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Demystifying Medicine 2016: The Intestinal Microbiome and Inflammatory Bowel Disease


GOOD AFTERNOON. I WANT TO BRING TO YOUR ATTENTION SOMETHING — THERE’S A CHANGE IN THE PROGRAM, NOT TODAY BUT WE HAD TO JUGGLE THINGS AROUND A LITTLE WITH BIT AFTER THE FIRST POSTERS WERE ALL MADE, SO THE POSTERS HAVE BEEN CORRECTED, BUT I JUST WANT TO BRING TO YOUR ATTENTION THAT NEXT WEEK, THE TOPIC IS ATOPY, ALLERGY, THE COMMON AND RARE ALLERGIES IN THE GENOMIC ERA. THIS IS REALLY A VERY EXTRAORDINARILY EXCITING BUSINESS, YOU’VE PROBABLY ALL READ SOMETHING ABOUT ASTHMA AND THE INCREASING RATES AND SO FORTH. AND THE SPEAKERS ARE JOSH MILNER FROM NIAID AND PAMELA GUERRERIO, WHO’S ALSO FROM NIAID. SO THAT’S NEXT WEEK. THEN THE FOLLOWING WEEK, JEFF COHEN OF NIAID AND LESIA DROPULIC, ALSO FROM NIAID, ARE GOING TO REVISIT SHINGLES, HERPES ZOSTER. THEY ACTUALLY SPOKE TO THE GROUP WOULD YEARS AGO, BU — TWO YEARS
AGO BUT SO MUCH HAS HAPPENED IN THAT FIELD, THE EPIDEMIC PROPORTIONS HAVE BECOME CLEARER AND CLEARER AND THEY’VE MADE SOME EXTRAORDINARY ADVANCES WHICH I THOUGHT THEY SHOULD PRESENT. AND THE TOPIC THAT HAD BEEN ON THE 16TH, THE ORAL MICROBIOME MEETS CELL BIOLOGY AND PERIODONTAL DISEASE, THAT WILL BE PRESENTED ON MARCH 29TH. SO ALL OF THIS IS ON THE POSTERS. THE FLOOD OF EMAILS WILL COME OUT IN THE CORRECT THING, BUT IF YOU WERE LOOKING AT THE OLD SCHEDULE, JUST MAKE A NOTE TO CHECK THE WEBSITE BECAUSE THAT’S WHERE THE NEW SCHEDULE IS, JUST IN CASE THERE’S SOMETHING THAT YOU WANTED TO HEAR THAT YOU DIDN’T. SO I THINK WE HAVE A FAIR NUMBER OF NEW FACES, PEOPLE HERE, SO I’LL JUST MENTION BUT NOT BELABOR THE POINT THAT EVERYBODY KNOWS THAT THIS IS THE BAY BRIDGE IN SAN FRANCISCO. RIGHT? THIS IS THE BROOKLYN BRIDGE. PROBABLY THE MOST FAMOUS BRIDGE IN THE WORLD, AND YOU DON’T WANT TO GET ME STARTED ABOUT IT. WHY DO WE HAVE THIS HERE FOR DEMYSTIFYING MEDICINE? BECAUSE WE ARE LIKE THE PEOPLE ON THE CATWALK, WE ARE BRIDGING THE GAP BETWEEN ADVANCES IN REALLY EXCITING BASIC AND OTHER SCIENCES AND THEIR RELATIONSHIP TO MAJOR HUMAN DISEASES. SO WE’RE ALL BRIDGE BUILDERS. SO SIT BACK AND ENJOY THE VIEW. THERE IS A FINAL EXAM IN THIS COURSE, BY THE WAY, WHICH IS ELECTRONIC, AND IT’S NOT BASED ON THE MEDICAL SCHOOL PRECEDENT THAT YOU’RE SUPPOSED TO MEMORIZE EVERYTHING AND QUOTE BACK AND EVERYTHING ELSE. THIS IS IDEAS AND CONCEPTS, AND THOSE WHO PASS IT AND ARE HERE FOR HALF THE SESSIONS CAN RECEIVE A CERTIFICATE FROM THE NIH. NOW, I WANT TO TAKE A COUPLE OF MINUTES — SO THIS IS A QUIZ. OLD AGE — THIS IS A QUOTE. OLD AGE IS AN INFECTIOUS CHRONIC DISEASE MANIFESTED BY DEGENERATION AND EXCESSIVE MACROPHAGE ACTIVITY WHICH DISTURB CELL EQUILIBRIUM SETTING UP STRUGGLE WITH TOXINS “REACTIVE OXYGEN” ENDING AND AGING IN DEATH. TRANSFORMING THE WILD POPULATION OF THE INTESTINE INTO A CULTURED POPULATION CAN INCREASE THE QUALITY OF LIFE AND MAYBE ITS DURATION. ARE THERE ANY TAKERS AS TO WHERE YOU THINK THIS CAME OUT OF THE NIH LAST WEEK? YOU MIGHT BE RIGHT. IT COULD HAVE, EXCEPT THE WORDS WOULD HAVE CHANGED A LITTLE BIT. WE WOULD HAVE READ REACTIVE OXYGEN AND A FEW OTHER THINGS WHICH YOU’LL HEAR ABOUT TODAY. ANYBODY KNOW WHERE THIS COMES FROM? SO THIS COMES FROM THE FOUNDER OF PROBIOTICS, PROBABLY ONE OF THE GREATEST SCIENTISTS EVER TO GRACE THE PLANET, A MAN NAMED ELI MITCHNEKO. T, WHO DISCOVERED THE MACROPHAGE, AND WHO IS WELL-KNOWN ERRONEOUSLY FOR HAVING PUSHED THE IDEA THAT EATING YOGURT OR OTHER LACTIC ACID PRODUCING NUTRIENTS PROTECTS THE BODY AGAINST TOXINS AND PROLONGS LIFE. NOW THERE’S A FASCINATING STORY ABOUT THIS WHICH I WILL NOT BELABOR. SECOND PART OF THE QUIZ. THESE EXPERIMENTS, WHEN AND WHERE? WHEN IN THE NIH WOULD HAVE THIS HAVE BEEN DONE IN BABY ARE RA BITS, NEWBORN, FED ONLY THE MOTHER’S MILK, ARE RESISTANT TO CHOLERA, BUT THEY BECOME SUSCEPTIBLE WHEN THEY’RE FED A DIET THAT CONTAINS MEAT-LIKE MATERIAL, BUT THE SAME RABBITS, IF THEY’RE FED A DIET THAT’S MAINLY OF VEGETABLE SOURCE, ARE RESIST AT THAT PARTICULAR
TIMRESISTANT. WHERE DOES THIS COME FROM? THE IDEA THAT INTESTINAL FLORA CAN PRODUCE OPPORTUNISTIC INFECTIONS, AND TOXINS WHICH CONTRIBUTE TO AUTO INTOXICATION, OR WHAT WE MIGHT CALL CHRONIC DISEASE. LASTLY, WHO DID THE EXPERIMENT WHERE RABBITS, WHICH WERE GIVEN TOXIN-INDUCED COLITIS, WERE PROTECTED BY GIVING EITHER YOGURT ENEMAS, OR DOG FECES? FECAL TRANSPLANT. ANYBODY HAVE ANY IDEA WHAT BUILDING THIS WOULD HAVE COME OUT OF? WELL, IT DIDN’T. IT ALL CAME OUT OF METCHNIKOPF. WHO WAS THE DIRECTOR OF THE PASTEUR INSTITUTE WITH PROFESSOR ROO, FAMOUS FOR ANOTHER REASON, AND THEY WON THE NOBEL PRIZE IN 1908. ACTUALLY FOR TREATMENT OF SYPHILIS, NOT FOR THIS. AND IF YOU READ FRENCH AND WANT TO IT READ SOMETHING REALLY FANTASTIC, I PUT THIS REFERENCE AND I’LL PUT IT ON THE WEBSITE, WHICH IS THE METCHNIKOFF VIEW OF THE PHILOSOPHY OF LIFE, THE INTERRELATIONSHIP BETWEEN THE INTESTINAL BACTERIA AND WHAT THEY CAN DO THAT’S GOOD AS COMPARED TO WHAT THEY CAN DO THAT’S BAD, AND HOW THE REST OF THE BODY PAYS THE PRICE OF IT. AND IF YOU LIKE IT ONLY IN ENGLISH, THERE’S A WONDERFUL ARTICLE BY A PHYSICIAN HIS TORE YAL AT THE UNIVERSITY OF OF CALIFORNIA IN IRVINE, DEBRA JAN BIBEL, WHICH IS THE STORY OF METCHNIKOFF’S SO CALLED BACILLUS OF LONG LIFE. IT’S INTERESTING, METCHNIKOPF NEVER TALKED ABOUT YOGURT PROLONGING LIFE, AND I WAS FASCINATED BY THIS, BECAUSE YOU ALWAYS ASSOCIATE HIS NAME WITH THIS THING, WHICH TURNS OUT TO HAVE BEEN A HUGE SCANDAL AT THE TIME BECAUSE HE WAS RUSSIAN, THIS WAS PREWORLD WAR I,, RUSSIANS WERE VERY HAPPY IN THE ACADEMIC ENVIRONMENT IN FRANCE, SO WHEN HE LENT HIS NAME OH A COMMERCIAL PRODUCT WHICH WAS A FORM OF YOGURT, HE DIDN’T MAKE ANY MONEY FROM IT, HE JUST THOUGHT IT WAS A GOOD IDEA THAT PEOPLE SHOULD EAT THAT, BUT HE GOT BLASTED, AND IT WAS AN ENGLISHMAN WHO WROTE A REVIEW OF METCHNIKOFF’S WORK AND CALLED IT THE BACILLUS OF LONG LIFE. HE NEVER SAID “LONG LIFE.” HE SAID BETTER LIFE, QUALITY OF LIFE. AND THAT’S WHERE WE ARE TODAY. WE EAT A SENSIBLE DIET, YOU EXERCISE LIKE CRAZY, YOU LIVE AS LONG AS YOU WOULD HAVE LIVED IF YOU DIDN’T DO THOSE THINGS, BUT THE QUALITY OF LIFE BY AND LARGE IS MUCH BETTER, AND PERHAPS THE END IS MORE CATALYTIC OR CATASTROPHIC RATHER THAN CHRONIC DISEASE ALL THE WAY. AT ANY RATE, ENOUGH OF THIS. SO WE’RE VERY FORTUNATE INDEED OF HAVING TWO NIH SCIENTISTS OF CONSIDERABLE RENOWN TO DISCUSS THIS FASCINATING BUSINESS OF LIFE, OUR THIRD WORLD, THE INTESTINAL MICROBIOME. AND YOU PROBABLY ALL KNOW FROM THE LITERATURE, FROM THE POPULAR PRESS AND EVERYTHING, YOU GO INTO A NATUROPATHIC STORE AND PEOPLE ARE SELLING ALL KINDS OF STUFF THAT’S GOING TO IT PROLONG
