>> GOOD AFTERNOON, EVERYONE. WELCOME TO THE WEDNESDAY AFTERNOON LECTURE. IT'S A PARTICULAR DELIGHT FOR ME TO BE ABLE TO DO TODAY'S INTRODUCTION BECAUSE THE SPEAKER WAS A POST-DOC IN MY LAB A LITTLE MORE THAN 20 YEARS AGO, RIGHT AT THE POINT I JUST ARRIVED AT THE NIH FROM THE UNIVERSITY OF MICHIGAN, WAS SETTING UP VARIOUS EXPERIMENTS IN MOLECULAR GENETICS AND DR. WIJMENGA CICSA AS I USUALLY REFER TO HER, JOINED US ALONG WITH A COUPLE OF OTHER PEOPLE WHO ARE HERE, PAUL LOU, ALSO AT THE SAME TIME MIKE URDOSE IN MY LAB ALL THAT TIME AND NOW INCLUDINGND WE DID SOME PRETTY INTEREST THINGS AT THAT POINT PARTICULARLY IN THE AREA OF MOLECULAR BIOLOGY OF M 4 TYPE ACUTE LEUKEMIA. SINCE THEN HAS GONE ON TO DO AMAZING THINGS AND NOW AS A DEPARTMENT CHAIRZv IN THE NETHERLANDS, COMES TO SPEAK TO US TODAY ABOUT GERMS, GENES AND HOST DEFENSE. IT SEEMS TO ME -- SHE GOT HER Ph.D. IN LYDON WORKING ON HUMORAL MUSCULAR DYSTROPHY WHICH AT THE TIME WAS QUITE A PUZZLE AND GOT FIGURED OUT. AFTER POST DOCKING IN MY LAB HERE AT NIH WHICH WAS A WONDERFUL EXPERIENCE FOR ME AND HOPE FOR HER, SHE THEN MOVED TO UTRIX WHERE SHE WAS ASSISTANT PROFESSOR AND THEN FULL PROFESSOR AND THEN SINCE 2007 HAS BEEN AT UNIVERSITY MEDICAL CENTER GRONINGEN IN THE NETHERLANDS WHERE SHE'S HEAD OF THE GENETICS DEPARTMENT. SHE ALSO HAS ADJUNCT PROFESSORSHIP MEDICINE FROM THE UNIVERSITY OF OSLOW. SHE RECEIVED A NUMBER OF OF AWARDS INCLUDING ELECTED MEMBER OF ROYAL HOLLAND SCIENCES AND HUMANITIES. SHE RECEIVED THE SPINOZA AWARD, MANY CONSIDER THE DUTCH NOBEL PRIZE. AND SHE'S A MEMBER OF THE DUTCH ROYAL ACADEMY OF ARTS AND SCIENCES. HER RESEARCH WHICH SHE WILL TELL YOU ABOUT, IS DEVOTED FOR QUITE A FEW YEARS ON UNDERSTANDING THE MOLECULAR BASIS OF THE HOST IMMUNE RESPONSE AND HOW GENETIC VARIATION LEADS TO DISREGULATION THAT PROPER RESPONSE AND PARTICULARLY HOW IT PLAYS OUT IN SILL YAK SPRU AND SYSTEMIC CANDIDIASIS. TO STUDY THAT SHE'S FOUNDED A NUMBER OF COHORT STUDIES WHICH I SUSPECT WILL APPEAR IN HER PRESENTATION DIGGING DEEPLY INTO TRYING TO UNDERSTAND IN HUMAN BIOLOGY HOW CAN WE LEARN ABOUT THE IMMUNE SYSTEM AND ITS ROLE, AND PARTICULARLY HOW WE CAN THINK OF THE HUMAN ORGANISM Z PA SUPERORGANISM INCLUDING THE MICROBIOME WHICH HAS GOTTEN A LOT OF ATTENTION LATELY AND IN FACT CICSA'S LAB CONTRIBUTED SUBSTANTIALLY TO WHAT WE'RE BEGINNING TO LEARN ABOUT HOW THE MICROBIOME INTERSECTS WITH HUMAN CELLS AND HUMAN ORGANISM TO CREATE HEALTH OR DISEASE. PLEASE JOIN ME IN WELCOMING PROFESSOR CICSA WIJMENGA. [APPLAUSE] >> THANK YOU, FRANCIS FOR THIS LOVELY INTRODUCTION. IT'S BEEN A GREAT PLEASURE TO SPEND THE PAST COUPLE OF DAYS, FANTASTIC TO COME BACK AFTER INDEED MORE THAN 20 YEARS. AS YOU CAN SEE FROM THIS SLIDE, YOU MAY RECOGNIZE THE PEOPLE, FRANCIS, PAUL, WE ALL KNOW A LITTLE BIT YOUNGER. QUITE SPECIAL THAT EVEN AFTER SUCH A LONG TIME WE STILL STAY IN CLOSE CONTEXT. BEING A POST DOC WAS AN IMPORTANT TURNING POINT FOR MY SCIENTIFIC CAREER. IT WAS HERE I LEARNED THAT WE COULD ALSO REALLY WORK ON THE GENETICS OF COMMON COMPLEX DISEASES REALLY INSPIRED BY THE WORK FRANCIS STARTED OFF ON TYPE TWO DIABETES. AND FOR ME, THAT WAS REALLY AN EYE OPENER KNOWING THAT MORE THAN 50% OF THE WORLD WILL SUFFER FROM CHRONIC DISEASES AND YOU WILL OF US AS WE'RE SITK HERE PROBABLY WILL BE GAINING ONE OF THOSE DISEASES OVER OUR LIFETIME. SO THAT WOULD BE FANTASTIC IF WE HAVE A SOMEWHAT BETTER UNDERSTANDING OF THOSE DISEASES AND EVENTUALLY PREVENT OR TREAT THEM. THAT LED TO MAIN RESEARCH INTEREST THAT I STARTED OFF WHEN I STARTED MY OWN LAB IN GRONINGEN IN CILIAC DISEASE, THAT'S BEEN THE MAIN THING SINCE THEN BUT I WON'T TALK ABOUT IT TODAY. SO WHERE IS GRONINGEN? THIS IS THE NETHERLANDS WHICH IS A TINY COUNTRY, SQUEEZED IN BETWEEN GERMANY AND BELGIUM AND CLOSE TO THE UK. YOU PROBABLY ALL HEARD OF AMSTERDAM. AND GRONINGEN IS REALLY UP IN THE NORTH OVER HERE. MAYBE YOU HAVE BEEN HEARD ABOUT IT RECENT LE BECAUSE THE NOBEL -- RECENT WILL I BECAUSE THE NOBEL PRIZE IN CHEMISTRY WAS AWARDED TO MY COLLEAGUE BEN SERING AND WE WERE PROUD OF HIM AS YOU CAN IMAGINE. GRONINGEN ALSO HAS A LARGE UNIVERSITY, IT WAS ESTABLISHED MORE THAN 400 YEARS AGO AND IT HAS MORE THAN 30,000 STUDENTS. IT'S ONE OF THE LARGEST UNIVERSITIES IN THE COUNTRY. AND ASSOCIATED TO THAT IS ALSO A LARGE MEDICAL CENTER AND THAT'S REALLY WHERE MY DEPARTMENT IS LOCATED. THAT MEDICAL CENTER HAS ABOUT 1400 BEDS AND IS LARGEST TEACHING HOSPITAL IN THE COUNTRY. COMING BACK TO THOSE COMMON COMPLEX DISEASES YOU ARE ALL AWARE OF THE FACT OF COURSE THAT OVER THE PAST TEN YEARS OR SO, PEOPLE HAVE BEEN DOING THOSE GENOME WIDE ASSOCIATION STUDIES. AND I CAN HARDLY BELIEVE OF ANY TRAIT OR DISEASE THAT HAS NOT BEEN USED IN THIS TYPE OF STUDY SO WE HAVE NOW LOCI FOR ALMOST ALL OF THEM. AND THE BIG -- AND THE SAME HAPPENS OF COURSE FOR CILIAC DISEASE WHERE I HAVE BEEN DEVOTING A LOT OF MY SCIENTIFIC CAREER TO. SO NOW WE HAVE 43 DIFFERENT LOCI THAT EXPLAIN ABOUT 50% OF THE HERITABILITY. ONE OF THE MOST INTRIGUING OBSERVATIONS THAT WE MAKE IS THAT THE LOCI THAT WE IDENTIFY FOR CILIAC DISEASE ARE PARTLY SHARED WITH OTHER AUTOIMMUNE DISEASES LIKE TYPE ONE DIABETES, RHEUMATOID ARTHRITIS, CROHN'S DISEASE AND SO ON. THAT REALLY MEANS IF WE'RE GOING TO DISCOVER A LITTLE BIT MORE ABOUT BIOLOGY OF CILIAC DISEASE AT THE SAME TIME LEARN ABOUT OTHER DISEASES BUT THIS POST ERA IS AT AN EASY ROUTE TO TAKE. PROBABLYxD A COUPLE MORE YEARS BEFORE WE MAKE ANOTHER MAJOR DISCOVERY AND TRYING TO UNDERSTAND HOW ALL THIS GENETIC VARIATION CONTRIBUTES TO DISEASE BIOLOGY. THAT IS WHAT WE HAVE TO DO NOW. WE HAVE TO UNDERSTAND HOW ALL THOSE