and the microbiota over the past 60 years roughly we have changed everything that surrounds birth in terms of mode of birth and environment we have changed nutrition a lot and of course physical activity as well and we have changed exposure to I will say chemicals in the environment this is true also for animal breeding and this will have an impact on the microbiota just a few snapshot birth mode c-section today a cesarean section is one birth out of ten or nine birth out of ten in some places on earth in Rome and cameos it's actually 80% of births so it's a decision we do not need to go this far but when we take this decision we break the transition or the transmission of microbes from the mother to the child so we expand into a new new world in a way new biology do we want to continue that we want to find ways to circumvent that nutrition we brought down the contribution of fiber to our diet to around 15 grams per per day in in Europe this is low this is down below the recommendations which are 25 to 30 grams per day and this is neglecting that we are micro role as I mentioned already and it will also have an impact in the way we manage intensive animal production so if we take the various disease conditions that are concerned by an impact on the microbiota they concern the central nervous system they concern the Gastroenterological area metabolism immunity also what we do in the clinics will have an impact on that and in those contexts what we do see is indeed we can document an alteration of the microbiota in some cases we can document very fine signatures of alteration of the microbiota but this is not the whole story it's not just the microbiota we also see on the host side alterations leaky gut syndrome or increase in gut permeability sometimes hyper permeability we see an inflammatory State very often low-grade inflammation and coming with this we have oxidative stress that can be systemic concerning the whole body and I will document how this can actually turn into a vicious circle for all these conditions were we do not have prevention in many cases and we for sure do not have cure in many of those chronic what we call non transmissible conditions so the picture we can give if we consider those elements microbiota gut barrier inflammation oxidative stress is that of many interactions when everything goes fine when we have similar sees and then upon various stress conditions we will induce alteration so we have documented alteration of the gut microbiota just in a few words it's a breeded reduction in richness of the microbes or the genes of the microbes its loss of Symbionese the dominant population that is usually present in Health will be will tend to disappear and it's increasing paths or biomes very often run negative for inflammatory bacteria but at the same time we see alteration of intestinal permeability with inflammation with the oxidative stress and what I list right here is this can go into a sort of vicious circle auto aggravate or sustain one another and in fact we would like to to be in this situation well we have a continuum between health and disease if we see things going on the right hand side towards the red then we just find the solution to bring it back to the green or the blue and everything was fine but if you have the possibility of establishing a vicious circle then what Martin Schaffer tells us in Wageningen working on ecological theories is that there's no continuum anymore you can have a break and you can have alternative stable state the disease condition becoming a stable state because of the vicious circle so that leaves us with four targets and we can use those four targets we have not done that today in terms of diagnosis prediction prevention and therapy so just keep that in mind for the rest of my talk we could be dealing with in terms of diagnosis prediction prevention therapy the possibility to deal with all four of those elements and in fact it goes beyond the illustration of the alternative stable state is given here so you have a stable state in green this is the health condition a stable state in red this is the disease condition and if you press on stress conditions to the right then for a long time you will keep in a situation where you can be resilient it can go back to normal but if you push too far then you go beyond the robustness of the system and you end up with the alternative disease state but then if you return to lower stressful conditions you will not immediately go back to the normal state you will stay in the stable disease state for a long time actually so you need to go back to very very low stress condition if you want to eventually return to the normal condition so just keep that in mind this illustration tells you that we are we have to think of it so one way to think of it is we have tools that are available for the moment in human nutrition what we play with is essentially the microbiota so we we use soluble insoluble fibers we use prebiotics sometimes fate or quorum sensing modulators to modulate the microbiota add the clinics the med is the clinician deals with symptoms and organs and so for the gut for example they will deal with inflammation so they we'll use anti-inflammatory drugs if they don't work then they use corticoids and if they don't work then they have to remove parts of the body essentially and so what I'm showing here is we have tools to deal with all four elements of the visual circle