PROLONG YOUR LIFE BY CHANGING THE BUGS IN THE INTESTINE, THE PRO BUY TO TICPRO BUYPROBIOTICERA. BUT THERE’S AN ENORMOUS AMOUNT OF SCIENCE THAT COMES FIRST. THIS IS A FIELD OF EXPLOSIVE POTENTIAL INVOLVING MANY, MANY AREAS. SO OUR FIRST SPEAKER TODAY IS GOING TO BE YASMINE BELKAID, WHO RECEIVED HER PH.D. FROM THE PASTEUR INSTITUTE, WHERE METCHNIKOFF WAS THE DIRECTOR, SO THIS IS DIRECT LINEAGE PASSING ON TO YOU, YASMINE. SHE HAD A POSTDOCTORAL IF FELLOWSHIP HERE AT NIAID, WENT TO CINCINNATI IN 2000, SHE CAME BACK AND WAS APPOINTED A SENIOR SCIENTIST IN 2008. SHE’S THE CHIEF OF THE MUCOSAL IMMUNOLOGY SECTION, AND CO-DIRECTS THE ENTIRE TRANS-NIH META ORGANISM INITIATIVE. THE MICROBIOMES FROM ALL OVER. NOW HER WORK IS PARTICULAR
PARTICULARLY INVOLVED IN THE MICROBIOTA AND DIETARY F FACTOR, MAINTAINING IMMUNITY AND HOMEOSTASIS. OUR SECOND SPEAKER, WARN WARREN STROBER, IS CHIEF OF THE SECTION OF MUCOSAL IMMUNITY IN THE LABORATORY OF HOST DEFENSES. WARREN GRADUATED FROM THE UNIVERSITY OF ROCHESTER SCHOOL OF MEDICINE, AND A YEAR LATER CAME TO THE NIH, IN 1964. HE’S ONE OF THE STALWARTS OF THIS INSTITUTION, PRIMARILY OR GREATLY BECAUSE HIS RESEARCH HAS REALLY BEEN AT THE FOREFRONT OF TRYING TO UNDERSTAND THIS COMPLEX OF INFLAMMATORY BOWEL DISEASES, CROHN’S DISEASE, ULCERATIVE COLITIS AND A FEW OTHERS, AND THESE TWO WORLDS INTERSECT ACROSS THE BRIDGE. SO THAT’S WHAT WE’RE GOING TO BE FORTUNATE ENOUGH TO HEAR ABOUT, AND PERHAPS, YASMINE, YOU WOULD BEGIN.>>SO THANK YOU VERY MUCH FOR HAVING ME HERE. DISCLAIMER, I’M JUST THE OPENING ACT FOR THE REAL STAR OF THE SHOW THAT’S GOING TO TALK ABOUT IBD, BUT I’M GOING TO DISCUSS SOME OF THE MAIN — OF THE FIELD AND SOME OF THE DISEASES HAVE BEEN ACTUALLY NAMED, TWO OF THEM, THE MICROBIOTA — IT’S INTERESTING ACTUALLY TALKING ABOUT PASTURE INSTITUTE BECAUSE A LOT OF THE CONCEPT THAT’S RELATED TO THE MICROBIOTA ARE SOMETHING I HEARD EARLY, TRYING TO UNDERSTAND ALL THE MICROBIOTA AND THE WORD HOMEOSTASIS THAT IS SO PREVALENT, I THINK A LOT OF MY RESEARCH REALLY WAS INSPIRED BY PEOPLE THAT SURROUNDED ME DURING MY PH.D. SO THIS IS JUST AN OPENING SLIDE TO REMIND YOU THAT IT’S VERY DIFFICULT TO ESCAPE — IF YOU DON’T WANT TO TALK ABOUT IT, IT WOULD BE PROBABLY A NEWSPAPER, MAGAZINE IN WHICH THIS WORD IS GOING TO BE PRESENTED. AND THE CONCEPT THAT THE MICROBIOTA PLAYS AN IMPORTANT ROLE IN HUMAN HEALTH HAS REALLY TAKEN CENTER STAGE RECENTLY. SO I’M NOT GOING TO TALK TO MUCH ABOUT — BEAUTIFUL DISCUSSION EARLIER ABOUT METCHNIKOFF, THE IMPORTANCE — I’M GOING TO HIGHLIGHT A COUPLE OF POINTS. THE FIRST ONE IS ACTUALLY THAT — THE FIRST IDENTIFICATION OF MICROBES LIVING IN — IT WAS ACTUALLY DONE ABOUT BY A DUTCH SCIENTIST WHOSE NAME I WILL NOT PRONOUNCE THAT ACTUALLY DEVELOPED MANY DIFFERENT FORM OF MICROSCOPE, AND BY DOING THAT, HE WAS ACTUALLY ABLE TO REALLY SHOW A MICROBE THAT WAS ACTUALLY PRESENT, AND ACTUALLY JUST DESCRIBE THEM, I WOULD BE SURPRISE TODAY SEE HOW WE COULD SEND THAT TO A JOURNAL TODAY. BUT THIS IT ACTUALLY WAS THE FIRST IDENTIFICATION OF MICROBE — HIGH IT DENSITY — I THINK YOU GUYS ARE GOING TO HEAR ABOUT –>>[INAUDIBLE]>>HE DID? YEAH. OH, YES, IT’S A MISTAKE. [LAUGHTER] BECAUSE HE ACTUALLY TOOK HIS PRO BUY — PROBIOTIC. THAT’S THE MESSAGE. THE SECOND IS HIGHLIGHTING HOW YOU CAN DO THAT BY FISH, THAT WAS ACTUALLY MORE RECENT, THAT HIGHLIGHTED THE COMPLEXITY OF THESE MICROBES LIVING IN THIS ENVIRONMENT. ONLY VERY FEW WORDS ABOUT, AGAIN, HISTORY BECAUSE METCHNIKOFF WAS ACTUALLY WELL DESCRIBED BUT YOU HAD ACTUALLY EARLIER DISCOVERY AND THE IMPORTANT ROLE OF THE MICROBIOTA, THE GATE KEEPER WAS DISCOVERED IN THE CONTEXT OF THE VAGINAL ENVIRONMENT IN WHICH LACTOBACILLI — THAT WAS REALLY THE FIRST DEMONSTRATION OF THE COMPETITIVE ROLE OF THE MICROBIOME — THE CONCEPT OF — SYSTEMS IN THE — SURFACES. THIS CAPACITY TO COMPETE FOR RESOURCES IS REALLY THE FIRST LINE OF DEFENSE THEY OFFER TO THE HOST BY COMPETING FOR SPACE AND RESOURCE. SO TODAY, IT’S NO LONGER SUR SURPRISING — HIGHLIGHTED THE IMPORTANCE OF THE MICRO BIOCIDE IN HUMAN HEALTH, WHERE YOU FEEL VERY GOOD ABOUT YOURSELF, REMEMBER YOU ARE JUST A — IN YOUR OWN BODY WITH AN ENORMOUS AMOUNT OF — ORIGIN. THERE IS PROBABLY MORE THAN 10 TIMES NUMBER OF MICROBES AND CELLS AND — GENES EXPRESSED AT ANY GIVEN TIME IN THE HUMAN BODY. SO WE ARE AN ENVELOPE THAT CARRY ALL THESE MICROBES THAT COVER ALL THE DIFFERENT SURFACES. SO THE POINT I WOULD LIKE TO HIGHLIGHT IS THE FACT THESE MICROBES ARE NOT JUST PRESENT IN THE DNA, OF COURSE IT’S WHERE THE HIGHEST DENSITY OF MICROBE IS AND IT’S ACTUALLY WHY IBD IS ONE OF THE DISEASES PREVALENT, HOWEVER, THESE MICROBES ARE PRESENT EVERYWHERE, IN ANY SURFACES. THEY ARE PRESENT ALSO IN THE EYE, THEY ARE PRESENT IN THE SKIN, THEY ARE PRESENT IN THE LUNG, AND THIS MICROBE REALLY OCCUPIES UNIQUE NICHES IN THE UNDERLYING TISSUE. I’M GOING TO COME BACK TO THIS POINT LAYER IN THE CONTEXT IT OF SKIN, FOR EXAMPLE, NOT ONLY THE MICROBES ARE THE SURFACE OF THE SKIN, BUT THEY’RE ALSO EMBEDDED IN DEEP STRUCTURES — GLANDS. STABLE THOUGH LOW IN DENSE
IT,ITY, SO EVERY SINGLE SURFACE OF THE HUMAN BODY IS COVERED BY MICRO BIOTA. THESE DIFFERENT — CONSTANTLY INTERACTING AND REHABILITATING EACH OTHER. THERE’S A LOT OF FEEDBACK — THE MICROBE INFLUENCE THE HUMAN CELLS BUT THE HUMAN CELLS INFLUENCE MICROBE — AND FUNCTION. ALTHOUGH — ARE FIXED STRUCTURES, ONE OF THE THEM, MICROBIOTA, IS NOT. SO CHANGING — THE FUNCTION IS POSSIBLE. SO THIS ACTUALLY OFFERS ENORMOUS — FOR MEDICAL INTERVENTION BY MANIPULATING THE GENOME, ALL THE COMPOSITION OF THE MICROBES IN THE CONTEXT OF INFLAM RI DISORDERS — SO THESE MICROBES ARE ACQUIRED AT BIRTH FOR THE MOST PART. THERE’S ACTUALLY SOME DISCUSSION THERE IS YOU’LLLY SOME MICROBE — ENVIRONMENT BUT IT’S ACTUALLY NOT COMMONLY DEMONSTRATED. MOST OF THE MICROBE REALLY INVADED DIFFERENT SU SURFACES AT BIRTH. THE MICROBIOTA OF THIS CHILD WILL BE MOSTLY ACTUALLY — C-SECTION, FOR EXAMPLE — TO THE SKIN MICROBIOTA, THIS ACTUALLY HAS BEEN PROPOSED AS ONE OF THE DETERMINANT EVENTS IN THE DEVELOPMENT OF INFLAMMATORY DISORDERS OF CHILDREN THAT ACTUALLY ARE DELIVERED BY C-SECTION. THEN THE MICROBIOTA INVOLVED — EXTREMELY IMPORTANT — THE DIET IN THE G.I. TRACT WILL BE A FUNDAMENTAL DETERMINANT OF THE KIND OF MICROBE IN THIS ENVIRONMENT. IN OTHER SURFACES — EXTRAORDINARY TOOL BY WHICH YOU CAN ACTUALLY MANIPULATE THE MICROBIOME. CHANGES IN DIET CAN ACTUALLY CHANGE THE MICROBIOTA FUNCTION AND COMPOSITION IN LESS THAN 24 HOURS. THERE’S ALSO CHANGE THAT OCCUR IN THE CONTEXT OF DEVELOPMENT. FOR EXAMPLE, DURING TEENAGER YEARS, TH THE ENTIRE MICROBIOTA