GENETIC VARIANTS REALLY TRANSLATE TO PHENOTYPES, OTHER DISEASE PHENOTYPES OR MORE GENERAL PHENOTYPES IN THE GENERAL POPULATION. AND THIS IS PRETTY BLACK BOX. IT IS CLEAR, HOWEVER, THAT WE HAVE TO GO BEYOND THE GENOME, IT'S NOT ENOUGH TO ONLY LOOK AT GENETIC INFORMATION. WE HAVE TO DO MORE HOLISTIC APPROACH AND FOR THAT IS IMPORTANT TO ALSO HAVE INFORMATION ON THE TRANSCRIPTOME, METABALOME PROTEOME EXPOESOME, THERE'S ALSO OF EXPOSURES WE ARE CONFRONTED WITH ALL THE TIME. AND ALSO THE MICROBIOME. SO BOTH IN THIS COUNTRY AND AS WELL AS IN THE NETHERLANDS THERE IS A LOT OF EXCITEMENT THAT PEOPLE THINK WE WILL BENEFIT FROM STUDYING LARGE COHORTS OF PEOPLE FROM THE GENERAL POPULATION. THAT IS FOR MANY DIFFERENT REASONS, ONE IS USUALLY LARGE SAMPLE SIZES, WE COLLECT PHENOTYPES FROM THOSE PEOPLE INCLUDING OMICS DATA, WHAT I THINK IS EXTREMELY IMPORTANT IS THAT THE DATA IS COLLECTED IN A STANDARDIZED WAY, THAT WE FOLLOW PEOPLE PERSPECTIVELY. THAT MEANS THAT WE HAVE DATA COLLECTED BEFORE THEY GET A PARTICULAR DISEASE, DURING THE TIME OF DISEASE AND ALSO AFTER DISEASE ONSET AND HOPEFULLY AT THE TIME BEING TREATED IF POSSIBLE. SO YOU HAVE THIS WONDERFUL PROJECT HERE IN THE U.S. THE PRECISION MEDICINE INITIATIVE. AND WE'RE TRYING TO SET UP SOMETHING VERY SIMILAR IN THE NETHERLANDS, CALLED THE HEALTH RESEARCH INFRASTRUCTURE OR HEALTH RI. REALLY ONE OF THE CORNERSTONES OF RI IS OUR BIOBANKING INITIATIVE THAT'S BEEN ONGOING NOW FOR APPROXIMATELY TEN YEARS. THAT IS REALLY BECAUSE WE HAVE MANY BIOBANKS TRADITIONALLY IN THE NETHERLANDS, THEY ARE BOTH POPULATION BASED AS WELL AS CLINICAL COHORTS AND TODAY THERE'S MORE THAN 200 DIFFERENT ONES, AND THEY'RE ONLY UNITED IN THIS BIOBANKING RESEARCH INFRASTRUCTURE THAT REALLY TRIES TO HARMONIZE DATA AND ALSO MAKE IT POSSIBLE THAT PEOPLE CAN CONNECT DATA FROM THE DIFFERENT SINGLE INITIATIVES. AND THOSE BIOBANKS ARE SPREAD ACROSS THE COUNTRY. SO THEY REALLY COME INTO MANY DIFFERENT FLAVORS, WE HAVE SMALLER ONES AND ALSO LARGER ONES, THEY ARE PARTLY HEALTHY POPULATION AND PARTLY SPECIFIC PHENOTYPES, DISEASE PHENOTYPES. AND THEY'RE BOTH CROSS SECTIONAL AND LONGITUDINAL. HOWEVER, IF YOU TAKE ALL THE PEOPLE THAT PARTICIPATE IN ANY OF THOSE BIOBANKS TOGETHER IT TURNS OUT ABOUT 6% OF THE DUTCH POPULATION WHICH IS SOME 1 MILLION INHABITANTS, ARE ALREADY PARTICIPATING IN BIOBANKS AND THAT'S REALLY A FANTASTIC RESOURCE THAT WE CAN USE TO AT LEAST UNDERSTAND A LITTLE BIT BETTER WHAT THE EFFECT IS OF GENETIC IN THE GENERAL POPULATION. A COUPLE OF EXAMPLES OF BIOBANKS COMMONLY USED, YOU MAY HAVE COME ACROSS BY READING PAPERS ON SAY GWAS STUDIES, WE HAVE A BIG ONE IN AMSTERDAM WHICH IS THE DUTCH TWIN REGISTRY, IT HAS ABOUT 200,000 PEOPLE PARTICIPATING. AND THE OTHER OF COURSE VERY IMPORTANT TO ALSO ESTABLISH WHAT IS THE HERITABILITY OF TRAITS WE ARE STUDYING AND WE HAVE THE LONGEVITY STUDY FOCUSING ON PEOPLE THAT BECOME EXTREMELY OLD. WE HAVE THE ARE THE TEAR DAM STUDY THAT -- ROTTERDAM STUDY THAT FOLLOWS PEOPLE 55 YEARS OF AGE AND OLDER, IT'S SMALLER BUT IT HAS FOLLOW-UP DATA FOR MORE THAN 25 YEARS, ALSO A LOT OF INFORMATION ON NATURAL HISTORY OF DISEASES. AND THEN IN GRONINGEN WE HAVE THE LIFELINE COHORT STUDY THAT WAS STARTED SOME TEN YEARS AGO, THAT HAS 167,000 PEOPLE PARTICIPATING. THIS IS THE LARGEST POPULATION BIOBANK IN THE NETHERLANDS. A LOT OF WORK WE DO TODAY IN MY GROUP IS REALLY CENTERED AROUND THE LIFELINES POPULATION. REALLY THIS INITIATIVE HAS BEEN EXTREMELY IMPORTANT FOR THE RESEARCH COMMUNITY IN THE NETHERLANDS AND WAS FOR EXAMPLE INSTRUMENTAL IN A PROJECT THAT A COUPLE OFIERS AGO THE GENOME OF THE NETHERLANDS, THAT WAS MEANT TO GET A BETTER UNDERSTANDING OF THE GENETIC VARIATION IN THE DUTCH POPULATION. AND WHAT I THINK IS REALLY STRIKING, THE NETHERLANDS IS A TINY COUNTRY, IT'S ONLY 100-MILES WIDE AND IF GO NORTH, SOUTH, IT'S ONLY 175-MILES, YET LOOK AT GENETIC VARIATION WE SEE MAJOR DIFFERENCES SO PEOPLE IN THE NORTH ARE COMPLETELY DIFFERENT FROM PEOPLE IN THE SOUTH. AND THAT IS IMPORTANT BECAUSE IF YOU START TO USE CLINICAL SEQUENCING AND YOU WANT TO INFER WHETHER A VARIANT YOU FIND HAS TO DO WITH YOUR PHENOTYPE BUT YOUR PATIENT IS NOT MATCHED WITH CONTROL YOU MAY RUN INTO DEEP TROUBLE. SO THIS RESOURCE THAT WE NOW HAVE FOR A COUPLE OF YEARS IS REALLY USED AS A MAJOR REFERENCE FOR CLINICAL SEQUENCING IN EVERY CLINICAL GENETIC CENTER IN THE NETHERLANDS. OKAY. BUT WHAT I WILL DO FOR THE REMAINDER OF MY TALK IS GIVE YOU THREE VIGNETTES OF RECENT WORK COMING OUT OF THE DUTCH BIOBANKS. ONE IS FACTORS WE IDENTIFY THAT AFFECT GUT MICROBIOME COMPOSITION, ONE HAS TO DO WITH VARIATION OF CYTOKINE PRODUCTION, AND THE THIRD ONE IS FACTORS THAT ARE INVOLVED IN HEALTH RESPONSE TO FUNGI. MOST OF THIS WORK IS REALLY CENTERED AROUND TWO RELATIVELY SMALL COHORTS. ONE IS A SUBSET OF THE LIFELINES COHORT WHICH WE CALL LIFELINES DEEP AND THE OTHER ONE IS A COHORT -- IT'S 1500 PARTICIPANTS. AND THE OTHER ONE IS A COHORT OF ONLY 500 INDIVIDUALS FROM AREA OF -- AND THIS IS REALLY A PROJECT THAT WE RUN TOGETHER WITH THE BROAD INSTITUTE AND WITH THE RED BUD UNIVERSITY. AND THAT WE CHECK TVLY CALL THE HUMAN FUNCTIONAL GENOMICS PROJECT. THERE'S EVEN MORE SMALLER COHORTS IN THIS PROJECT. SO WHAT ABOUT GUT MICROBIOME COMPOSITION? THE FIRST QUESTION YOU MAY ASK YOURSELF, WHY WOULD YOU STUDY GUT FLORA AT ALL? AND FOR ME, THIS PAPER THAT WAS PUBLISHED A COUPLE OF YEARS AGO IN GASTROENTEROLOGY WAS AN EYE OPENER WHERE THEY SHOWED THAT IF YOU TRANSPLANT FECAL MATERIAL FROM HEALTHY LEAN DONORS TO PEOPLE OBESE SUFFERING FROM METABOLIC SYNDROME, BY DOING THE SIMPLE SINGLE INTERVENTION, THE