if we want we can use fibers use commensal strains or probiotics or amino acids to deal with the barrier we can use commensal probiotics or small molecules we deal with inflammation and we even have tools to deal with oxidative stress to my knowledge this has not been done yet so my talk is dealing with meta tools meta technologies so essentially we deal with the whole ecosystem as a start and I will not talk so much of 16s ribosomal DNA work I did a lot myself but I really immediately bring you to what we call metagenomic so it's true Huell genome shotgun sequencing based characterization of the system so essentially it calls for what is shown your DNA extraction and it's possible bias here even sample collection leads to possible bias whole genome sequencing and then we assemble we annotate genes we want to be able to build a reference catalogue and essentially in a few clicks what we have done is indeed build the reference catalogue and I will give you illustrations of that we have been able to design bioinformatics to cluster genes into genomes for bacteria that have never been cultured in culture collection we have looked at ecological distributions of microbes and we described what we call enterotypes its ecological settings in the human population and we identified loading count or low richness low diversity as a key have stratify ER and then we looked at the microbiome in many clinical conditions essentially chronic clinical conditions like type 2 diabetes obesity or inflammatory conditions liver disease and now we are working on brain related neurodegenerative or neuropsychological so just a few few I lights the reference catalog we started in 2010 with a 3.3 million reference catalog and we expanded that after that 2014 we published this catalog based on 1267 human micro biomes it's 10 million gird genes it's our reference to days actually and what is shown in color if you look at the red curve these are the genes that are almost conserved between humans and well it shows that after 100 individuals we had already captured those few genes that are highly conserved within the human population and that correspond to a few species that we share or we tend to share most what is still increasing is rare genes we will find genes that are specific of each and every person essentially so we have our own microbiome now for the for the animals for the human we have these 10 million genes it's a well now today it's close to 2000 metagenomic species or genomes that we have been able to reconstruct we've worked on pigs and chicken the same tool basically we want to design the reference catalog because this is an essential asset for future work for the pigs we have seven point seven million genes out of close to 300 animals and they represent 700 metagenomic species for the chicken 300 animals and this is actually 30 different groups of 10 animals are very different breeds and raising conditions high diversity massive diversity nine point seven million genes 23,000 metagenomic species already identified and this is progressing still today so the pipeline we we use on my unit method you know policies illustrated here we start with a recommendation for sample collection already at this point it's really critical actually I can tell you DNA extraction also very critical and then we shotgun sequence and we generate short fragment so we do not construct genes and genomes anymore what we do is with the small fragments that we generate by millions we map on the reference catalog so very quickly we have an idea of the distribution of the genes within any sample that we collect and of course interfacing those gene abundance and species abundance with clinical conditions then we can assess or identify relevant microbial players at the species level or build prediction models standardization has been a big part of our work for a period of five years actually and the standard operating procedures we made available in 2015 on the website that is indicated here and they were actually published in 2017 so this is just an illustration of the reconstruction of microbial genomes from metagenomic data so we do not culture we just use the metagenomic data and we look for very finely Co abundant genes if they are finely Kommandant whichever the sample they are present in then they very likely belong to the same genome and so using that we have been able to describe several hundred large metagenomic units that do correspond to bacterial genomes some we know and many others 85% we did not know before and also very small metagenomic units that correspond to phages to plasmids or CRISPR elements and that very often actually as illustrated on the right hand side will cluster with genes of the genome as we would expect looking at the species we here highlight those that are mostly conserved so we have fifty-seven species that we will find in ninety percent of the human population we have been studying so far and if we really get close to 100% conservation then we only have eighteen species that pop up some gram-positive dominant of the Firmicutes phylum some grand negative dominant especially of the Bacteroides and tella groups its small proportion it's 20 or less than 20 out of very often 200 dominant species per individual so there's an illustration of very high inter individual variation inter individual variation we did find actually when we looked at ecological distribution we were looking at the genus