IS SHIFTING, FROM ONE — COMPLETELY BECAUSE OF COURSE THE HORMONAL PRESENCE IN THE SKIN AND THE CHANGE IN THE NUTRIENTS AND ESPECIALLY INCREASE IN SLEEPING, THE SKIN SHIFTS COMPLETELY THE MICROBIOTA OF THIS ENVIRONMENT. IT’S ACTUALLY QUITE FASCINATING IN THE LAST TRIMESTER OF WOMEN THAT ARE PREGNANT, THE MICROBIOTA CHANGE IMMEDIATELY — POTENTIALLY THE MICROBE COULD BE ACTUALLY ADEQUATE FOR THE CHILD. — IN THE LAST TRIMESTER OF PREGNANCY. AND OF COURSE MICROBIOTA – KEEP EVOLVING IN AGE. THERE IS A CHANGE IN MICROBIOTA COMPOSITION WITH AGING, HOW THIS RELATES TO HEALTHY AGING OR NOT IS SOMETHING THAT REMAINS TO BE ACTUALLY DISCOVERED. THERE IS ACTUALLY VERY BIG NICHE OFTIVE WORLDWIDE TO TRY TO UNDERSTAND THE EXTENT OF HEALTHY AGING AND THESE STUDIES INCLUDE, OF COURSE, THE INCLUSION OF THE MICROBIOTA. SO MANY DIFFERENT STUDIES, I’M NOT GOING TO JUST DESCRIBE MANY OF THEM, HAVE ACTUALLY USED THE MICROBIOTA TO A LARGE FUNCTION — OF COURSE THE MICROBIOTA — FUNCTION OF THE G.I. TRACT. IF YOU DON’T — HAS BEEN LINKED TO DEVELOPMENT OF BEHAVIOR, FOR EXAMPLE OF. IN MICE, YOU USUALLY CAN — THIS ACTUALLY PUTTING SOME — INCREASED ANXIETY IN THE ANIMALS, AND ACTUALLY HAS BEEN LINKED — TO MODEL OF IT — WHICH OF COURSE IS A MODEL, BUT NONETHELESS, POTENTIALLY — OF THIS REGULATION OF THE MICROBIOTA RELATIONSHIP WITH BEHAVIOR. OF COURSE IT’S AN ENORMOUS AMOUNT OF WORK TO TRY TOWPPED STAND — IMMUNE CYST IT TEM IN TERMS OF REGULATING THE INNATE AND ADAPTIVE HUMAN CYST TE. THE G.I. TRACT OF AN ANIMAL IS NOT FULLY DEVELOPED IN THE PRESENCE OF MICROBES, YOU NEED — TO ALLOW THE DEVELOPMENT OF THE STRUCTURES. SO IT’S ALL BEEN LINKED ONE WAY OR THE OTHER TO THE MICROBIOTA. ONE WAY OR ANOTHER THROUGH THE PRESENCE OF THE MICROBE. I’M JUST GOING TO GIVE YOU A COUPLE OF EXAMPLES IN WHICH EXPERIMENTS — IN THE COULD BE TEXT OF SKIN, BECAUSE THIS IN FACT RELATES TO THE DISCUSSION THAT WE ACTUALLY FOLLOW IN THE G.I. TRACT. SO THE SKIN AS I MENTIONED BEFORE IS ALSO COLONIZED BY MICROBIOTA IN THE GLAND OR SWEAT GLANDS. IN THIS COMPARTMENT, FUNGI AND BACTERIA, YOU CAN SEE AN IMAGE OF THE HAIR FOLLOW KEUL TAKEN BY — HEID HIGH HEIDI KONG. AS I MENTIONED BEFORE, DEEP EMBEDDED IN THE STRUCTURE OF THE SIN AND AS SUCH, THE IMMUNE SYSTEM OF THE SKIN. THESE MICROBES ACTUALLY ARE PRESENT AND IT’S A VERY INTERESTING STUDY DONE YEARS AGO AT THE NIH BY HEIDI KONG HIGHLIGHTING HOW THE HUMAN SKIN IS INFECTED BY THE — COMMUNITY. IN A HEALTHY INDIVIDUAL — MICROBES IN BACTERIA, BECAUSE THE COMPOSITION OF THE MICROBE IS VERY MUCH DEFINED BY THE NUTRIENT PRESENT — SO THAT’S ACTUALLY SHAPED DID — AND IN FACT — CONSERVED BECAUSE — CONSERVED. THEY’RE EXACTLY THE SAME AS JUN JIFUNGI — IN THE TOENAIL, FOR EXAMPLE. SO BACTERIA AN FUNGI REALLY ARE SITE-SPECIFIC IN HUMANS AND RELATIVELY CONCERNING BETWEEN HORSES. SO THIS IS ACTUALLY HOW WHEN YOU WANT TO STUDY EXPERIMENTALLY, YOU NEED TO HAVE A SYSTEM YOU CAN CONTROL TO THE KIND OF MICROBE YOU HAVE, AND FOR THAT — DEVOID OF MICROBE — GERM FREE MICE — THESE KIND OF ANIMALS HAVE BEEN USED VERY MUCH INCLUDING THE ONE PEOPLE HAVE LOOKED AT THE BEHAVIOR OF ANIMALS. INTERESTING OBSERVATION, THE MALES GERM-FREE FROM NOT EXRE SIEVE — ACTUALLY INTERESTING POINTS THEY PROVIDED. SO EXAMPLE OF HOW THE MICROBIOTA CONTROL IMMUNITY. ACTUALLY IN THIS CASE — WE INJECTED THEM IN THE PRESENCE OR ABSENCE OF LIVE MICROBES TO SEE IF — THIS IT ACTUALLY DEMONSTRATES TWO POINTS. THE FIRST ONE IS THE FACT THAT IF THE ANIMAL HAS A MICROBIOTA HERE — ALSO DUE TO THE IMMUNITY. IN MANY CASES, INFLAMMATION AND TISSUE DAMAGE ARE CAUSED NOT BY THE PARASITE BUT CAUSED BY ACTUALLY — AS YOU CAN SEE, YOU CAN INFECT THE ANIMAL IN ABSENCE OF LIVE MICROBE, THEY ARE NOT ABLE TO GIVE INFLAMMATORY RESPONSES. THIS ACTUALLY — THE MICROBIOTA IS IMPORTANT FOR INFLAMMATORY RESPONSES. LUS DON’T HAVE ADAPTIVE IMMUNITY AND INDEED THE ANIMAL — TO GIVE UP THE GOOD IMMUNITY HEERY FLECTED BY — AND CMS — IT’S REALLY SIGNIFICANTLY REDUCED WHEN THE ANIMAL DOES IT NOT HAVE LIVE MICROBES. THE MICROBIOTA CANNOT ONLY CONTROL INFLAMMATORY RESPONSES BUT IS A PRIMARY ADJUVANT OF THE IMMUNE SYSTEM. JUST OH SHOW YOU AGAIN HOW YOU PROVE — OF THE MICROBIOTA BECAUSE AS I MENTIONED BEFORE, IF YOU DON’T HAVE MICROBES, YOU CAN HAVE DEFECTS IN THE IMMUNE SYSTEM, SO YOU NEED TO DO — EXPERIMENTS, THIS IS SUFFICIENT TO RESTORE THE CAPACITY OF THE ANIMAL AGAINST THE IMMUNITY OF THE MICROBE AND CONTROL THE INFECTION. SO THIS AGAIN SUPPORTS THE IDEAD THAT LIVE MICROBES ARE ACTUALLY IMPORTANT FOR IMMUNITY. THESE HAVE ACTUALLY BEEN DEMONSTRATED IN MANY CAN DIFFERENT SYSTEMS IN WHICH — ALMOST EVERY SINGLE — HAS BEEN NEUTRALIZED DIRECTLY OR INDIRECTLY BY THE PRESENCE OF THE MICROBES. AS I MENTIONED BEFORE, THE NORMAL ADAPTATION — IN HEALTH, AND THIS ACTUALLY IS SUPPOSED TO REALLY CONTROL — MOST OF THE ELEMENTS THAT ACTUALLY ARE REQUIRED FOR SURVIVING — SYSTEM IT — SYSTEM. HOWEVER THINGS ARE NOT ALWAYS PERFECT, AND INDEED WE ALL KNOW THAT ACTUALLY — ON THE RISE WORLDWIDE AND IN WHICH YOU HAVE ACTUALLY HIGH INCOME LEVELS. AND THESE AFFECT TISSUE THAT COLONIZE THE MICROBIOTA. IF WE DO THE G.I. TRACT, WE’RE GOING TO HAVE A DISCUSSION ABOUT IBD — — IN THE CONTEXT OF THE SKIN. — THE PRIMARY — DRAMATIC RISE ACTUALLY IN HIGH INCOME COUNTRIES. AND THIS ACTUALLY IS BELIEVED TO BE AT LEAST IN PART DUE TO THE FACT THERE IS A DISREGULATION OF THE NORMAL RELATION BETWEEN ACTUALLY THE TISSUE AND ITS MICRO BIOTONE. SO OF COURSE THERE ARE THINGS THAT — WE CAN REALLY DO, IT ACTUALLY HAS BEEN SHOWN TO BE IMPORTANT TO CONTROL THE QUALITY OF THE MICROBIOTA WE HAVE. IN FACT THESE ACTUALLY HAVE BEEN SHOWN THERE STRONG EVIDENCE — WE HAVE. IMPORTANT BY THE WAY — C-SECTION IN THE CONTEXT OF NATURAL BIRTH. IT CAN ALSO BE INFLUENCED BY AGE AND THE PLACE YOU LIVE IN. THE WAY OF EATING, EXERCISE, FOR EXAMPLE, THE DIET COULD BE VERY DETRIMENTAL, THIS ACTUALLY IS NOT JUST THE G.I. TRACT, IN OUR SKIN OR OUR LUNGS, THE MICROBIOTA AT LARGE. OF COURSE THE WAY WE’RE ACTUALLY CHANGING HYGIENE, IT’S ACTUALLY VERY GOOD THAT WE HAVE PUSHED — OVERUSE OF SANITIZERS HAVE BEEN ACTUALLY SHOWN TO HAVE A DRAMATIC EFFECT ON THE MICROBIOTA WE HAVE AND THERE IS OF COURSE THE PRESENCE OF INFECTION. WE HAVE ACTUALLY — FOR EXAMPLE THEY HAVE BEEN REMOVED THAT HAVE BEEN REPLACED BY DIFFERENT FORM OF INFECTION. WE HAVE A LOT OF ACUTE INTUCKTION IN A VERY HEALTHY IMMUNE SYSTEM, AND THAT MEANS THAT THAT SYSTEM IS CONSTANTLY CHALLENGED. THESE CAN ACTUALLY CHANGE THE KIND OF MICROBE WE HAVE, MAYBE THE NOT FOR THE BEST. SO THERE’S BEEN A LOT OF WORK TRYING TO UNDERSTAND — INFLAMMATORY IT DISORDERS. AND AS SUCH, A LARGE NUMBER OF INFLAMMATORY DISORDERS HAVE BEEN LINKED TO THE DISREGULATION OF — THIS COULD BE OF COURSE IBD THAT IS BELIEVED TO BE DUE TO COLLAPSE OF RELATION WITH THE MICROBIOTA BUT ALSO IN THE CONTEXT OF CANCER, THERE IS ACTUALLY EXPERIMENTAL EVIDENCE, I’M GOING TO COME WHACK TO THAT