METABOLIC SYNDROME IMPROVED IN A PERIOD OF SIX WEEKS TIME. SO REALLY TELLING US THAT THE GUT FLORA MAYBE A TARGET TO MODULATE HUMAN HEALTH AND MIGHT HAVE DRAMATIC CONSEQUENCES FOR CHRONIC DISEASES, FOR EXAMPLE. OUR GUT MICROBIOME IS REALLY ESSENTIAL FOR HUMAN PHYSIOLOGY. ON THE ONE HAND IT HAS A VERY IMPORTANT ROLE FOR OUR METABOLISM, IT SYNTHESIZES FOR EXAMPLE CERTAIN VITAMINS, BUT IS ALSO THERE TO DIGEST VERY COMPLEX MOLECULES LIKE STARCH. ON THE OTHER HAND IT'S VERY IMPORTANT FOR OUR IMMUNE SYSTEM, IT REALLY TRAINS OUR IMMUNE SYSTEM AND IS ALSO A BARRIER AGAINST ALL KIND OF PATHOGENS. IF WE LOOK A LITTLE BIT MORE IN DETAIL, THEN WE SEE THAT REALLY THE MAJORITY OF THE BACTERIA OF OUR BACTERIA CAN BE FOUND IN OUR GUT. IN OUR GUT THERE IS MORE THAN -- SOMEWHERE BETWEEN 500 AND # THOUSAND DIFFERENT -- 1,000 BACTERIAL SPECIES. IF YOU THINK ABOUT IT, IT MEAN THERE'S 150 TIMES MORE GENES PRODUCED BY OUR BACTERIA THAN BY THE HOST GENOME. BUT GIVEN THERE'S SO MANY SPECIESES IN OUR GUT, IT ALSO MEANS THAT ALL OF US HAVE A DIFFERENT GUT MICROBIOME THAT CAN BOTH IN COMPOSITION AS WELL AS DIVERSITY SO WE CAN HAVE ALL DIFFERENT NUMBERS OF THE SAME MICROBE. AND UNTIL RECENTLY IT WAS HARD TO GET A GOOD UNDERSTANDING OF THE BACTERIA THAT ARE THERE BECAUSE IT HAS BEEN REALLY DIFFICULT TO CULTURE BACTERIA FROM YOUR GUT BECAUSE WE DON'T UNDERSTAND THE CULTURE AND CONDITIONS. BUT NOW WITH NEXT GENERATION SEQUENCING, WE CAN OF COURSE DO THAT. THERE'S TWO WAYS THAT PEOPLE TRY TO APPROACH THIS, BY SEQUENCING THE 16S RNA GENE YOU GET INSIGHT INTO THE TAXONOMY, PRETTY BROAD BUT YOU CAN SEQUENCE EVERYTHING SO SHOTGUN META GENOMIC SEQUENCING AND YOU GET MUCH MORE INFORMATION ABOUT SPECIES LEVEL, NOT ONLY SEQUENCE BACTERIA, YOUc SEQUENCE EVERYTHING ELSE LIKE FUNGI, PARASITES, AND THERE'S LOTS OF VIRUSES ACTUALLY BUT YOU SEQUENCE EVERY GENOME IN YOUR BACTERIA YOU CAN INFER WHAT IS FUNCTIONAL CAPACITY OF THE BACTERIA IN YOUR INTESTINE SO YOU CAN MOVE CLOSERjF TO WHAT THEY ARE DOING INSTEAD OF BACTERIA THAT ARE THERE. THAT IS VERY IMPORTANT IF WE WANT TO UNDERSTAND HOW THE GUT MICROBIOME INFLUENCES OUR PHYSIOLOGY. REALLY THINKING ABOUT THE GUT MICROBIOME AND READING PAPERS WHEN WE STARTED THIS PROJECT ABOUT FIVE YEARS AGO, IT WAS REALLY CLEAR THAT THERE WAS NOT -- NOBODY REALLY KNEW WHAT IS A NORMAL MICROBIOME. AND WHAT ARE THE FACTORS THAT INFLUENCE THAT, ARE THERE BEING GENETIC PHENOTYPIC OR ENVIRONMENTAL? IF WE HAVE THIS LIFELINE DEEP COHORT WITH LOTS OF DATA, WE THOUGHT THIS MIGHT BE AN OPPORTUNITY TO STUDY THAT. ALL THE 167,000 PEOPLE PARTICIPATING IN LIFELINES WE HAVE ABOUT 1500 PHENOTYPES. THAT IS DATA ON DIET PEOPLE TAKE, MEDICATION, SMOKING HABITS, BUT ALSO INFORMATION ON ALL KINDS OF PHYSIOLOGICAL PARAMETER, BLOOD PRESSURE, BLOOD LIPIDS, SO ON. BUT IN ADDITION, IN THIS SMALLER COHORT OF 1500 INDIVIDUALS WE HAVE VERY DEEP OMICS DATA. SO WE HAVE GENOTYPES, WE ALSO HAVE METHYLATION DATA, TRANSCRIPTOMICS, PROTEINS, FROM BLOTS OR CYTOKINES AD POENECTINS. WE MEASURE METABOLITES, EXHALED AIR ORGANIC COMPOUNDS ADS WELL AS PLASMA AND 16S R RNA SEQUENCING AS WELL AS META GENOMICS SHOTGUN SEQUENCING OF OUR GUT MICROBIOME. THAT IS ALL BASED ON STOOL SAMPLES. SO WE SET OUT A COMPREHENSIVE STUDY TO SEE WHAT IS THE AFFECT OF THOSE FACTORS ON THE GUT MICROBIOME. NOT ALL THE PARTICIPANTS DID PARTICIPATE IN COLLECTING STOOL SAMPLES, WE HAD STOOL FROM JUST OVER 1100 PEOPLE. AND BY SEQUENCING THEM WE COULD DISTINGUISH MORE THAN 1600 DIFFERENT BACTERIAL SPECIES. THEN WE CORRELATED THAT WITH 78 DIFFERENT FACTORS ON DIET PEOPLE WERE TAKING, 44 CATEGORIES OF DRUGS, 5 CATEGORIES OF SMOKING, 39 DIFFERENT DISEASES THAT WERE PRESENT IN THAT GROUP OF PEOPLE. AND 41 INTRINSIC FACTORS AND THEN YOU SHOULD THINK ABOUT FACTORS LIKE AGE, GENDER, LIPID LEVELS, ET CETERA. AN INTERESTINGLY WHAT WE FOUND, THE SINGLE MOST IMPORTANT FACTOR THAT DETERMINES VARIATION IN OUR GUT FLORA IS OUR STOOL TYPE. HOW DOES YOUR STOOL LIKE? AND WHEN WE'RE MEASURING THAT FROM PEOPLE GIVING THEM WHAT WE CALL THE BRINGS STOLE STOOL CHART, I DON'T THINK IT'S SELF-EXPLORATORY, THE ONLY THING I HAVE TO SAY IS TYPE 17 BEING VERY HARD TO TYPE 1 TO DIARRHEA FORM, IF YOU HAVE THE TYPE 7 AND EVERYTHING IN BETWEEN. BUT IT TURNS OUT IT REALLY MATTERS WITH RESPECT TO HOW DIVERSE YOUR MICROBIOME IS. THAT DEPICTED IN THE PICTURE THAT CAME UP FROM OUR PUBLICATION BUT FROM GROUP IN BELGIUM THAT DID MORE OR LESS THE SAME. IS IF YOU HAVE A DIARRHEA FORM OF STOOL AND YOU'RE PROBABLY FLESH OUT A LOT OF BACTERIA IN YOUR INTESTIN AND ALL OF A SUDDEN YOU HAVE A MUCH LOWER DIVERSITY OF BACK FEARIA. -- BACTERIA, COMPARED TO PEOPLE THAT HAVE HARDER STOOL TYPES. AND IN GENERAL THAT IS CONSIDERED MORE VARIETY IS BETTER SO THAT MEANS THAT YOU EITHER WANT TO BE IN THIS CORNER AND NOT SO MUCH ON THE DIARRHEA SIDE. BUT IF YOU WOULDN'T HAVE KNOWN THIS INFORMATION IT ALSO MEANS THIS CAN BE A MAJOR CONFOUNDER OF YOUR DATA AND SO FAR I HAVEN'T SEEN THAT ALL THE MICROBIOME STUDIES ARE COLLECTING THIS TYPE OF INFORMATION. BUT GIVEN THAT IT'S SUCH A MAJOR DETERMINANT, THIS IS REALLY SOMETHING PEOPLE SHOULD TAKE INTO CONSIDERATION AND REALLY CONTROL FOR. NOT SURPRISING OF COURSE IS THAT WHAT WE EAT ALSO VERY MUCH DETERMINES WHAT'S HAPPENING WITH THE BACTERIA IN OUR DIET BECAUSE THEY ARE ALSO IN PART DEPENDENT ON OUR FOOD. WE HAVE TWO CATEGORIES, FOOD IRONS THAT REALLY ENRICHED OUR DIVERSITY AND ALSO THE ONES IN GREEN AND AGAIN, MORE DIVERSE IS CONSIDERED TO BE BETTER. AND THERE ARE FOOD ATTEMPT NOT AS GOOD BECAUSE THEY REDUCED DIVERSITY. IT IS INTERESTING TO SEE THE ITEMS THAT REALLY INCREASE