level seeing well how does this person and that person compare and we identified three groups of population in the general human population we were looking at that are dominated by one specific genius but that also contain rule ecology Bacteroides from in a caucus prevotella or of the dominant genre this was really unexpected we still don't know exactly finally what it means in terms of disease or risk of disease we start to have some hints what we connected that immediately with his food so Gary who in the US was working on humans and looking at the distribution in enterotypes and showing that if you are the fast food type of eater then you will tend to be on the back row either side if you are having dietary habits rich in plant material in fruits and vegetables then you will tend to be on the right-hand side of the picture and it's also connected with gene count so we did explore gene count in a greater detail and what the blue curve is showing here is the distribution in number of individuals as a function of gene count at the bottom so we find from less than 200,000 genes in the dominant microbiome to more than 800,000 some people 1 million actually and what you see is the distribution is not the usual Gaussian even distribution there's a kink to the left so we have individuals with low richness microbiota individuals with high richness microbiota and we worked a bit more on that connecting that with with disease as I will illustrate so to summarize that each dominant microbiota gathers on average 6 thousand genes but you see there's variation we are different by genes by antara types or ecology by species richness the microbiota can be characterized by quantitative method genomic profiling and that gives you access to genes and to pathways and a small proportion of the diversity is well conserved constitute a shared metagenomic core and yet we differ as I mentioned so where can we go from there in terms of innovation and that will link to your concern in terms of animal breeding so what I'm saying here is true for all context basically the microbiome is allowing us to develop tools for stratification for monitoring over time it's a giving tools for targeted modulation of the microbiota there's potential for identification of novel bioactives novel targets for therapies and microbes can also be used as drugs of their own and so I will illustrate some of that and microbiome profile we can go all the way to try to identify predictors so I already shown this this slide what we have been able to show is that individuals that have a low richness microbiome they are in the green curve non obese individual roughly 10% in the healthy human population in the overweight moderately obese population 25% in extreme obesity actually it's 75 percent of the population on the left-hand side those individuals are those that have less healthy metabolic and inflammatory traits especially in overweight or obesity we find in those higher cholesterol level higher triglyceride higher inflammation biomarkers we find also in this group the highest insulin resistance so diabetes tendency for diabetes and hence aggravation towards morbidities but this is also the individuals that will not respond to a certain treatment calorie restriction in the context of obesity immunotherapy in the context of cancer and in the context of liver disease there also or richness is also a marker of aggravation of severity so just illustrations of that in our cohort of 50 individuals in which we had an intervention it was low fat high protein high diverse fiber diet we could very easily separate hygiene count and loading count and what we could show is that if you belong to the hygiene count then we can improve your situation based on the diet essentially will reduce here high sensitivities Europeans inflammation but if you are on the loading downside then we have a hard time to do anything in terms of weight gain or weight reduction but also inflammation and lipid parameters triglycerides for example in the context of cancer what we were able to observe is that if you are on the low richness side then essentially you will be among those that have shorter progression free survival upon treatment with immunotherapy etics here it's untie PD one anti-cancer drugs on the left-hand side this is true for non small cell lung cancer on the right hand side us colleagues the group of Jennifer go work on melanoma patients same observation this is alpha diversity based on 16s ribosomal DNA profiling and well those that are unknown responders to the treatment have lower diversity going into greater details the group of wogo showed that there's highlights of the bacterial composition Seikaly bacterium the genetically bacterium is associated one present with a longer progression free survival whereas the genesis of the order back to adonis is associated with shorter progression-free survival so even at the fine level or finer level gut microbiota composition will impact and while the observation ethically bacterium was striking for us because we've been working on this genus for for quite a while now we described the Kali bacterium as a marker of Health in inflammatory bowel conditions in colorectal cancer in an irritable bowel syndrome it was also observed we were able to show that it expresses anti-inflammatory activity and it's a predictor of the length of remission or the remission time after biologics treatment in Crohn's