BACK TO TH
AT LATER, BEEN SHOWN IT TO INTERVEER OR TO PROMOTE CANCER TREATMENT. THERE IS ACTUALLY OF COURSE A LINK BETWEEN MICROBIOTA AND ANXIETY BUT MOST OF THE DISORDER HAS BEEN STUDIED SO FAR HAVING LINKED ONE WAY OR ANOTHER TO THE MICRO BIOTA, SO AGAIN, FIELD OF ENORMOUS INTEREST. AT THE MOMENT, A LARGE NUMBER REMAIN EXPERIMENTAL BUT THERE IS ACTUALLY — TWO DIFFERENT DISORDERS, AND I’M GOING TO COME BACK TO THAT LATER. SO I’M GOING TO GIVE YOU A FEW EXAMPLES IN THE LITERATURE, ESPECIALLY EXAMPLES THAT HAVE — TO CLINICAL EVIDENCE. SO SOME OF THE — THAT WAS DONE BY — THAT REALLY HAVE — THE KIND OF MICROBE YOU HAVE AND OBESITY. WHAT ACTUALLY WAS DONE OVER THE YEARS WAS TO TRANSFER MICROBIOTA FROM OBESE HOST TO — GENE HOST AND SHOW THE TRANSFER WAS SUFFICIENT TO TRANSFER GAIN WEIGHT. I’M DESCRIBING HERE AN EXPERIMENT THAT IS EXTREMELY WELL CONTROLLED EXPERIMENT BECAUSE THEY USE DISCORDANT TWINS, TRANSFERRED — AS I MENTIONED BEFORE AND THESE WERE SUFFICIENT TO TRANSFER GAIN WEIGHT. SO REMARKABLE OBSERVATION THAT SHOWS AND IN FACT IN SOME INDIVIDUALS — THEY ACTUALLY PRETTY — SO OF COURSE CAN ACTUALLY –>>[INAUDIBLE]>> — SO BASICALLY THEY HAD DIFFERENT KIND LIFE AND THIS IS NOT — IN THE CONTEXT OF THE STU TI, BUT THEY WERE ACTUALLY BASICALLY — ONE WAS — AND ONE WAS NOT. THE — WASN’T CLEAR BUT THEY WERE ACTUALLY OBESE. ONE WASN’T. SO THEY WERE ACTUALLY NATURALLY OBESE. ANOTHER THING THAT HAS BEEN PROPOSED, THE OVERUSE OF ANTIBIOTICS AS A DRAMATIC DID — FOR INFLAMMATORY DISORDERS. SO EXPERIMENTS DONE BY GLAZER THAT ACTUALLY SHOWED THAT ISSUE ACTUALLY GAVE A LOT OF ANTIBIOTICS IN MICE, YOU CAN ACTUALLY, IN FACT, PREDISPOSE THE MICE TO IT OBESITY AGAIN. AND AGAIN, THIS WAS ACTUALLY — NOW THEY ACTUALLY DO CLINICAL OBSERVATIONS SHOWING USE OF ANTIBIOTICS EARLY IN LIFE IN CHILDREN LEADS TO GAINING WEIGHT. IT’S BEEN USED FOR A LONG TIME BY FARMERS THAT UTILIZE THIS STRATEGY TO MAKE THE COWS DPAIN MORGAINMORE WEIGHT, THEY GIVE
LOTS OF ANTIBIOTICS TO MAKE SURE THAT ANIMALS GAIN WAIT. SO THIS ACTUALLY IS AN IMPORTANT OBSERVATION BECAUSE ANTIBIOTICS HAD BEEN HIGHLY OVERUSED NOT ONLY FOR BACTERIAL INFECTION, AND THIS IS SOMETHING THAT CAN PREDISPOSE TO LONG TERM CONSEQUENCES. SO THERE IS ACTUALLY A LOT OF — YES? SO THE QUESTION — MORE PRONE TO INDUCE THIS KIND OF THING THAN OWESOTHERS, WHICH ONE? YES. [INAUDIBLE] SPHWHRITS A VERY INTERESTING QUESTION. IN THE STUDY I MENTIONED, I DON’T THINK THEY USED BROAD SPECTRUM ANTIBIOTICS BUT THIS STUDY ACTUALLY HAS BEEN DONE, MORE — THAN OTHERS. SO ANOTHER FORM OF — A LOT OF ATTENTION RECENTLY — IMPACT TO DIABETES ACTUALLY. THE FIRST EVIDENCE LINKING — DIABETES AND MICROBIOTA WAS IN MICE THAT WERE SUSCEPTIBLE — THEY FOUND CHANGING THE MICROBIOTA — COULD PREDISPOSE OR NOT TO THE — OF THE DISEASE. PLUSH THERE IS SOME FASCINATING OBSERVATION — WE’VE ACTUALLY — TO DIABETES DEVELOPMENT WITH ANOTHER THREE IMPORTANT FINDINGS. AND A VERY INTERESTING OBSERVATION THAT WAS DONE ACTUALLY RECENTLY THAT SHOW THAT — IN FOOD MAY ACTUALLY BE VERY DETRIMENTAL BECAUSE IT ALLOWS THE OUTGROWTH OF MICROBES THAT THEMSELVES ARE SUFFICIENT IT TTO PREDISPOSE — FASCINATING BODY OF — MANY INFLAMMATORY DISORDERS AND DIABETES IS ACTUALLY ONE OF THEM. A LOT OF WORK HAS BEEN DONE IN CANCER DEVELOPMENT, THE FIRST WORK WAS DONE BY USING — ACTUALLY IT WAS HUMAN STUDIES THAT SHOW — COLON CANCER OF PATIENTS. BACTERIA WAS TAKEN AND PUT BACK IN ANIMALS PREDISPOSED TO CANCER DEVELOPMENT — SUFFICIENT TO TRANSFER — TO PROMOTE — CANCER DEVELOPMENT. AGAIN, A GREAT BODY OF WORK TRYING TO UNDERSTAND THE ADAPTATION BETWEEN MICROBES AND DEVELOPMENT OF CANCER, BUT MANY DO ACTUALLY — THEY CAN INDUCE DNA DAMAGE, THEY CAN ENTER — SIGNALING AND CAN, OF COURSE, INCREASE — SIGNALS SO A LOT OF RESEARCH YET TO BE DONE TO UNDERSTAND THE TISSUES IN DIFFERENT MICROBES AND CANCER DEVELOPMENT. ALL THAT WAS DONE IN — REALLY HIGHLIGHTED THE IMPORTANCE OF THE FINE MICROBE IN THE IT G.I. TRACT IT — CHEMOTHERAPY. THE STUDY SHOWS IF YOU CHANGE THE MICROBIOME YOU CAN PROMOTE OR PREVENT — RESPOND IT TREATMENT. THIS IS QUITE FASCINATING BECAUSE IT WAS NOT — MANY — NOT ONLY TO TREATMENT BUT ALSO PD1 TREATMENT — HAVE BEEN SHOWN ACTUALLY TO ALSO — YOU HAVE AND FASCINATING STUDY THAT WAS RECENTLY TO HAVE SHOWN THAT IF IT YOU TAKE THE MICROBIOTA — TREATMENT FOR THERAPY, AND TRANSFER IT TO ANIMAL, WE CAN ACTUALLY TRANSFER THE FAILURE OF TREATMENT. SO AGAIN, THAT SHOW HOW VERY EASY YOU CAN ACTUALLY PROMOTE TREATMENT — THE EFFICIENCY OF TREATMENT OF CANCERMENT I’M GOING TO FINISH BY REALLY SOME OF THE SPECTACULAR OBSERVATION AND WORK THAT WAS DONE AND I’M GOING TO DISCUSS THAT BECAUSE THIS ACTUALLY IS GOING TO BE A PROOF OF CONCEPT TO CHANGE THE FIELD. C. DIFFICILE IS A VERY IMPORTANT DISEASE, CAUSE AS LARGE NUMBER OF DEATHS IN AMERICA AND WORLDWIDE, ESPECIALLY PEOPLE IMMUNOSUPPRESSED OR IN HOSPITAL SETTINGS. AND REALLY THE ONLY KIND OF TREATMENT THAT IT REALLY SEEMS TO HAVE WORKED OVER THE LAST YEARS IS, IN FACT, FECAL TRANSPLANT, AND REMARKABLY, PROOF OF CONCEPT FINISHED YEARS AGO DEMONSTRATED OVER 95% OF PEOPLE CAN ACTUALLY BE CURED JUST BY A FECAL TRANSPLANT. AGAIN, IT YOU HAD ACTUALLY OBSERVED FARMERS BEFORE WE HAD KNOWN THIS WAS ACTUALLY KNOWN, ACTUALLY FARMERS THEMSELVES HAVE USED FECAL TRANSPLANT IN COWS. THIS IS ACTUALLY QUITE REMARKABLE, ET CETERA LED TO FASCINATING DISCOVERY IN THE FIELD. WHAT HE DID IT IN THIS STUDY WAS NOW TRY OH JUST — TRANSFERRING THE MICROBIOTA FROM ONE PERSON TO ANOTHER COULD CREATE — AS YOU’VE JUST DONE IN HUMAN UNFORTUNATELY, COULD ALSO POTENTIALLY TRANSFER PATHOGEN THAT YOU’RE NOT AWARE OF, SO — VALUABLE APPROACH FOR THE LONG TERM. TO IT DEVELOP ALGORITHMS TO UNDERSTAND THE BEST PREDATORS — SETTING OF THE G.I. TRACT AND DEFINE A MICROBIOTA OF CONTROL OF THIS INFECTION AND DEVISE A STRATEGY IN ANIMALS TO ACTUALLY CONTROL THE INFECTION, SO IT’S A REALLY RATIONAL APPROACH OF THIS TREATMENT BY TRYING TO UNDERSTAND WHAT ARE THE BEST PREDATOR OF THIS PATHOGEN. SO WHY IT’S ACTUALLY FASCINATING IS BECAUSE THIS IS IT GOING TO BECOME PROBABLY ONE OF THE MOST DEVELOPMENT TREATMENTS FOR C. DIFFICILE BUT THIS ACTUALLY LED TO THE — OF DRUGS, GOING TO TREAT C. DIFFICILE AND THE WAY BY WHICH IT WAS ACTUALLY APPROVED IS BECAUSE THIS COMPANY, THAT I’M NOT GOING TO SHOW THE NAME OF, UTILIZE — MADE IN A WAY THAT’S ACTUALLY COMPATIBLE WITH — DEVELOPMENT AND IT ACTUALLY IS GOING TO CHANGE THE FIELD BECAUSE UNTIL THEN, PEOPLE WERE VERY SKEPTICAL, HOW ARIN ARE YOU