OUR DIVERSITY ARE ALSO INCLUDING COFFEE AND RED WINE, IT'S NOT SOMETHING YOU WOULD EXPECT UP FRONT BUT ALSO FRUITS, VEGETABLES AND YOGURT. WHEREAS BEER AND SODA IS SOMETHING YOU PROBABLY SHOULD AVOID. SINCE WE ALSO HAD MEDICATION USE FROM THE -- WE CAN ALSO LOOK WHAT IS EFFECT OF TAKING MEDICATION ON GUT FLORA. WE SAW A LOT OF THE MEDICINES PEOPLE TAKE HAVE QUITE SOME EFFECT ON YOUR GUT MICROBIOME. BY DOING SO CAUSE ALL KINDS OF SECONDARY CONSEQUENCES LIKE INFECTION, GUT INFLAMMATION OR HAVE AN EFFECT ON HOST ME TAB LIMB. IF YOU GO THROUGH THE LIST THERE IS LOTS OF MEDICATIONS THAT ARE WIDELY PRESCRIBED LIKE STATINS, ORAL CONTRACEPTIVES BUT ALSO ANTIDEPRESSANT MEDICATION. BUT REALLY WHAT IS ON THE TOP OF THIS LIST, ARE THE PROTON PUMP INHIBITORS. THEY REALLY HAVE A MAJOR EFFECT ON THE VARIATION OF OUR GUT MICROBIOME. THIS IS A VERY WIDELY PRESCRIBED DRUG. WE ALSO KNOW IF YOU CONTINUOUSLY USE PROTEIN PUMP INHIBITORS YOU INCREASE YOUR RISK FOR CDIF. THERE'S A LOT OF EPIDEMIOLOGICAL STUDIES THAT REALLY SHOW THAT AND WE ALSO KNOW THAT THERE IS A REALLY, AN INCREASE OF PEOPLE THAT ARE HOSPITALIZED WITH C-DIFF. SO WHEN WE LOOK INTO THE GUT MICROBIOME OF PPI USERS, IT WAS REALLY CLEAR THAT WE HAD MAJOR SHIFTS IN 20% OF THE BACTERIAL -- SO WE SEE PEOPLE INCREASE ALL THE BACTERIA THAT ARE GIVEN HERE IN RED, MORE INTRO DA CUSS STREPTOCOCCUS AND E. COLI, AND THESE ARE POTENTIALLY THE BAD BOOKS IN YOUR GUT, AND REDUCE THE MORE BENEFICIAL -- IN PARTICULAR THE BIFFIDO BACTERIA. WE ALSO KNOW THAT IF YOU TAKE P PI, YOU REDUCE THE PH IN YOUR GUT AND THAT PROBABLY IS THE REASON FOR BIG CHANGE IN THE LOCAL ENVIRONMENT THAT ON THE ONE HAND YOU ALLOW OTHER BACTERIA TO TAKE OTHER NICHES THAT ARE EMPTIED. AND PATHOGEN BACTERIA WOULDN'T SURVIVE BECAUSE OF ACIDITY, ALL OF A SUDDEN CAN SURVIVE. BUT IT WAS INTERESTING THAT WE ALSO HAVE MICROBIOME FROM THE ORAL CAVITY FROM A SMALL SUBSET OF PEOPLE, WE SAW THE BACTERIA THAT WERE IN THE GUT FROM PEOPLE WITH THE PPI WAS MORE REMINISCENT OF THE BACTERIA IN THE ORAL CAVITY. REALLY TELLING US THAT YOU GET A SHIFT FROM YOUR BACTERIAL COMPOSITION. SO WE HAVE TO BE MORE CAREFUL IN PRESCRIBING PPIs BECAUSE OF THOSE DRAMATIC EFFECTS ON YOUR GUT MICROBIOME. SO IF YOU PUT ALL DATA TOGETHER WE ANALYZE, AND I SHOWED YOU COUPLE OF EXAMPLES, WE HAD IN TOTAL 126 FACTORS. AND AGAIN, MAINLY COMING FROM MEDICATION, DIET AND SOME OF THE INTRINSIC FACTORS LIKE LIPID LEVELS, AND THEY EXPLAIN NEARLY 20% OF THE VARIATIONtH$R' OUR GUT MICROBIOME, THAT'S A SUBSTANTIAL PROPORTION. FROM TWIN STUDIES, HOWEVER, WE ALSO KNOW THERE ARE CERTAIN BACTERIA THAT ARE QUITE HERITABLE. AND IT WOULD SUGGEST THEY ARE NOT SO MUCH INFLUENCED BY OUR ENVIRONMENTAL FACTORS LIKEok DIET AND MEDICATION BUT MAYBE MORE BY OUR HOST GENOME. AND THIS IS WORK DONE BY THE GROUP OF THE INSPECTOR ON THE 20 UK COHORT AND IT REALLY SHOWS THAT SOME OF THE BACTERIA ARE HERITABLE, WHEREAS OTHERS ARE NOT SO SEEMS TO BE A DIVIDE IN OUR BACTERIAL COMMUNITY. SO WE WERE REALLY ASKING OURSELF THE QUESTION, CAN WE DETECT AN EFFECTIVE HOST GENETICS ON THE GUT MICROBIOME ESPECIALLY GIVEN THAT THERE IS SO MUCH NOISE FROM ALL THE OTHER FACTORS. COMING FROM THE ENVIRONMENT FACTORS. SO TO ADDRESS THAT QUESTION, WE AGAIN MADE USE OF THE LIVE LINE DEEP COHORT, WE TOOK PEOPLE ON ANTIBIOTICS AND HAD REPLICATION IN THE 500 FG COHORT AS WELL AS A SMALLER COHORT AND WE USED THOSE FOR REPLICATION. SO DOING THAT EXPERIMENT, WE SAW INDEED THAT THERE IS AN EFFECT OF GENETIC FACTORS ON OR GUT MICROBIOME. THOUGH THIS IS A MODEST EFFECT. AND WE HAD BOTH ASSOCIATION TO SINGLE BACTERIA AND SOME ARE ALSO BACTERIA THAT HAVE A REASONABLE HERITABILITY SO THIS IS ALSO WHAT YOU WOULD EXPECT BECAUSE THE MORE HERITABLE BOX. AND WE ALSO HAD ASSOCIATIONS TO METABOLIC PATHWAYS. I WILL GIVE YOU A COUPLE OF EXAMPLES OF DATA THAT WE IDENTIFIED. ONE ON THE LCT STORY.MY AND ONE ON THE C LEPTON GENES. BUT THIS ASSOCIATION WAS INTERESTING WITH THE GENUS BLODIA BECAUSE WE SAW A SNP IN OR NEAR THE LINKO 2 GENE ASSOCIATED WITH OBESITY AND BMI. AND WE KNOW THAT THERE IS REALLY STRONG EFFECT OF THE MICROBIOME ON BODY WEIGHT. SO WE SAW IN FACT MANY DIFFERENT GENETIC VARIATION, MANY DIFFERENT GENES THAT MAKE UP THE LEPTON RECEPTORS. SO ALL THE -- SO WE HAVE DIFFERENT LEPTON RECEPTORS AND THERE'S MANY GENES INVOLVED. BUT ALL THE ONES IN THE RED ARE THE ONES IDENTIFIED IN THIS STUDY AS BEING ASSOCIATED WITH THE GUT MICROBIOME. SO WE KNOW THAT THOSE RECEPTORS RECOGNIZE INTESTINAL MICROBIOTA AND AFTER ACTIVATION CAN REALLY MODULATE THE PRODUCTION OF7s– PRO-INFLAMMATORY CYTOKINES. SO PROVIDING THE LINK BETWEEN THE MICROBIOME AND THE IMMUNE SYSTEM PROBABLY MODULATED IN PART TO -- THROUGH OUR HOST GENOME. ANOTHER INTERESTING OBSERVATION WE MADE IS THE GENOTYPE THAT MAKES US LACTOSE DEFICIENT. SO YOU KNOW THE STORY THAT WE NEED THE LACTASE ENZYME TO DIGEST DAIRY PRODUCTS BECAUSE IT CAN BREAK DOWN THE LACTOSE WHICH IS THE SUGAR IN DAIRY PRODUCTS. AND THE G GENOTYPE IN THE GENE IS THE GENOTYPE ASSOCIATED WITH LACTOSE DEFICIENCY. AND PEOPLE THAT CARRY THAT GENOTYPE HAVE MUCH HIGHER LEVELS OF DIFFICIL BACTERIA THAN CARRIERS THAT DON'T. THAT'S ARE THE CARRIERS COMPARED TO ONE ALLELE OR WILD TYPE. YOU CAN SEE A MAJOR DIFFERENCE IN THE AMOUNT OF BACTERIA IN THE GUT OF THE GG CARRIERS. INTERESTING, HOWEVER, THIS IS ONLY THE CASE WHEN PEOPLE DRINK A LOT OF MILK. THIS SOUND WEIRD BECAUSE IF YOU'RE LACTOSE DEFICIENT YOU THINK PEOPLE CANNOT CONSUME MILK BECAUSE THEY DON'T DIGEST IT. THOUGH THIS IS NOT THE CASE SO SINCE WE HAVE THIS NICE COHORT WE CAN ALSO CHECK HOW MANY PEOPLE HAVE THIS LCT