disease patients and you can even see here the time without relapse of the disease when you have a Kelly back your own presidency present above the median a population then you have a curve that resembles that of of the cancer patients so it's a among the strongest predictors of response to immuno immunotherapy ticks in cancer together with prior immunotherapy and there's a connection with antibiotic treatment if you treat with antibiotics patients that will undergo immunotherapy ticks in the month before or in the month after then actually they lose chances of responding to the treatment so this is immediately applicable in the clinics what the red curve shows is the survival curve of patients with in this case non-small-cell lung cancer or renal cancer or urethane carcinoma when they have been exposed to antibiotics in the period around the the treatment so very major importance now looking at animals we've looked at the meta-genome of pings and focused on antibiotic treatment this is the overall distribution on a PC a plot of pigs from China in red from Denmark in green and France in blue and what you see is the Chinese pigs will separate from the French and Danish pigs and the drivers in terms of antibiotics will be May on the Chinese side were it's easily available so it's used a lot actually less on the European side with vancomycin and tako planning as the main driver so they will be used in an extreme veterinary conditions and so essentially what you see is an impact of the the ban for growth promoters in in Europe that is visible yet not 100% probably and when you look at the composition of the microbiota in terms of a prevalence of antibiotic resistant genes then you still see that there is a higher proportion for for the Chinese speak these are the antibiotic families that we were able to detect by molecular assessment the green and the red and the red or on the blue are always below although for some of them it's not so so marked so antibiotic usage for prophylaxis and treatment are still authorized for a while livestock but there's regulation of growth promoter use in Europe that has some some visible impact it will take a bit of time probably and then I want to illustrate work we are doing together with the the University of Ghent with VD Panda and Russia and also Adisa we have this model of animals that was designed at Gant where animal have this diet switch antibiotic cocktail back to whole cocktail area exposure and we sample the animals at 8:26 essentially it's mimicking the extreme severe stress conditions that you could have in real life and what we have done is we explore the composition of the metal genome of those animals and look for species of bacteria metagenomic species at the level of meta-genome that will be segregating controls and challenge animals and we identify a lot Phillipe already identified at the level of 16s ribosomal DNA markers we identify the same and more in this context where we we scan although all the genes available so there's 150 that are enriched in controls and 25 that are enriched in a challenge animal so I only show some of them here in terms of distribution for each species what you see here is 40 genes and it's color coded so white or blue is low abundance and towards the red is high abundant so some you will see are really highly discriminant and so we also look at impact or connection with parameters of Health and what we see is that well the blue part of the tree on the left hand side at the top is the control animals the green is the challenge animal they really nicely separate in this analysis and we look at what we call GMM switch gut microbiota metal metal volume or metabolic pathways and we see that there is also a connection so what you see is video script we lose to [ __ ] ratio village length or body weight or nicely positively correlated with your control condition negatively correlated with the challenge condition and it's the reverse for over transferring colony Coralie all for city 3 area for crib death coccidiosis score or dysbiosis score and this is connected with many parameters of microbiota metabolism to which we access by metagenomics among those which read production is on the health side so to speak polysaccharide degradation or the ability to manage oxidative stress radicals on again on the left hand side peroxidase propionate or lactate metabolism on on the right hand side on the stress or challenged animal side and so just to summarize what we have seen is there's over representation in control animals of several groups of bacteria among which I highlighted here Faye Kelly bacterium which Orissa caucus that were already described by by Philip was a boreal Lucknow Clostridium as well there's several genera among those that are known to produce butyrate thereby to act as potentially anti-inflammatory microbes and many other functional modules including for example meta-gene methanogenesis and acetate metabolism on the challenge side klaudia a common sia lactobacillus some like nose puree see also are over-represented and while the functional modules essentially centered around lactate propionate and peroxidase or oxidative stress generation now a microbiome can be used as a target or even as a drug so I will illustrate some of that one slide on targeting I already showed that illustration were we we have this intervention with high protein low fat high diverse fiber diet and what we were able to show