GOING TO — THIS ACTUALLY — YOU CAN ACTUALLY DEVELOP A DRUG BASED ON THE MICROBIOTA AND IS NOW ON PHASE 3 OF CLINICAL TRIALS ALSO IN THE CONTEXT OF IBD AND ACTUALLY DO SOMETHING THAT’S PROBABLY GOING TO NOT NOW BRING THE MICROBIOTA IN THE CLINICS. SO I’M JUST GOING TO JUST — MY LAST SLIDE, TWS ACTUALLY MY INTERIT DUCKS TO WARREN STROBER, JUST TO IT SAY THAT ISHED HAS BEEN LIPGED — IT’S A COMPLEX DISEASE AND THIS MICROBIOTA PRESENCE HAS BEEN BELIEVED TO BE ONE OF THE IMPORTANT INITIATOR OF THE — OF THIS DISORDER AND WILL NOW HAVE A BEAUTIFUL DISCUSSION ON THIS TOPIC. YOU WANT TO TAKE QUESTIONS BEFORE — NO? [APPLAUSE]>>EARLY ON YOU MENTIONED THE DIFFERENCE BETWEEN VAGINAL AND DID — HOW LONG IS THAT DIFFERENCE IN MICROBIOME LAST IN LIFE?>>IT’S NOT PERMANENT. BUT ACTUALLY THIS IS ACTUALLY — THE FIRST KNEW MONTHS IS GOING TO BE DETERMINANT. DETERMINE THEN OF COURSE IT’S GOING TO BE — ENVIRONMENTAL EXPOSURE, DIET, ET CETERA, BUT — EARLY SHIFT AND YOU LOOK AT NEONATES — ACTUALLY DIFFERENT.>>IS ANYTHING IT — ABOUT THE MECHANISM OF SAY ANTIBIOTIC INDUCED OBESITY, WHAT HAPPENS TO THOSE CALORIES?>>WHAT HAPPENS TO THOSE CALORIES?>>WELL, YOU MIGHT REDUCE COMPETITION, SO I DON’T KNOW WHETHER THAT’S A SIGNIFICANT ADDITION TO THE PROBLEM.>>THE MECHANISM — I THINK THERE IS — AND SUFFICIENT TO ACTUALLY METABOLIZE THE POOD IN A WAY THAT’S APPROPRIATE. THAT’S ONE OF THE ELEMENTS THAT CONTRIBUTES TO THE — OF CALORIES. THE OTHER THING IS — THE MICROBIOTA ALSO THEMSELF CAN ACTUALLY REGULATE ABSORPTION, THIS HE CAN ALSO CREATE METABOLITES THAT ARE IMPORTANT IN THE CONTEXT SO THE WAY THE MIEB TA INTERFERE WITH APPROPRIATE — OF CALORIES IS PROBABLY AT MANY DIFFERENT LEVELS, NOT ONLY — BUT TO THEMSELF — PEOPLE TO METABOLIZE APPROPRIATELY THE FOOD THAT IS ACTUALLY PROVIDED.>>CAN YOU ISOLATE ANYTHING FROM THE BACTERIA WHICH ISN’T REMOVED BY THE ANTIBIOTICS?>>I DON’T THINK IT HAS BEEN SHOWN YOU CAN ACTUALLY ACHE A
TAKE A SINGLE — I THINK IT’S GOING TO BE MORE THAN — BUT INFLAMMATION INFLAMMATION — THAT’S ANOTHER ELEMENT NA THE MICROBIOTA CAN — BY INCREASING INFLAMMATION. SO IT COULD BE AT MANY DIFFERENT LEVELS.>>CAN YOU SPEAK TO THE PRELIMINARY ASSOCIATION BETWEEN THE MICROBIOME AND THE NEUROLOGICAL CONDITION SUCH AS AUTISM?>>THIS IS SPAIRM MENTAL DATA AND I THINK THIS IS A VERY SENSITIVE SUBJECT THAT SHOULD BE APPROACHED WITH A LOT OF CAUTION. EXPERIMENTALLY, I CAN EXPLAIN TO IT YOU WHAT THEY HAVE ACTUALLY DONE. IT WAS TO TAKE ANIMAL THAT IF YOU PROVIDE — I THINK IT WAS — DURING PREGNANCY, CAN ACTUALLY DEVELOP SOME OF THE OFFICIAL DEFECT THAT HAS BEEN — AND IN THIS ANIMAL, IF YOU ACTUALLY HAVE — KIND OF MICROBE AT BIRTH BIRTH — BEFORE DELIVERY, YOU CAN PREVENT OR MITIGATE SOME OF THE EFFECTS THAT IS ACTUALLY DEVELOPED. SO THESE ACTUALLY — THESE STUDIES SUGGEST THEY LIMIT INFLAMMATORY RESPONSES THAT ARE DETRIMENTAL TO THE DEVELOPMENT OF THE FETUS. NOW IN THE CONTEXT OF ADULT ANIMALS, IT’S DIFFERENT. IT WAS ACTUALLY SHOWN YOU CAN TRANSPLANT — MICROBIOTA AND TRANSPLANT ANXIETY, ANGCYT,
ANXIETY IT SELF CAN BE TRANSPLATED THROUGH THE MICROBIOTA. THE STAGE OF COLLECTING REMARKABLE OBSERVATION AND I THINK IT’S GOING TO TAKE YEARS TO UNDERSTAND THE MECHANISM.>>SO YASMINE, HOW CLOSE TO YOU THINK WE ARE TO ROUTINE MICROBIOME TESTING FOR PEOPLE PROFILE THE MICROBIOTA TO EVALUATE WHETHER IT’S HEALTHY OR NOT, AND DO YOU THINK THERE’S AN UNDERSTANDING WHAT CONSTITUTES A HEALTHY MICROBIOTA, DOES IT DEPEND ON WHERE YOU LIVE IN THE WORLD, YOUR ETHNIC BACKGROUND?>>YOU’RE ABSOLUTELY CORRECT, I THINK WHEN I USE THE WORD IT — IT’S VERY — CAUTION, BECAUSE THERE WOULD NOBODY BE A SINGLE PRINT OF THE MICROBIOTA, YOUR MICROBIOME MAY BE HEALTHY FOR YOU, MAY BE DETRIMENTAL FOR ME. I THINK WE ARE FAR FROM ACTUALLY TRYING TO UNDERSTAND WHAT THE IDEAL MICROBIOTA FOR EACH PERSON, BUT I THINK IN TERMS OF ACTUALLY KNOWING THE KIND OF MICROBE WE HAVE IS SOMETHING THAT IS GOING TO COME — QUICKLY. I THINK THIS IS BECOMING SIMPLER AND SIMPLER AND I WOULD IMAGINE AT ONE POINT RELATIVELY SOON WHEN EVERYONE COMES IN TO THE CLINICAL CENTER, WE CAN EVALUATE WHAT KIND OF MICROBIOTA THEY HAVE AND HOW THE TREATMENT HAS CHANGED AND THIS COULD BE IMPORTANT BECAUSE IT WILL SHOW HOW YOU METABOLIZE A DRUG, EITHER THROUGH CONTROLLED BY THE KIND OF MICROBE YOU HAVE. SO EFFICIENCY OF TREATMENT COULD ALSO BE IMPAIR WID WHAED BY WHAT
KIND OF MICROBIOME YOU HAVE.>>I NOTICED THAT THROUGH WROUGHT YOUR TALKTHROUGHOUT YOUR
TALK, YOU MENTIONED LIVE MICROBES. HAVE YOU TRANSFERRED NON-LIVE MICROBES AND CONSTITUTING THE SAME KIND OF PHENOTYPE IN THESE MICE?>>YES, SO IN THE CONTEXT OF HOW — THERE WAS A DIFFERENT KIND OF ELEMENT, ZOO FA SO FAR
AT LEAST FOR US, WE’VE USED LIVE MICROBES. IT’S BEEN RELATIVELY CHALLENGING TO FIND — CAN ACTUALLY HAVE SOME OF THE EFFECTS OF THE PACK TIER YOF THEBACTERIA IT SELF —
OVERALL EFFECTS. UNIQUE NICHE TO HAVE A VERY SPECIFIC MODE OF INTERACTION, AND I THINK WHAT WE NEED TO UNDERSTAND NOW IS HOW WE ACTUALLY LEVERAGE –>>JASMINE, JAS YASMINE, YOU
HAD BEHAVIOR