GENOTYPE AND HOW MANY OF THEM STILL DRINK MILK. IT'S QUITE A REASONABLE AMOUNT. HAVING THIS G GENOTYPE AND DRINKING MILK ONLY THEN YOU HAVE INCREASED LEVELS OF BACTERIA, REALLY TELLING US THAT IF YOU DRINK MILK AND HAVE THE BAD GENOTYPE YOU KIND OF COMPENSATE FOR THAT BUT INCREASED LEVELS OF BACTERIA BECAUSE IT METABOLIZES LACTOSE AND DIMINISH THE EFFECT OF NOT HAVING TESTIMONY GENE. SO THIS -- HAVING THE GENE. SO ALL THIS IS A GENE ENVIRONMENT INTERACTION AND THERE'S MANY MORE TO BE DISCOVERED IN THE DATA THAT WE HAVE GENERATED. BUT THESE WILL BE HARD OF COURSE TO DETECT AS WELL. SO SO FAR WE HAVE MANY, LOOKING AT WHOLE COMMUNITIES BUT IN ORDER TO REALLY UNDERSTAND HOW BACTERIA PROVIDE OR FUNCTION WE HAVE TO MOVE ON TO SINGLE STRAINS AND EVENTUALLY ALSO UNDERSTAND WHAT ARE THE METABOLITES BEING MADE BY THE BACTERIA, HOW DO THEY SIGNAL BACK TO THE HOST. SO TO DO THAT WE HAVE COLLECTED A MUCH LARGER SAMPLE SIZE OF 10,000 PEOPLE, BUT ALSO SITUATED WE CAN CULTURE SINGLE BACTERIA THAT WILL HELP US HOPEFULLY TO GO A LITTLE BIT MORE DEEPER INTO MORE FUNCTIONAL STUDIES. AT THE SAME TIME WE ALSO DO LONGITUDINAL EXPERIMENTS BECAUSE WE REALLY HAVE TO UNDERSTAND WHAT IS CAUSE AND CONSEQUENCE, BECAUSE EVERYTHING I SHOWED YOU SO FAR IS JUST ASSOCIATION. THAT ALSO INCLUDES 1500 NEWBORNS WHERE WE CAN ALSO SEE HOW THIS MICROBIOME IS TEACHING OUR IMMUNE SYSTEM ADS WELL. AND THEN WE HAVE TO ALSO ENRICH DATA. SO WE DID ALSO FECAL METABOLITES FOR EXAMPLE TO REALLY UNDERSTAND A LITTLE BIT BETTER WHAT DO THE BACTERIA ARE„i MAKING THEMSELVES. SO THAT WAS MY FIRST VIGNETTE. SO NOW I WANT TO MOVE TO THE SECOND VIGNETTE AND THAT IS ABOUT FACTORS THAT INCLINE VARIATION AND CYTOKINE PRODUCTION. THIS GOES BACK TO MY INTEREST IN AUTOIMMUNE DISEASE BECAUSE WHAT IS REALLY GOING ON IN AUTO-IMMUNITY IS THAT YOUR IMMUNE SYSTEM IS NOT WORKING PROPERLY, IT'S OVERREACTING TO SOMETHING IT SHOULDN'T DO. BUTD ON OTHER SIDE OF THE COIN YOU HAVE AN IMMUNE SYSTEM THAT IS NOT WORKING GOOD ENOUGH AND LEADS TO SUSCEPTIBILITY TO INFECTION. SO IT IS REALLY IMPORTANT THAT WE HAVE A PROPER BALANCE TO HAVE AN APPROPRIATE IMMUNE RESPONSE THAT DOESN'T GO IN EITHER DIRECTION. AND SO REALLY, WE'RE CONFRONTED AS HUMAN BEINGS ALL THE TIME WITH ALL KINDS OF PATHOGENS OF COURSE AND TO REALLY ELIMINATE THOSE, WE NEED BOTH SPECIALIZED CELLS AS WELL AS A SPECIFIC SET OF CYTOKINES THAT TAKE CARE OF THAT. VERY SIMILAR TO OUR STUDY IN THE MICROBIOME, OUR CURRENT UNDERSTANDING OF THE VARIATION IN THE HOST WITH RESPECT TO IMMUNE SYSTEM IS– LIMITED. SO WE REALLY DON'T KNOW WHAT IS THE NORMAL VARIATION, AND WHAT ARE THE FACTORS THAT ARE REALLY INFLUENCING THAT EITHER BEING GENETIC INTRINSIC OR FUNCTIONAL FACTORS. SO FOR THAT WE TURN TO THE 500 FG COHORT, VERY SIMILAR IN DESIGN AS THE LIFELINES-DEEP I SHOWED YOU EXCEPT IT HAS IN ADDITION A VERY DEEP IMMUNE PHENOTYPING. SO WE HAVE A LOT OF DATA ON PLATELET ACTIVATION, WE HAVE DIFFERENT IMMUNOGLOBULINS, DETAILED INFORMATION OF THE DIFFERENT CELL TYPES PRESENT, WE FLOW SAW 7 # DIFFERENT ONES -- 73 DIFFERENT ONES AND THEN INFORMATION ON CYTOKINES IN RESPONSE TO STIMULI. WE LOOK TO SIX DIFFERENT CYTOKINES AND 18 STIMULI. AND ALL IN 500 PEOPLE. SO GENERAL CHARACTERISTICS OF 500 FG, WE HAVE A WIDE 8 RANGE BUT THERE'S A SKEWING TOWARDS PEOPLE IN THE AGE RANGE BETWEEN 20 AND 30. BECAUSE THESE ARE STUDENTS CONTRIBUTING TO STUDY, WE HAVE A NORMAL BMI WE HAVE EQUAL MALES AND FEMALES, HALF THE FEMALES USE ORAL CONTRACEPTIVES, ABOUT 13% COHORT IS SMOKERS. AND WE HAVE INFORMATION ABOUT THE SEASONALITY BECAUSE SAMPLES WERE CHECKED OVER A ONE AND A HALF YEAR TIME PERIOD. SO BETWEEN JULY 2013 AND JANUARY 2015, WE CAN REALLY ALSO SEE WHAT IS THE EFFECT OF SEASON. YOU CAN IMAGINE THAT IT REALLY MATTERS WHETHER IT'S WINTER OR SUMMER IF YOU ARE FOR EXAMPLE EXPOSED TO FLU VIRUS YOUR IMMUNE SYSTEM MAYBE IN ADIFFERENT STATE THAN WHEN YOU DON'T HAVE THIS EXPOSURE. SO WE TOOK BLOOD AND PBMCs AND STIMULATED WITH THREE DIFFERENT FUNGI, SEVEN BACTERIA, ONE VIRUS. FOUR BACTERIAL LIGANDS. AND THREE METABOLIC STIMULI, THIS WAS EX-VIVO. MEASURED AFTER 24 HOURS TNF ALPHA IL-6 AND IL-# BETA, THIS IS REGARDED AS MONOCYTE DERIVED CYTOKINES. AND AFTER TWO DAYS AND SEVEN DAYS WE MEASURED INTERFERON GAMMA, IL-17 AND IL-22 WHICH WE THEN WITH REGARD AS T-CELL CYTOKINES. SO WE HAD FOR EVERY INDIVIDUAL, WE HAD A LITTLE BIT OVER 500 AND 95 DIFFERENT CYTOKINE MEASURES. AND THE FIRST QUESTION WE WERE ASKING OURSELF IS HOW ARE THOSE CYTOKINE RESPONSES BUILT? IS IT SO THAT IF YOU ENCOUNT ERR CERTAIN PATHOGEN AND YOUR RESPONSE IS CERTAIN LEVEL OF TNF ALPHA, DO YOU THEN ALSO HAVE THE SAME LEVEL OF IL 1 BETA AND I ALREADY-1? OR IS IT THAT ONCE YOU ARE A HIGH TNF ALPHA RESPONDER TO LET'S SAY A CERTAIN BACTERIA, ARE YOU ALSO A HIGH RESPONDER TO A VIRUS OR TO A FUNGUS? SO WHEN WE LOOK AT THE CORRELATION OF ALL THE CYTOKINES PRODUCED AFTER STIMULATION WITH THOSE DIFFERENT STIMULI, AND UNSUPERVISED CLUSTERING, IT IMMEDIATELY BECAME CLEAR THAT ALL THESE STIMULATIONS IN RESPONSE TO BACTERIA GROUPING TOGETHER AS WELL AS THE FUN GUY AS WELL ADS -- FUNGI AS WELL AS VIRUSES TELLING US THAT THE THINGS ARE BUILT IN A PATHOGEN SPECIFIC WAY AND THIS IS JUST TO BLOW UP TO SHOW IN MORE DETAIL. IF YOU STIMULATE WITH LPS OR CANDIDA OVER STAPH AUREUS, YOU HAVE A CORRELATED RESPONSE WITH THE THREE DIFFERENT CYTOKINES. SO REALLY TELLING US, IT'S THE PATHED WAY THAT -- THE PATHOGEN THAT THIS–r IS DETERMINING THIS. SO THAT MEANS IF YOU RESPOND WELL TO A BACTERIA, YOU MAY NOT RESPOND VERY WELL TO A FUNGUS, FOR EXAMPLE SO THERE'S PLASTICITY IN THE RESPONSE TO PATHOGENS. IT