even though in the loading count individuals we have our time to modulate their health status still we can increase by 25 percent the richness of their microbiome and as we see it today it's very likely essentially due to primary substrates and their diversity so if you increase the diversity of plant fibers in the diet then you will promote diversification throughout the microbe all food chain you will feed the degraders that will feed the rest of the microbiota essentially now you can go a bit further with metagenomics this is a more complex story but we are using a very classical tool essentially human report human cells with a reporter system that are commonly used to test the ability of pathogens to induce response for example inflammatory response so it's either cultural strength or DNA libraries what we do is we overlay that with our ability to extract long fragments of DNA 40 kilo base fragments so it's 40 to 50 genes of any gut microbes there is no culture here and then we clone that into e.coli and that's the e.coli loans so essentially a fragment of genome of a gut bacterium and its products that we expose on to human cells and we do identify modulation of various activities we started publishing on that in 2007 we have at hand today actually close to 500,000 metagenomic clones that we can use for testing any condition so far we work on essentially human cell models that tell us about modulation of immunity modulation of proliferation of metabolism or endocrine functionalities ie production of neuro active peptides for example pyy glp-1 that act on the brain on modulation of our perception of satiety so we work on entire endocrine cells in this context but a lot also on epithelial cell models I will just illustrate one segment we did on NF kappa-b we screen thousands of clones we find some that or active inducers of NF kappa-b response or some that or down regulators of NF kappa-b responds with one of those clones that pops up as an activator of immune defenses outside of a general massive contribution of clones that do not vary much compared to the control in black we occasionally find anti-inflammatory or inhibitors of the NF kappa-b pathway well we took one of the top ones and we looked at its ability to modulate the integrity of human intestinal tissue so we use big segments of tissue using the the tool that maraschino has developed in Milan and while we overlay on top of that either the clone or the e.coli that we use for construction of the clone library or just control medium what you see is if everything remains fine then you have control medium control E coli and our NF kappa-b modulating clone the tissue is intact everywhere if we expose the tissue to a toxin or genic Salmonella strain then actually you destroy the tissue but you destroy the tissue with the control medium you destroy with the control ecoli but it remains intact with our metagenomic loans so not only does it modulate an F Kappa B pathway but it also will have an impact via interleukin production for example on the preservation of the integrity of the gut tissue so it goes all the way to potentially bioactivity in vivo in the in the intestine I'm going back a little bit to fake le bacterium just to tell you where we are today it's been a 15 years work actually the first key publication was that of a so called in 2008 well we could show that if you have faked a live at your own present in the gut then it's protective for even patients that we we operate they remove the ileocecal region of the gut then you put back in continuity and if you have fake early bite your own present they are protected if you do not have fake a live at your own presence six months later all of them will have a relapse of the disease and so it seemed to be key then we could document its ability to act as an anti-inflammatory but this is IL 8 production by HT 29 cell that are stimulated by TNF alpha and you see that even the last ones shown in in the on the underlined in blue there are new strains they are also active anti-inflammatory potential and we could identify candidate in anti-inflammatory metabolites one protein so far and several small molecules that can contribute to the bio activity this is work of my colleague Philippe la jolla today now following this story there's been a new company this is the second line here that was created very recently it's called next biotics and essentially what it's doing is its mass culturing fake elevator elasticity and then life realizing put it in capsules and going for a clinical trial where you administer the strain to humans and try to see whether you get the bio activity in humans it will have to be a phase one in healthy individuals before you go to Phase two in inpatients this is also true for many microbes tell about your own processes only one but back to arias fragilis with the work of a Sarkis mazmanian you bacterium Holly without masks you drop like a monster machine if you lay with the rock of batteries candy some of them for which we have an idea of at least one of the key bioactive molecules and many of those come with a small company that is again doing the same so there's many developments and there could be the same for animals actually that go for the production of the the strains tours application as alive biotherapeutics this is using single strains what is really emerging today very rapidly is the application of ecosystem whole ecosystem as a drug so