. CAN YOU EXPLAIN THAT?>>THE ANXIETY BEHAVIOR OR FEAR AND ACTUALLY IT WAS VERY FASCINATING STUDIES WHEN YOU LOOK AT STUDIES IN IT MICE SHOWING REALLY THAT YOU CAN CHANGE THE BEHAVIOR OF ANIMALS BY CHANGING THE MICROBIOTA. THIS IS IN THE CONTEXT OF THIS STUDY OF AUTISM MODELS. SO IF YOU’RE IN THAT MOOD –>>LET ME SLIP IN ONE OTHER QUESTION. WE’RE GOING TO GET TO THIS WITH THE PERIODONTAL DISEASE. THE FORMATION OF BIOFILMS, WHAT IS THE ROLE OF MICROBIOME IN THE PRODUCTION OF A BIOFILM?>>IT IS THE BIOFILM.>>IT IS?>>YEAH.>>SO INTESTINE REALLY HAS –>>ACTUALLY –>>A BIOFILM?>>ABSOLUTELY. SO BIOFILM, AS CLINICIANS, PEOPLE THINK OF IT AS, THIS IS ACTUALLY AN INFECTION SYSTEM. IN FACT, A LOT OF MICROBES CAN LIVE AS BIOIT FILL ILL M, THE ONE IN YOUR MOUTH ARE BIOFILM AND THEY ARE THE MICRO BIOSOME. SOUND NORMAL CIRCUMSTANCES — SO THERE IS ACTUALLY HEALTHY BIOFILM FORMATION THAT IS REALLY IMPORTANT, WHAT I’M SENSING IS ACTUALLY IMPORTANT INTERACTION ALSO IN THE CON EX-IT OF THE MICROBIOME IT SELF. SO THOSE MICROBES ARE ALL ALIVE AND COMMUNICATE WITH EACH OTHER.>>I THOUGHT THE BIOFILM HAD SOMETHING TO DO WITH RESISTANCE TO ANTIMICROBIALS.>>IN THE CONTEXT OF PATHOGENIC INFECTION, ABSOLUTELY, IT’S GOING TO PRESENT ACTUALLY, IT’S GOING TO MAINTAIN THE PATHOGEN AND ITS — TO TREATMENT, BUT ACTUALLY HEALTHY MICROBES CAN ACTUALLY ORGANIZE THEMSELVES –>>OKAY. WELL, THERE WILL BE TIME — OH, NO, THERE WON’T BECAUSE YASMINE HAS TO LEAVE AT 5:30, BUT THANK YOU VERY, VERY MUCH. THANKS AGAIN.>>IT’S A PLEASURE TO BE HERE AGAIN. I’VE GIVEN VARIOUS LECTURES, WE HAVE TO CHANGE BECAUSE THIS IS SUCH A RAPIDLY DEVELOPING FIELD. I WANT TO THANK YASMINE FOR THIS REALLY EXTRAORDINARY BEGINNING. IT MAKES MY LECTURE MUCH MORE SIMPLE TO DELIVER. WELL, INFLAMMATORY BOWEL DISEASE IS REALLY TWO DIFFERENT DISEASES. THEY’RE REALLY QUITE DIFFERENT. ONE IS CROHN’S DISEASE AND THE OTHER IS ULCERATIVE COLITIS. I’M NOT GOING TO TALK ABOUT ULCERATIVE COLITIS VERY MUCH TODAY BECAUSE OF TIME CONSIDERATIONS, BUTLY TALK ABOUT CROHN’S DISEASE QUITE A BIT, AND WHAT IS CROHN’S DISEASE LIKE? WELL, IT’S A CHRONIC RELAPSING FULL THICKNESS INFLAMMATION OF THE GUT, AFFECTS THE SMALL BOWEL, AFFECTS THE LARGE BOWEL, THE COLON, OR BOTH, IN ABOUT EQUAL NUMBERS OF CASES. IT CAN CAUSE FIS LA FISTULA,
BETWEEN THE GUT AND THE SKIN AND/OR OTHER STRUCTURES, IT CAN CAUSE ABDOMINAL PAIN, BLEEDING, DIARRHEA, WEIGHT LOSS, FEVER AND LEATHEANDLETHARGY. IT’S ASSOCIATED WITH A NUMBER OF EXTRA INTESTINAL MANIFESTATIONS LISTED HERE, AND THE PATIENTS CAN BE SPLIT BETWEEN 70% CHRONIC RELAPSING AND 70% OF PATIENTS REQUIRE SOME SORT OF SURGERY. YOU CAN SEE HERE THE AREA OF NARROWING OF THE GUT THAT OCCURS, YOU CAN SEE SOME OF THE SKIN MANIFESTATIONS AND YOU CAN SEE OVER HERE THE GRAN LOMA TUS INFLAMMATION THAT OCCURS IN THESE PATIENTS CAN BE VERY, VERY DIFFICULT DISEASE INDEED. NOW OVER THE YEARS, WE’VE DEVELOPED A CONCEPT OF THE DISEASE WHICH HAS BEEN QUITE USEFUL, AND THAT IS THAT THE DISEASE IS CAUSED BY A DISREGULATED RESPONSE TO IT MUCOSAL LIGANDS AND ANTIGENS. SO YOU CAN SEE THAT ON YOUR LEFT, THE NORMAL GUT IS IN HOMEOSTASIS WITH WHACK TIER YAL MICROBIOME OR THE FUNGAL MICROBIOME AS WELL, AND THERE’S RELATIVELY LITTLE INFLAMMATION, AND THERE’S A NORMAL CONTROL BETWEEN EFFECTOR CELL RESPONSES AND REGULATORY CELL RESPONSES. BUT ON YOUR RIGHT IS THE INFLAMED GUT, AND SOMEHOW THE SAMELY GANSAME LIGANDS AND
BACTERIA CAUSE INFLAMMATION IN THE CELL POPULATIONS IN THE GUT, THE DENDRITIC CELLS, MACROPHAGES AND THE T CELLS. THERE’S THE ELABORATION OF EFFECTOR CYTOKINE SUCH AS THE INTERFERON GAMMA AND IL SENSING ALPHA. IN FACT, ANY OF THE BIOLOGIC MEANS OF CONTROL THE DISEASE DEPENDS ON GIVING — VERY EFFECTIVE IN A LARGE PERCENTAGE OF PATIENTS COMING ON BOARD IS THE USE OF ANTIIL12, P40, DIRECTED IMENS TH AGAINST THE
IL17 RESPONSE AND THE INTERFERON RESPONSE, SO THESE ARE VERY EFFECT TIEFFECTIVE MECHANISMS OF TREATMENT. I’D LIKE TO START BY TALKING IN GENERAL TERMS ABOUT THE MICROBIOME AND GUT INFORMATION, AND THEN GIVE YOU SOME HIGHLY DEVELOPED BIOCHEMICAL STUDIES TO SHOW YOU HOW — DIG DOWN AND UNDERSTAND HOW THE MICROBIOME CAN ACTUALLY AFFECT THE CELLS OF THE GUT TO CAUSE INFLAMMATION. NOW THERE’S BEEN A GREAT DEAL OF STUDY OF THE NATURE OF THE MICROBIOME ABNORMALITIES, BOTH IN — AND PATIENTS WITH CROHN’S DISEASE AND PATIENTS WITH ULCERATIVE COLITIS. THIS IS MORE OR LESS A SUMMARY OF WHAT HAS BEEN FOUND AT THE FILO LEVEL, THE ABNORMALITIES TEND TO BE LIMITED TO THE SMALL BOWEL AND MORE PREVALENT IN CROHN’S DISEASE PAIRKTS THA
PATIENTS THAN
IN ULCERATIVE COLITIS. BACTEROIDETES OR DECREASED OR INCREASED DEPENDING ON THE STUDY. FAECALIBACTERIUM PRAUSNITZII IS DECREASED. THERE’S NO EVIDENCE THAT THERE IS A PATHOGENIC ORGANISM IN THE GUT OF THESE PATIENTSMENT SO THESE ARE THE NORMAL BACTERIAL SPECIES, AND THEY’RE REACTING TO THE — IN THE GUT ENVIRONMENTS TO CAUSE INFLAMMATION BECAUSE OF PATH LO SWRIPATHOLOGIC REASONS. NOW THERE SEEMS TO BE A DIVISION OF LABOR IN THE GUT BETWEEN VARIOUS ORGANISMS AND THE KINDS OF RESPONSES THEY CAN ELICIT. THERE’S A GOOD DEAL OF STUDY ABOUT THE BACTERIAL COAT, POLPO –IT’S BEEN SHOWN TO —
CELLS TO PRODUCE TGF DATA 2 AND THEN FOX P3 REGULATORY CELLS, POSITIVE REGULATORY CELL. SO THIS IS CONSIDERED TO BE A MAJOR WAY, A MAJOR TYPE OF BACTERIA — REGULATORY CELL RESPONSE, AND THIS WOULD BE PROTECTIVE, THIS WOULD PREVENT DISEASE, AND WHETHER THIS DOES SO IN THE NORMAL INDIVIDUAL IS STILL UNDER INVESTIGATION. IN THE MIDDLE IS A VERY IMPORTANT GROUP OF BACTERIA, THE CLOSTRIDIUM, YOU’VE ALREADY HEARD ABOUT CLOSTRIDIUM DIFFICILE CAUSING INFECTION. I’M GOING TO TALK ABOUT THIS TO SOME EXTENT. THIS INDUCES CELLS — EPITHELIAL CELLS TO PRODUCE TGF BETA, WHICH IN TURN INDUCES FOX P3 REG LA RI CELLS, SO HERE AGAIN, HERE IS A PROTECTIVE RESPONSE, PREVENTION OF INFECTION, PREVENTION OF INFLAMMATION. ON THE RIGHT IS THE SFDs, THESE ARE ORGANISMS THAT HAVE BEEN NEWLY DISCOVERED BY DAN AND HIS ASSOCIATES, THEY ENHANCE — TO THE EPITHELIUM, THEY INDUCE CELLS IN A COMPLEX WAY, SERUM AMYLOID A, WHICH REDUCES DENDRITIC CELLS TO REDUCE — TO BECOME IL17 CELLS. HAD IS AN IMPORTANT WAY IN WHICH IL17 CELLS, EFFECTOR CELL, ARE INDUCED IN THE GUT. NOW THE ORGANISMS THE OF THE GUT MICROBIOME HAS I’VE ALREADY IMPLIED CAN EITHER PREVENT OR CAUSE INTESTINAL INFLAMMATION. THE ONES THAT CAN INDUCE LEG LA TRI RESPONSES, INDUCED REGULATORY T CELLS, ON THE OTHER HAND, CERTAIN KINDS OF E. COLI, FOUND IN THE GUT OF CROHN’S PATIENTS IN PARTICULAR, THEY CALLED ADHERENT — ADHERENT INDUCTIVE E. COLI, AIEC, INDUCED MACROPHAGES PRODUCE EFFECTOR CYTOKINES. WE’LL TALK ABOUT THAT AS WELL. NOW LET’S TALK FOR A MOMENT ABOUT THE CLOS TRID YAL ORGANISMS. THIS HAS BEEN EXTENSIVELY STUDIED BY A NUMBER OF JAPANESE WORKERS, HONDA IN PARTICULAR HAS LED A GROUP OF WORKERS, THEY HAVE FOUND THAT CERTAIN MEMBERS OF THE CLOSTRIDIUM FAMILY, CLUSTERS 4, 14A AND ALSO 18 NOT SHOWN HERE, CAN INDUCE CELLS — DENDRITIC CELLS TO INDUCE REGULATORY T CELLS. EXACTLY HOW THE CLOS TRID YAL ORGANISMS ACTUALLY INDUCE HE’S REGULATORY CELLS IS STILL UNDER INVESTIGATION, BUT IT’S THOUGHT THAT THEY ELABORATE SHORT CHAIN FATTY ACIDS — IN PARTICULAR, WHICH THEN ACT ON EP THEEL WRAL CELLS, AND THE EPITHELIAL CELLS THEN INDUCE SUBSTANCES TO ACT ON DEN IT DRI TICK CELLS TO IT MAKE THEM MORE INDUCTIVE OF REGULATORY RESPONSES. SO THIS IS AN IMPORTANT FINDING, BUT WHETHER