SEEMS WE ALSO HAD OF COURSExD THE GENETIC INFORMATION COMBINED WITH THE FACT THAT THERE WAS A LOT OF VARIATION BETWEEN INDIVIDUALS, WE COULD ASSESS, IS THIS PRODUCTION OF CYTOKINES, IS THIS UNDER GENETIC CONTROL. IF YOU INTERSECT THE TWO TYPES OF DATA, YOU CAN SEE DEPENDING ON GENOTYPE PEOPLE HAVE HIGHER OR LOWER LEVELS OF CYTOKINES BEING PRODUCED SO CYTOKINE QTLs. SO BY DOING THAT, WE SHOW THIS IS INDEED THE CASE FROM THIS SMALL COHORT OF JUST OVER 500 INDIVIDUALS, WE SAW 17 LOCI IN THE GENOME WHERE GENETIC VARIATION IMPACTS THE LEVEL OF CYTOKINES YOU PRODUCE IN RESPONSE TO A CERTAIN STIMULUS. AND THIS IS A MANHATTAN PLOT, DIFFERENT FROM WHAT YOU'RE USED TO, WE HAVE CHROMOSOME ONE ALL THE WAY TO CHROMOSOME 22. THE DIFFERENT COLORS JUST TELL YOU WHAT IS THE LIGAND WE USE FOR THE STIMULATION. SO THE BLUE IS THE BACTERIAL AND WE SEE REALLY THE MAJORITY OF THE CYTOKINE QTLs ARE IN RESPONSE TO BACTERIAL LIGANDS. AND WE SEW A FEW, THE -- SEE A FEW THE PINK ONES THOSE ARE FUNGI. THERE IS A STRONG -- HERE THAT IS THE TOLL LIKE RECEPTOR GENE. AND THE SNP IS REALLY A POINT MUTATION IN THE TOLL LIKE RECEPTOR 1 GENE SO POINTING TO THE FUNCTIONAL VARIANT. INTERESTINGLY ENOUGH, WE SEE THAT IN PARTICULAR THE PRODUCTION OF IL-6 AND IL-1 BETA IS UNDER GENETIC CONTROL SO OUT OF 17, 10 ARE IL-6 OR IL-1 BETA. WE SEE LESS FOR THE OTHER CYTOKINES. AND THE OTHER INTERESTING OBSERVATION IS WHEN WE INTERSECTED THOSE CYTOKINE DATA WITH GWAS DATA ON EITHER AUTOIMMUNE DISEASES OR INFECTIOUS DISEASES WE SAW THESE CYTOKINES THAT WE REGARD AS LOCI DERIVED SO IL-6, IL-1 BETA AND TNF ALPHA OVERLAP WITH SNPS ALSO ASSOCIATED WITH INFECTIOUS DISEASES, WHEREAS T-CELL DIRECT CYTOKINES MAINLY OVERLAP WITH THE AUTOIMMUNE DISEASES WHICH ARE ALSO REGARDED MAINLY ADS T-CELL DISEASES, SO THAT IS AN INTERESTING OBSERVATION BECAUSE ONE HAND IT PUTS FUNCTION TO GWAS SNPS BUT ALSO TELLS US ABOUT EFFECTOR CELLS IN THOSE DIFFERENT PHENOTYPES SO BEING THE INFECTIOUS DISEASE IS MORE MONOCYTE RELATED AND THAT FITS WITH THE FACT THESE ARE MORE INNATE PHENOTYPES, WHEREAS THE AUTOIMMUNE DEESS ARE MORE THE T-CELL -- DISEASES IS THE MORE T-CELL TYPE, THE MORE ADAPTIVE IMMUNE RESPONSE. SINCE WE HAVE SO MUCH INFORMATION ON THOSE INDIVIDUALS WE CAN ALSO SEE WHAT IS THE CONTRIBUTION OF OTHER FACTORS ON CYTOKINE PRODUCTION AND REALLY THE MAJORITY OF THE EFFECT IS COMING FROM GENETICS OF SNPS AS WELL AS GENE EXPRESSION THOUGH IT'S UNDER GENETIC CONTROL SO NOT INDEPENDENT OF EACH OTHER. AND THEN WE SEE A LITTLE BIT OF AFFECT OF CELL COMPOSITION, NOT AS MUCH AS WE EXPECTED. WE SEE A LITTLE EFFECT OF SEASONALITY. REALLY NOT SO MUCH ABOUT AGE IN GENERAL, WE PROBABLY WOULD HAVE EXPECTED MORE THERE BUT FOR THE AGE IT COULD BE ALSO THAT WE -- THOUGH WE HAVE A WIDE AGE RANGE, MAJORITY OF PEOPLE ARE BETWEEN 20 AND 30 YEARS OF AGE, WHAT'S INTERESTING IS THAT WE SEE ALSO SOME EFFECT OF MICROBIOME ON THE PRODUCTION OF CYTOKINES. SO WHAT WE'RE DOING NOW IS REALLY -- I THOUGHT I HAD ANOTHER SLIDE. TO SEE CAN WE PUT ALL THIS DATA TOGETHER TO KIND OF PREDICT HOW PEOPLE WOULD RESPOND TO A CERTAIN PATHOGEN. AND THIS MAY BE INTERESTING IN THE FUTURE, IF WE WANT TO UNDERSTAND BETTER WHO IS AT HIGHER RISK FOR EITHER GETTING INFECTIOUS DISEASES IN SAY HOSPITAL PEOPLE OR IN THE ELDERLY. AND REALLY IT DEPENDS ON THE TYPE OF PATHOGEN WITH THE CYTOKINE IF WE CAN DO SO. SO HERE IS AN EXAMPLE, HERE WE PUT ALL THE DIFFERENT CATEGORIES OF DATA THAT WE HAVE TOGETHER AND IF YOU STIMULATE WITH E. COLI AND -- WE CAN PREDICT WITH 80% ACCURACY HOW YOU WOULD RESPOND WITH TNF ALPHA LEVELS. WHEREAS, IF YOU STIMULATE WITH INFLUENZA, WE CANNOT DO IT ADS GOOD, IT'S ONLY ABOUT 50%. BUT THIS IS STILL PRELIMINARY WORK SO HOPEFULLY WHEN WE ADD MORE INFORMATION WE CAN REALLY DO THIS A LITTLE BIT BETTER, NOTHING THAT IS QUITE INTERESTING. -- THAT IS QUITE INTERESTING SO BACK TO THIS MICROBIOME THAT EXPLAINS HOW 10% OF THE VARIATION IN CYTOKINE PRODUCTION, IT'S INTERESTING ALSO HERE THAT WE SEE SOME SPECIFICITY IN BOTH STIMULUS AS WELL AS CYTOKINES THAT WE SEE. WE MAINLY SEE THE TNF ALPHA AND INTERFERON GAMMA CYTOKINES AFFECTED BY BACTERIA IN YOUR GUT. AND WE SEE A LOT IN RESPONSE TO CANDIDA FOR EXAMPLE. SO REALLY TELLING US IF WE TALK ABOUT THE GUT MICROBIOME IN MY FIRST PART OF MY TALK, I SHOWED YOU THAT MEDICATION AND DIETND AND GENETICS HAS AN EFFECT BUT WE ALSO SHOW CYTOKINE PRODUCTION CAN BE UNDER CONTROL OF THE GUT MICROBIOME IN PARTICULAR INTERFERON GAMMA AND TNF ALPHA. WHEREAS FOR OTHER CYTOKINES LIKE IL-6 AND IL-1 BETA, I SHOWED YOU THEY ARE MUCH MORE UNDER GENETIC CONTROL. SO WE'RE STARTING TO TEASE THIS APART. BUT THIS IS INTERESTING BECAUSE IT ALSO TELLS YOU MAYBE THROUGH DIET OR MEDICATION, WE CAN AT LEAST MAYBE MODULATE CYTOKINE RESPONSES IN THE FUTURE. THIS IS OF COURSE EARLY WORK BUT AT LEAST IT SHOWS POTENTIAL. OKAY. SO ONLY A FEW SLIDES LEFT. TELL YOU A LITTLE BIT ABOUT CAN WE NOW USE THAT INFORMATION THAT WE GENERATED FROM THE POPULATION BIOBANKS TO ALSO UNDERSTAND A LITTLE BIT BETTER INFECTIOUS DISEASES. AND WHY WOULD YOU DO THAT? INFECTIOUS DISEASES ARE A MAJOR HEALTH PROBLEM, ABOUT ONE-THIRD OF THE POPULATION DIES BECAUSE OF INFECTION. AND WE ONLY HAVE A VERY LIMITED UNDERSTANDING AS OF TODAY WHAT ARE REALLY THE GENETIC FACTORS THAT CONTROL THAT. SO WE SET OUT TO STUDY CANDIDA BECAUSE IT IS A VERY SERIOUS BLOODSTREAM INFECTION THAT KILLS 150,000 PEOPLE A YEAR. IT'S REALLY HARD TO DO GENETICS ON DISEASES LIKE SYSTEMIC CANDIDEMIA, BECAUSE IT'S VERY DIFFICULT TO GET LARGE ENOUGH COHORTS TO STUDY. AND OVER THE YEARS WE HAVE BEEN STUDYING A COHORT OF 217 CASE, YOU WILL START