this is the end of my presentation essentially what is shown here is the result of the van nude publication dealing with fecal microbiota transfer in the context of recurrent Clostridium difficile infection so essentially is the result of an ecological stress very often antibiotics in the clinics that alter the microbiota lead to loss of barrier function colonization by austrian difficile and if you cannot remove it with the first antibiotic treatment then in most cases it will remain chronically and it was shown that if you use or if you compare the last resource antibiotic vancomycin on the right in red to fecal microbiota transfer then what you see is with vancomycin you will eradicate the pathogen in 30% of the patients if you combine with gut cleansing it doesn't help whereas in microbiota transfer you cure more than 80 percent of the patients with a single try if it doesn't work then you can try again and you will call cure more than 90 percent of the patients in fact when the trial was run there was an intermediary analysis and it was considered non ethical to continue because the new treatment was so way more effective than the usual one so every patient was transferred to a fecal microbiota transplantation and today it's acknowledged as a treatment by the regulatory agencies the FDA in the US NSM in France same in Italy it's applied every day so there's been thousands of patients that have been cured or their loss um difficile by this treatment now I work with a small company as scientific advisor the name is Matt Pharma it's based in France in in lyon and matt is developing the preparation of human intestinal content as a tool for treatment especially in cancer patient and what I'm in the straighting here is a phase 1 b2 a trial so it's really the pilot trial you start with in acute myeloid leukemia patients its patients that have not been treated so much before they arrive in the hospital and upon diagnosis when you determine that they have AML what we could do in this case is collect a stool sample before they go into induction chemotherapy this is the first treatment very harsh that aims to remove white blood cells that are cancerous and then they go for antibiotics they have really highly reduced immunity for another 15 days after 21 29 days what we did is we re administer their own microbiota to the patient so it's autologous to demonstrate or to try to demonstrate that we would be able to rebuild completely the microbiota and then the patients are back in the hospital ten days later for consolidation chemotherapy and then they're followed over time for twelve months and what we were able to show at the bottom here as a summary we get 90% recovery of the microbiota probably this is related to the fact that we are autologous so you already have the adaptation between the immune system and the microbiota of the patient and so on the first left hand side figure you have the breaker tease dissimilarity how much you alter the microbiota from v1 to v2 after chemotherapy antibiotic treatment you alter dramatically the microbiota and after we add ministration autologous transfer then you reconstruct and that's where you reconstruct 90% at the level of diversity index at the level of species similarity or genus similarity in the center we focus or we zoom on you tried producing bacteria that are rapidly called beneficial bacteria here it can be seen as a biomarker of competitive exclusion in a way they are completely altered at v2 but they are fully reconstructed at V 3 and many of those are extremely oxygen sensitive so the process that mad Pharma is using allows to preserve those bacteria very well so that they can actually be reestablished and if you look at the inflammation biomarker in this case neutering on the right hand side while you have an inflammatory burst after the the treatments and again you restore complete immuno meal stages after the autologous transplantation looking at overall gut health the patients recover normal transit within within a few days within one day centrally after administration and they survive better actually we had 94 percent survival after one year when the usual historical control data is 70 percent now this is small cohort of individuals 25 patients so you cannot expand so much on that but this was very encouraging so to summarize we humans share a core microbiome yet we differ in details at the level of genes of species ecology or gene count and microbiome gene count is really a key strategy failure of health these biases should be viewed as not just a microbe at a story but really an alteration of the whole context of symbiosis and I mentioned the vicious circle the possibility of long term alteration microbiota modulation should be considered as a target especially if you want to work on personalized or individualized nutrition for humans towards reinforcement or adjuvant strategy in combination with care and therapy in patients and nutrition and within nutrition fibers probiotics or live microbes singles friends or cocktails or even Huell ecosystems may be strategic bioactives for the maintenance for the preservation or the restoration of man microbe symbiosis and my summary quoting biology art actually from a deseo a major way of leveraging prevention will probably be a nutritional ecology thank you very much for your attention on this slide you have the list of my colleagues who contributed and our founders [Applause] [Music]