IT APPLIES TO HUMANS OR NOT IS STILL NOT KNOWN. IT CERTAINLY APPLIES TO MICE, AND IF YOU TAKE GERM FREE MICE, FOR INSTANCE, AND GET POPULATIONS OF CLOSTRIDIAL ORGANISMS, AND INJECT THEM IN TO GERM-FREE MICE, THEY WILL MANIFEST THE MUCH HIGHER LEVEL OF REGULATORY T CELLS AND BE PROTECTED FROM VARIOUS INFLAMMATORY CONDITIONS. NOW, YOU COULD TALK ABOUT — WE JUST TALKED ABOUT REGULATORY — BACTERIA THAT INDUCE REGULATORY CELLS. ONE COULD ALSO TALK ABOUT COLITOGENIC ORGANISM, ORGANISMS THAT INDUCE INFLAMMATION. I WANT TO MAKE A VERY IMPORTANT DISTINCTION, COLITOGENIC ORGANISMS CAN BE DEFINED AS ORGANISMS THAT ARE INTRODUCED INTO A NORMAL HOST WILL INDUCE INFLAMMATION IN A NORMAL HOST. THERE DOESN’T HAVE TO BE INFLAMMATION OR — PRESENT IN THAT HOST. THAT WOULD BE A TRUE COLITOGENIC ORGANISM. THERE’S ONLY ONE SITUATION IN WHICH A TRUE COLITOGENIC ORGANISM HAS BEEN FOUND, STUDIES OF SO-CALLED TRUCK MICE, COMPLEX MICE, THEY LACK T CELLS, THEY’RE ALSO — IN A TRANSCRIPTION FACTOR KNOWN AS T — THEY MAKE A LOT OF T & F ALPHA, IL17 AND IL23. AND YET IT’S A COLITIS. THE REMARKABLE THING ABOUT THESE MICE IS THAT IF YOU TAKE THE GUT MICROBIOTA FROM THESE MICE AND PUT THEM INTO NORMAL HOSTS, THEY WILL CAUSE DISEASE IN NORMAL HOSTS. THE RECIPIENT ANIMAL COULD BE COMPLETELY NORMAL. SO IF YOU COHOUSE NORMAL ANIMALS WITH THE TRUCK MICE, THE NORMAL ANIMALS WILL GET COLITIS, AT LEAST FOR A CERTAIN PERIOD OF TIME. THESE ARE — THEY CAN CAUSE DISEASE IN NORMAL HOSTS. NOW IN IT CONTRAST TO THAT, ARE ORGANISMS THAT DEVELOP IN NLRP3 — MICE. THESE ARE ANIMALS THAT LACK A PARTICULAR KIND OF INFLAM ZONE PRESENT IN EPITHELIAL CELL. THESE ANIMALS DEVELOP COLITIS DUE TO PARTICULAR ORGANISMS, ONE OF THEM IS PREVOTELLA ORGANISMS. BUT THEY’LL ONLY CAUSE DISEASE WHEN YOU ALSO GIVE THE ANIMAL COLITIS. YOU HAVE TO TREAT THE ANIMAL WITH A SUBSTANCE, A CHEMICAL WHICH HAS A NEGATIVE EFFECT ON THE EPITHELIUM, CAUSES THE EPITHELIUM TO BE MUCH MORE PERMEABLE TO ORGANISMS. SO THESE ARE COLITOGENIC ORGANISMS BUT THEY ONLY CAUSE DISEASE IN AN ALREADY DISEASED HOST. SO THEY’RE NOT COMPLETELY ROLITOGENIC, THEY REQUIRE THE HOST TO HAVE AN ABNORMAL. NOD2 IS A GENE THAT ENCODES A PROTEIN WHICH REACT TO PART OF THE PROTEIN COAT OF BACTERIA, AND YOU CAN GIVE THESE MICE THIS DSS COLITIS, THAT IS, YOU CAN TREAT THEM AND INDUCE COLITIS. REMARKABLY, WHAT YOU SEE HERE, THE DSS COLITIS ANIMALS LOSE WEIGHT, AND THIS IS A STUDY OF THE SIGNAL-HOUSED MICE OR THE CO-HOUSED WILD-TYPE MICE, YOU CAN SEE THE CO-HOUSED WILD TYPE MICE LOSE MORE WEIGHT BECAUSE THEY’RE EXPOSED TO THE FLORA OF THTHE NOD2-DEFICIENT MICE. JUST DIRECT YOUR ATTENTION TO THE COLORED BARS, YOU CAN SEE THAT THE NOD2-DEFICIENT ANIMAL HAS A LOT MORE — A LOT LESS — A LOT MORE BACK TIER YA — SHOWN IN BLUE. SO THE — THAT HAS THE ENCLOSE STRID YUM. CLOSTRIDIUM. SO HAVING LESS FERMACUTES, THEY HAVE LESS ORGANISMS THAT ARE CAPABLE OF INDUCING REGULATORY CELLS. AND THAT MAY BE ONE OF THE REASONS WHY THEY DEVELOP MORE DSS COLITIS. NOW I TALKED ABOUT THE MICROBIOTA THAT INDUCE FOX 3 REGULATORY CELLS AND, THEREFORE, THEY’RE PROTECTIVE, AND I ALSO TALKED ABOUT TO SOME EXTENT THE E. COLI, THE ADHERENT PENETRATING E. COLI. TEASE ARTHESE ARE ORGANISMS THAT
OCCUR IN PATIENTS WITH CROHN’S DISEASE, NOT ALL PATIENTS BUT SOME PATIENTS WITH CROHN’S DISEASE, THEY GET INTO MACROPHAGES, AND THEY INDUCE THE MACROPHAGES WITH TNF. SO THESE ADHERENT INVASIVE E. COLI OR AIEC ARE A COLITIS PRODUCING OR INDUCING ORGANISM, BUT THEY’RE PROBABLY NOT CAUSING DISEASE. THEY ARE MEMBERS OF THE COLITOGENIC SUBPOPULATION THAT CAUSES — ALREADY DISEASE IN THE HOST, SUCH AS CROHN’S DISEASEMENCROHN’S DISEASE.SO
THIS ORGANISM
CAN BE FOUND IN NORMAL INDIVIDUALS AND DOESN’T CAUSE THE DISEASE IN NORMAL INDIVIDUALS, IT CAUSES HIGH NUMBERS OF KAFN SER PATIENTS
CANCER PATIEN
T, IT DOESN’T CAUSE COLITIS IN THE CANCER PATIENT. SO THERE’S MANY REASONS TO BELIEVE THAT THEY’RE SECONDARY, THEY ARE OCCURRING WITHIN AN INFLAMMATORY ENVIRONMENT, THEY BIND TO THE EPITHELIUM THROUGH A PROTEIN CALLED C CAN 6, THEY ENTER THE LAMINAR PROPRIA THROUGH ULCERS GENERATED THROUGH THE INFLAMMATION. THEY CAN AGGRAVATE DISEASE BUT THEY CAN’T CAUSE DISEASE PRIMARILY, AND IN FACT, THEIR ANTIBIOTIC — THEY CAN B CAN’T
BE KILLED BY ANTIBIOTICS BUT PATIENTS WITH CROHN’S DISEASE ARE NOT REALLY SUSCEPTIBLE TO ANTIBIOTIC TREATMENT. IF THEY WERE, THEN THESE E. COLI WOULD BE CONTROLLED BY THE ANTIBIOTICS AND PATIENTS WOULD GET BETTER. SWITCHING GEARS A LITTLE BIT, HAVING TALKED A LITTLE IN GENERAL ABOUT TYPES OF COLITOGENIC ORGANISMS, ALSO ORGANISMS THAT INDUCE REGULATORY CELLS AND ORGANISMS THAT ARE INDUCING EFFECTOR CELLS THAT CAUSE INFLAMMATION. I’D LIKE TO TURN OUR ATTENTION TO NOD 2. NOD 2 IS A KEY OF WHICH THERE ARE CERTAIN POLYMORMORPHISMS, CERTAIN POLYMORE OFISMS IN THE NOD 2 GENES ARE ASSOCIATED WITH CROHN’S DISEASE. THAT IS THE MOST COMMON GENETIC ASSOCIATION, CODED BY CARD 15. IT IS AN INTRO CYTOPLASMIC SENSOR OF A COMPONENT OF PEPTIDOGLYCAN. ABOUT 10 TO 15% OF PATIENTS WITH CROHN’S DISEASE, THEIR CARD15 POLYMORE OFISMS ARE MUTATIONS. THE NOD2 GENE CONSISTS OF A CARD REGION — AND THAT’S WHERE THE MOLECULE RECOGNIZES THE MDP, AND AS A RESULT OF THAT, YOU GET CROHN’S DISEASE. NOW WHAT IS A REASON WHY NOD2 MUTATIONS CAUSE CROHN’S DISEASE? IT HAS TO DO WITH THE WAY NOD2
NOD2 INTERACTS WITH THE MICROBIOME. THE FIRST THEORY THAT WAS PUT FORWARD IS THAT SINCE NOD2 ALSO — PANETH CELLS, WHICH ARE KINDS OF EPITHELIAL CELLS, YOU NEED THE NOD2 TO PRODUCE CERTAIN ANTIBACTERIAL SUBSTANCES CALLED DEFENSINS, AND AS A RESULT OF LACKING NOD2, THERE’S LESS DEFENSIN PRODUCTION AS THE EXPLOSION OF BACTERIA IN THE GUT AND THIS CAUSES THE INFLAMMATION. THE PROBLEM WITH THAT THEORY IS THAT, IN FACT, THE BEST DATA AVAILABLE SHOWS THAT MI AB NORMS OF DEFENSIN PRODUCTION THAT OCCURS IS ACTUALLY SECONDARY TO THE INFLAMMATION, IT’S NOT A PRIMARY ABNORMAL. IT’S NOT REALLY WELL PROVEN THAT NOD2 ACTS THROUGH REDUCING DEFENSIN PRODUCTION IN HUMANS. ANOTHER THEORY WE DEVELOPED HERE A NUMBER OF YEARS AGO IS THAT NONOD2 IS VERY IMPORTANT IN ALLOWING CELLS TO RESPOND WITH REGULATORY — IN A REGULATORY FASHION, NAMELY YOU STIMULATE THE ANIMAL WITH NOD2, WITH MDP, THROUGH NOD2, YOU GET GREATLY REDUCED IMMUNE RESPONSES. SO THIS IS A COMPLICATED SLIDE, I JUST WANTED TO DIRECT YOUR ATTENTION TO COMPARE THE PINK AND THE YELLOW, THESE ARE RESPONSES TO VARIOUS TLR LIGANDS LIGANDS, DOUBLE STRAND RNA, LPS, AND SO ON, SO ON. IF YOU COMPARE THE PINK AND THE YELLOW, THE PINK IS THE