LAUGHING IN THE GWAS AREA BECAUSE WE USE IT FOR THOUSANDS OF CASES FOR CILIAC DISEASE, FOR EXAMPLE 12,000 PATIENTS BUT THIS IS THE LARGEST COHORT THAT WE HAVE TODAY. SO WE HAVE TO DEAL WITH IT. NEVERTHELESS, A FEW YEARS AGO WE DID A GWAS STUDY USING THE IMMUNOCHIP, ONLY A LIMITED NUMBER OF LOCI IN THE GENOME AND MUCH TO OUR SURPRISE WE IDENTIFIED THREE LOCI WITH GENOME WIDE SIGNIFICANCE. IF YOU LOOK AT THE ALLELE FREQUENCY AS WELL AS OF THE ODDS RATIOS OF THOSE LOCI, WE SEE SOMETHING THAT'S COMPLETELY DIFFERENT FROM WHAT WE ARE USED TO IN THE OTHER COMPLEX DISEASES WE HAVE RARE ALLELES, THEY HAVE A HIGH ODDS RATIO. SO A MUCH STRONGER EFFECT THAN WHAT WE NORMALLY SEE, NORMALLY IN THE RANGE OF 1.2, 1.4 SO ALREADY TELLING US THE GENETIC ARCHITECTURE OF AT LEAST THIS INFECTIOUS DISEASE IS QUITE DIFFERENT FROM AN AUTOIMMUNE PHENOTYPE. NEVERTHELESS, THE LOCI WE IDENTIFY ARE ALSO IDENTIFIED FOR AUTO-IMMUNITY. SO IT'S INTERESTING NOW TO SEE IF THERE REALLY GOING INTO OPPOSITE DIRECTIONS AND WE ARE DOING WORK ON THAT AT THE MOMENT. BUT YOU ALSO SEE IN THIS MANHATTAN PLOT THERE IS A LOT OF SIGNAL THAT IS OF COURSE BELOW THIS LEVEL OF SIGNIFICANCE. BECAUSE OF THE SMALL COHORT WE HAVE, IT'S IMPOSSIBLE TO BOLSTER. SO WE WERE WONDERING IF WE CAN MAKE USE OF THE DATA THAT WE HAVE GENERATED IN OUR BIOBANKS TO SEE IF THERE'S ANY INTERESTING SIGNAL IN THAT AS WELL. AND FOR THAT, WE TURN TO 500 -- LIFELINE-DEEP AND 500 FG. SO LIFELINES-DEEP WE HAVE DATA AND IT HELP US DO A STANDARD ANALYSIS SO WE CAN IDENTIFY WITH ASSOCIATED SNPS WHAT IS THE GENE UNDER THE CONTROL OF THE SNP BY DEPENDING ON THE ALLELE YOU HAVE YOU MAKE HIGHER OR LOWER AMOUNTS OF THAT PARTICULAR GENE TRANSCRIPT. SO THAT REALLY LINKS SNPS TO GENES. ON THE OTHER HAND, WE HAVE THE 500 FG WHERE WE HAVE THE STIMULATION IS A DIFFERENT PATHOGEN AND NOW WE CAN SEE IN THE SAME INDIVIDUAL IS A GENE RESPONDING TO A PARTICULAR PATHOGEN OR NOT. SO IS IT REALLY CANDIDA RESPONSE GENE SO IF IT HAS THE SITUATION WE ONLY SEE SIGNAL WHEN WE STIMULATE WITH CANDIDA, THAT WAS BACTERIAL VIRUSES, THEN AT LEAST THE GENE HAS SOMETHING TO DO PROBABLY WITH THE INFECTION WITH CANDIDA. SO WHEN WE DID AN ANALYSIS FROM ALL THE SNPS IN THIS GREEN AREA, THIS WAS ONE OF THE INTERESTING SNPS WE IDENTIFIED. ON CHROMOSOME 7. THE P VALUE WAS NOT GENOME WIDE SIGNIFICANT, IT'S A RARE SNP WITH A REASONABLE ODDS RATIO. IF YOU CARRY THIS SNP YOU IMPACT THE LEVELS OF THE CERTAIN 1 GENE SO WE DIDN'T HAVE HOMOZYGOUS CARRIERS BUT HETEROZYGOUS AND THE LEVEL OF EXPRESSION IS LOWER THAN COMPARED TO THE HOMOZYGOUS FOR THE WILD TYPE ALLELE SO THE RISK ALLELE LOWERS THE LEVELS OF SERPIN 1, SERPIN 1 IS THE SAME AS ANTI TRYPSIN, THIS MAY RING BELL TO YOU. WHEN WE WENT TO THE CANDIDA INDUCED STIMULATION, WE ALSO SAW THIS GENE WAS INDUCED UPON STIMULATION WITH CANDIDA. HERE WE HAVE NO STIMULATION AT ALL, THEN AFTER FOUR HOURS WE SEE SOME INDICATION, AFTER 24 HOURS WE SEE STRONGER INDUCTIONS. SO PROVIDING SOME EVIDENCE THAT THIS MAY BE A GENE THAT HAS SOMETHING TO DO WITH CANDIDA INFECTIONS. THEN WE WENT TO MICE, WE HAVE OVEREXPRESSION OF SIREPIN 1 BECAUSE DELETION IS LETHAL. AND WHEN WE INFECTED THOSE MICE WITH CANDIDA WE SAW IF YOU HAVE HIGH LEVELS OF ALPHA 1 ANTITRYPSIN, YOU WILL SURVIVE THE CANDIDA INFECTION, WHEREAS THE WILD TYPE ALL DIE AFTER SIX DAYS. SO REALLY TELLING US THAT THIS GENE IS REALLY IMPORTANT FOR CLEARING THE CANDIDA. REMEMBER, THE -- IN THE FEDERALS THAT WERE HAVING THE T ALLELE HAVE REALLY LOWER LEVELS AND THAT MEANS THEY CANNOT CLEAR THE CANDIDA AS EASY AS POSSIBLE. SO THIS RAISES INTERESTING QUESTIONS THAT MAYBE BY RAISING THE LEVELS OF ANTI-1 ANTITRYPSIN THIS MAYBE A FUTURE OPTION FOR IN ACADEMIA. THIS NEEDS TO BE WORKED OUT IN MUCH MORE DETAIL BUT SHOWS US HOW WE CAN HOPEFULLY MOVE ON FROM THOSE OBSERVATIONS AND HOW WE CAN REALLY BRIDGE POPULATION BIOBANK WORK WITH MORE CLINICAL COHORTS. SO I GAVE YOU THREE EXAMPLES AND I HOPE I SHOWED YOU THAT BY STUDYING THE GUT MICROBIOME WE MAY GET SOME OPPORTUNITIES UPON HOW WE CAN IMPROVE OUR GUT HEALTH BY CHANGING OUR DIETS OR CHANGING OUR MEDICATION. I THINK FROM THE WORK ON THE CYTOKINES, I FIND IT EXCITING TO SEE MAYBE IN THE FUTURE MAYBE PREDICT HOW PEOPLE RESPOND TO SPECIFIC PATHOGENS, AND THIS MAYBE IMPORTANT IN AN AGING SOCIETY. AND BY COMBINING THE DATA FROM THE POPULATION DATA WITH CLINICAL COHORT IN ITSELF IS UNDERPOWERED, WE MAY FIND NEW INROADS INTO SINGLE -- FUNGAL INFECTIONS. IF YOU'RE INTERESTED TO READ MORE ON THE HUMAN FUNCTIONAL GENOMICS PROJECT, JUST LAST WEEK WE HAD THREE PAPERS OUTf‡ IN CELL THAT TALK ABOUT ENVIRONMENTAL FACTORS AN GENETICS AN CYTOKINE PRODUCTION. WITH THAT I WOULD LIKE TO STOP AND THANK AGAIN MEHI NATIA, MY LONG TIME COLLABORATOR ON THE HUMAN FUNCTIONAL GENOMICS PROJECT AND FOUR TALENTED PEOPLE IN MY GROUP THAT DID ALL THE WORK I TALKED ABOUT, YUNG LI AND VENUT K ORBSM ASHR DID THE CYTOKINE$x CANDIDA WORK AND GENE LONG FU AND SASHA VENACOVA DID ALL THE MICROBIOME WORK IN COLLABORATION WITH A LOT OF OTHER PEOPLE. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> CICSA, THANK YOU FOR AN INTERESTING SET OF EXPERIMENTS AND EXAMPLES. WE HAVE TIME NOW FOR SOME QUESTIONS. PLEASE USE THE MICROPHONE SO PEOPLE WATCHING BY VIDEO CAN HEAR YOU AND WE CAN START OVER HERE. >> ONE SIMPLE QUESTION, WITHIN YOUR COHORTS, DID YOU INCLUDE THE PARAMETER OF IMPLANTED MEDICAL DEVICES? THE REASON I'M ASKING THIS IS THEY CAN PRETTIES POSE TO BIOFILMS AND BIOFILMS IMPLIES SOME TYPE OF BACTERIAL INTERACTION WHICH COULD INTERACT WITH THE OTHER PARAMETERS YOU ARE USING. I THINK IF YOU GO THROUGH THE LITERATURE YOU WILL FIND BIOFILMS IN MEDICAL DEVICES, WHAT I'M TALKING ABOUT IS CHRONIC, SUCH AS A PACEMAKER, AN ORTHOPEDIC IMPLANT AND WITH THE INSULIN PUMP BEING PROBABLY EUROPE BEING FULLY APPROVED, THIS WOULD -- >> REALLY GOOD POINT. I DON'T THINK WE HAVE THAT INFORMATION. THOUGH I SHOULD GO BACK TO THE QUESTION BECAUSE THERE'S SO MANY DIFFERENT QUESTIONS OF COURSE. THAT'S DEFINITELY SOMETHING I WILL CHECK OUT. YES. >> THANK YOU. >> GOOD POINT. THANK YOU. >> YOU HAVE IDENTIFIED TWO GROUPS IN TERMS OF INTERACTIONS THAT FALLS INTO THE PERIPHERAL BLOOD MONOCYTE VERSUS THE OTHER GROUP OF INNATE IMMUNE IN TERMS OF TNF INTERFERON VERSUS INTERLEUKINS. SO IN THE AUTOIMMUNE DISEASE, HOW MUCH OF THE CONTRIBUTION MIGHT BE COMING FROM THE MICROBIOME VERSUS HOST IMMUNE RESPONSE? IS THERE ANY WAY YOU CAN DIFFERENTIATE OR AT SOME STATE THEY'RE PROBABLY WORKING TOGETHER TO MAKE -- SEQUENCE THEM WHAT IT SHOULD BE? >> THAT'S ALSO AN INTERESTING QUESTION. I DON'T THINK PEOPLE HAVE DONE SO MUCH ON THE MICROBIOME ENDORSED DISEASE PHENOTYPES, I KNOW PEOPLE ARE NOW STARTING TO DO IT IN INFLAMMATORY BOWEL DISEASE AND I THINK THEY ARE REALLY -- THE GROUP THAT'S REALLY THE FRONTmy RUNNERS. I HAVEN'T REALLY SEEN THAT TYPE OF DATA COMING OUT. >> SHORT QUESTION, YOU MENTIONED THE THERAPY. SO HOW MUCH DO YOU NEED FROM THERAPY, ONE SLIDE YOU SHOWED THERE ARE CAGES WHERE EVERYTHING MIGHT WORK FOR THE BENEFIT OF THE PATIENT. USING MICROBIOME THERAPY. >> SO THAT'S OF COURSE A REALLY GOOD QUESTION. AND I THINK WE REALLY NEED MORE LONGITUDINAL DATA TO ANSWER HOW QUICKLY IS THE MICROBIOME CHANGING, RIGHT? BECAUSE WE DID A VERY SHORT INTERVENTION WITH A GLUTIN FREE DIET AND DIDN'T SEE MAJOR CHANGES, WE DID SEE SOME AT THE STRAIN LEVEL BUT NOT A MAJOR DIFFERENCE. AND THAT MIGHT NOT BE A STRONG ENOUGH PERTURBATION OF YOUR MICROBIOME AND THE QUESTION IS WHAT HAPPENS IF YOU DO MORE DRAMATIC CHANGES. THESE ARE REALLY STUDIES THAT NEED TO BE DONE. WE HAVE TO BE ABLE TO DO INTERVENTIONS AND REALLY FOLLOW PEOPLE ON A DAY BY DAY BASIS. >> THANK YOU. >> THANK YOU VERY MUCH. COUPLE OF QUESTIONS. IN THE STUDIES THAT YOU MENTION WITH REGARD TO MEDICINE AND MICROBIOME, HAVE YOU NOTICED WHETHER THE VACCINES COULD HAVE A CHANGE IN THE ENVIRONMENT AND HAZARD RATIO MICROBIOME NATURE CHANGE? THAT'S ONE QUESTION. >> CAN I ADDRESS THAT FIRST? OTHERWISE I FORGET ALL THE QUESTIONS. >> OKAY. >> WE HAVEN'T LOOKED AT VAX MAKE HERE, THAT WOULD BE -- VACCINATION HERE, THAT WOULD BE FANTASTIC BECAUSE WHILE IN THE NETHERLANDS WE HAVE A PROGRAM OF VACCINATION IN KIDS, THESE ARE OF COURSE ADULTS, PEOPLE GET FLU VACCINATION OF COURSE. AND THAT'S SOMETHING WHICH WE DON'T MONITOR UNFORTUNATELY. WE'RE SETTING UP OUR BIRTH COHORT NOW, THERE WE SPECIFICALLY MAKE SURE THAT WE SAMPLE BEFORE AND AFTER THE VACCINATION PERIODS. TO REALLY ADDRESS THAT QUESTION. THAT WILL BE A WHILE BEFORE WE HAVE DATA ON THAT, ANOTHER FIVE YEARS OR SO. >> THANK YOU. THE OTHER ONE IS YOU MENTION THAT THE BACTERIA USUALLY HAS THE INNATE IMMUNE INVOLVEMENT AND AUTOIMMUNE DISEASE HAVE T-CELL, ADAPTIVE IMMUNITY, IS THIS BECAUSE YOU ARE COMPARING THE ACUTE INFLAMMATORY RESPONSE VERSUS THE UNRESOLVED, IF THE INFECTION CONTINUES AND YOU LOOK AT IT AT LATER STAGE YOU MAY SEE THE EVOLVEMENT OF THE T-CELLS. >> I THINK YOU'RE ABSOLUTELY RIGHT. AND I THINK THIS IS ALSO WHAT NOW AT LEAST IN THE FIELD OF AUTO-IMMUNITY BECOMES MUCH MORE CLEAR THAT YOU PROBABLY NEED INNATE SYSTEM FIRST TO REALLY START OFF AND THEN ADAPTIVE TAKES OVER. AND YOU'RE RIGHT. HERE WE ONLY LOOK UNTIL DAY SEVEN SO WE REALLY CANNOT ADDRESS THAT QUESTION BUT THE GWAS TELLS US THAT THIS MAY IN FACT BE THE CASE. >> THANK YOU VERY MUCH. >> CICSA YOU SHOWED THAT INTERESTING CIRCULAR MANHATTAN PLOT WITH CYTOKINE QTLs. AND IT WAS INTERESTING TO SEE HOW MANY SIGNALS CAME OUT OF A RELATIVELY MODEST SIZE STUDY SO YOU HAVE CLEARLY BIG GENETIC FACTORS HERE AT FAULTNAL THE EXPRESSION -- FAULT IN THE EXPRESSION OF CYTOKINES BUT YOU DIDN'T TELL US WHAT THOSE PEAKS ACTUALLY REPRESENT. DO THEY LEAD YOU OBVIOUSLY TOWARDS PATHWAYS, FOR INSTANCE THE ACTUAL STRUCTURAL GENE FOR WHAT YOU'RE MEASURING, DOES THAT TURN UP THERE OR -- THEY DON'T? >> THAT'S INTERESTING. YES. >> ARE THERE THINGS THAT DO PEAK YOUR INTEREST THERE WHERE THE PEAK IS CLOSE TO SOMETHING THAT WOULD MAKE SENSE AS A MODIFIER OF EXRELATION OF THOSE PARTICULAR CYTOKINE? >> YEAH. SO FIRST WE DON'T FIND THE CYTOKINE GENES THEMSELVES, THAT'S AN INTERESTING OBSERVATION. MANY, NOT MANY, ABOUT HALF ARE NON-CODED RNA GENES. SO REALLY TELLING US SOMETHING ABOUT GENE REGULATION. MANY ARE UNDER POSITIVE SELECTION. SO THIS IS PROBABLY BECAUSE AUTOIMMUNE SYSTEM. SO IN MANY GENES WE DON'T MAKE SENSE YET SO WE DID QTL MAPPING AND OF COURSE IF YOU GO TO THE PAPER THERE IS A LIST OF POTENTIAL BUT WE DON'T KNOW WHAT TO MAKE OUT OF IT BUT IT'S NOT CYTOKINE THEMSELVES. COULD BE REGULATORY. >> DO I THAT TEND TO BE GENES RATHER TISSUE SPECIFIC FOR THE IMMUNE SYSTEM OR EXPRESSED ALL OVER? >> THAT'S A GOOD QUESTION. I DON'T KNOW BY HEART. >> I WOULD BE INTERESTED TO SEW. >> DO THEY HAVE SUPER ENHANCER? >> THANK YOU. >> YOU HAVE SUPER ENHANCERS, DON'T YOU JOHN? >> THEY ARE ENRICHED MONOCYTE ENHANCERS, I DON'T KNOW IF THEY ARE IN STRETCH ENHANCERS THERE'S A TON OF WORK THAT NEEDS TO BE DONE NOW THAT WE HAVE ALL THIS DATA. ABSOLUTELY. >> IT KEEPS US BUSY. >> PEOPLE INTERESTED IN ADDITIONAL QUESTIONS TO POSE TO OUR SPEAKER, WE'RE ABOUT TO ADJOURN TO THE LIBRARY FOR A RECEPTION WITH SOME REFRESHMENTS SO PLEASE JOIN US THERE. BUT MEANWHILE, LET'S PLEASE THANKS CICSA AGAIN FOR A WONDERFUL SEMINAR. [APPLAUSE]