PRIMARY RESPONSE, THE YELLOW IS IF YOU STIMULATED THE CELLS FIRST WITH MDP AND THEN CAME BACK AND GAVE IT A SECOND STIMULATION. IN THE SECOND STIMULATION, THE RESPONSE IS MUCH LOWER. SO YOU COULD EITHER COMPARE THE UPPER LINE, WHICH IS IL12 — RESPONSES WITH THE LOWER, WHICH IS WITH THE IL6 RESPONSES, NO MATTER WHICH TLR LIGAND YOU SEE, IF YOU COMPARE THE PINK AND THE YELLOW, THE PRE-STIMULATION OF THE CELLS WITH MDP GIVES YOU A MUCH LOWER RESPONSE. NOW, WE LOOKED AT THIS VERY CAREFULLY AS TO WHAT THE BIOCHEMICAL MECHANISM WAS, AND WE LOOKED AT VARIOUS PROTEINS THAT COULD BE PRODUCED AS A RESULT OF MDP STIMULATION, AND WE FOUND THAT MDP STIMULATION INDUCES A LOT OF A SUBSTANCE CALLED IRF4, SHOWN CIRCLED IN IT RED. RF4 IS A VERY IMPORTANT PROTEIN IN THE CELL. IT’S INVOLVED IN B CELL DEVELOPMENT, IT’S BEEN SHOWN RECENTLY TO BE INVOLVED — VERY INVOLVED IN THE — OF DENDRITIC CELLS. SO IT TURNS OUT THAT MDP CAN INDUCE A LOT OF IRF4, AND YOU CAN ATHAT PERHAPS TH ASSUME —
THE ANIMALS
WITH THE MUTATIONS CAN LEAD TO TROUBLE. NOW, WE GET DID A VERY SIMPLE EXPERIMENT. WE HAD AN ANIMAL MODEL OF INFLAMMATION INDUCED BY A SUBSTANCE CALLED TNBS, WHICH IS GIVEN INTRAREC INTRARECTALLY. THE ANIMALS LOSE WEIGHT AND DEVELOP INFLAMMATION IN THE GUT. HOWEVER, IF AT THE SAME TIME YOU GIVE THE ANIMAL THE SUBSTANCE THAT INDUCES NOD2 RESPONSES, IF YOU GIVE THE ANIMAL — YOU CAN COMPLETELY PREVENT THE DEVELOPMENT THE OF THE INFLAMMATION. IT’S A VERY STRIKING PHENOMENON. SO HERE’S A SUBSTANCE THAT’S NORMALLY PRESENT IN THE GUT. BECAUSE IT’S PART OF THE BACTERIAL COAT OF BOTH GRAM POSITIVE AND GRAM-NEGATIVE ORGANISMS. BUT IF YOU GIVE AN EXCESS AMOUNT OF THIS MATERIAL, YOU CAN PREVENT INFLA NATION. INFLAMMATION. THIS STRIKING RESULT HAS BEEN REPEATED IN VARIOUS LABORATORIES AROUND THE WORLD. NOW, YOU CAN ALSO SHOW THAT THIS HAPPENS IN ANOTHER MODEL, WHICH I’VE ALREADY MENTIONED, DSS COLITIS, AND SHOWN HERE IS THAT ANIMALS LOSE WEIGHT, BUT IF YOU GIVE THE SUBSTANCE SHOWN IN ORANGE, THEY DON’T LOSE WEIGHT, THEY’RE PROTECTED FROM THE DSS COLITIS. BUT IF THEY LACK NOD2 BECAUSE THEY’RE NOD2 KNOCKOUTS, AND THAT’S SHOWN IN THE GREEN LINE, EVEN IF THEY’RE GIVEN MSM DP, NOMDP, IFTHEY LACK NOD2, THEY
ARE NOT PROTECTED BY THE M IT DP. MDP. HOWEVER, IF YOU DIRECT YOUR ATTENTION TO THE RIGHT SIDE, IF YOU HAVE AN ANIMAL THAT LACKS IRF4, WE WERE FORTUNATE AT THIS TIME TO BE ABLE IT TO GET THESE NKOUT ANIMALS, NOW THE MDP DOES NOT PROTECT THE ANIMAL, THE ANIMAL HAS TO HAVE IRF4. SO THIS INCREASE IN IRF4 THAT MDP INDUCES IS SHOWF VERY IMPORTANT IN PROTECTING THE ANIMAL FROM THE DEVELOPMENT OF COLITIS AS A RESULT OF SEEING MDP. SO AT THIS POINT, WE POSTULATED THE FOLLOWING IDEA, THAT MDP CAN GET INTO THE CELL AND INDUCE OR LATE NOD2, THE NOD2 THEN SOMEHOW INTERACTS WITH IRF4, THE IRF4 SOMEHOW CAPS — THE IL12, THE INTERFERON GAMMA AND THE IL17. SO HOW IS THAT REALLY HAPPENING, WHAT IS GOING ON? IS THE MDP ACTING THROUGH IRF4 TO PREVENT INFLAMMATION? I’LL STOP HERE TO SAY THAT THIS IS THE INTERACTION OF THE MICROBIOME BECAUSE THE MICROBIOME CONTAINS THESE — THIS MDP THAT CAN INFLUENCE THE DEVELOPMENT OF THE NOD2 RESPONSE. NOW SHOWN HERE IS THAT WHEN YOU STIMULATE EITHER NOD 1 OR NOD2, YOU STIMULATE NOD 1 OR NOD2, ONE OF THE THINGS THAT HAPPENS IS THAT A DOWNSTREAM KINASE CALLED RIP2 OR RIC, THE RIP2 IS EU BIC TI NATEED AND IT HAS A CERTAIN KIND, CALLED K63 UBIQUITI DIDNATION. POLYUBIQUITINATION. LIP2 HAS BEEN ACTIVATED WHEN IT UNDERGOES K63 POLYUBIQUITINATION K63 POLYUBIQUITINATION. THEN YOU INTERACT WITH DOWNSTREAM MOLECULES, THE MOST IMPORTANT OF WHICH IS TAC, TAC1 OR ANOTHER ONE IS TRAC6, AND THEN THIS INITIATES THE CASCADE. SO WE LOOKED AT THIS VERY, VERY CAREFULLY. IF YOU PRESTIMULATED CELLS, YOU GOT A BLUNTED RESPONSE, A DECREASED RESPONSE, A CHOLEIJENG RESPONSE. YOU LOOK HERE, CAN YOU SEE IT YOU PRESTIMULATE CELLS WITH MDP THEA SHOWN IN THE FIRST STIMULATION,, THE RI IRF4 IS REDUCED, AND IT INTERACTS WITH IT TRAF6. SO IT IS INDUCING RIP 2 INTERACT WITH RF4 AND IT T RMENT AF6. THIS IS ALSO SHOWN IN A VERY NICE WAY WITH STAINING, I’M NOT GOING TO DW INTO THIS BECAUS
THIS BECAUSE
OF TIME, BUT BINDING TO RICK, TRAF6 AND MYD88. LET’S GO ON TO POLYUBIQUITINATION. YOU CAN SEE IF YOU PREEL STIMULATE CELLS WITH MDP, IT’S SHOWN AS A SMEAR WHEN YOU PRESTIMULATE, YOU GET A SMEAR WHICH IS THE MOLECULE WHICH HAS BEEN UBIQUITINA IATE IT D. WHAT YOU CAN SEE IS THAT PRESTIMULATION INDUCES, IN THIS CASE, THE RICK TO UNDERGO K63, WHAT THE PRESTIMULATION DID IS PREVENT THE POLYUBIQUITINATION OF RICK, ALSO PREEIVET PREVENTS
THE K63 POLY — UBIQUITINATION OF TRAF6 BUT IT DOESN’T HAVE ANY EFFECT ON — YOU CAN ALSO SHOW THAT IF YOU REDUCE THE AMOUNT OF RF4, USUALLY — YOU CAN PREVENT THIS PREVENTION OF POLYUBIQUINATION. SO THE EFFECT OF THE MVP IS TO PREVENT THE — OF DOWNSTREAM SIGNALING MOLECULES. IF WE IT GO BACK TO WHAT WE SAW BEFORE AND YOU ADMINISTER — TO ANIMALS WITH TNBS COLITIS, YOU AGAIN SEE THAT THE ADDITION OF MDP PREVENTS THE COLITIS, THE ANIMALS DON’T LOSE WEIGHT, AND THEY DOND ACTIVATE THE SYSTEM SO THEY ARE PROTECTED FROM COLITIS COLITIS. BUT THEY ALSO — THE MVP TREATMENT ALSO INDUCES IRF4 INTERACTIONS AND IN ADDITION OF THE K K63 POLYUBIQUITINATION WITHIN THE COLON. WHAT SH SLIDE SHOWS IS THAT A RESULT OF MDP TREATMENT IS LACK OF IL4 INTERACTION WITH RICK THAT’S SHOWN WITH RED, YOU GET INTERACTION OF IF4 — IT AND WITH TRAF6 AS A RESULT OF THE MDP TREATMENT. WE CAN GO ONE STEP FURTHER AND ACTUALLY ADMINISTER AN RF4 AND INTRODUCE PLA MA T PLASMA TO THE
ANIMAL, DOES THE SAME THING AS THE — ITSELF, IT PREEIVETS TH IT
PREVENTS THE IN
FLA INFLAMMATION. SO THE ANIMAL HAS REDUCED AMOUNT OF ACT VASE OF MDP AND INTERACTION WITH RICK MYBBA IN IT TRAF 6. SO IN THE END WHAT WE SEE HERE AS A RESULT OF YOU GET INDUCTION OF RICK WHICH THEN INTERACTS WITH IRF4, THE IRF4, THEN, PREVENTS THE POLYUBIQUITINATION OF VARIOUS DOWNSTREAM MOLECULES SUCH AS TRAF 6 AND MYD # 8 AND THAT PREVENTS THE ACTIVATION OF –. SO IN THIS VERY COMPLEX WAY, WE SEE THAT THE GUT MICROBIOME, THROUGH ITS INTERACTION WITH — ITS INTERACTION WITH NOD2, IS DOWNREGULATING THE IMMUNE RESPONSE, AND IN PATIENTS WHO LACK NOD2 ACTIVITY BECAUSE OF A GENERIC DEFECT, THEY DON’T HAVE THIS REGULATION, AND YOU GET AN INCREASED RESPONSE AND YOU GET INFLAMMATION. WHICH WE CALL CROHN’S DISEASE. AT LEAST THE EXPERIMENTAL ANIMAL. IN FACT, ALL THE INVESTIGATORS HAVE SHOWN THAT ACTUAL PATIENTS WITH CROHN’S DISEASE, YOU GET DECREASED NOD2 RESPONSES. SO THIS IS THE SORT OF — IF YOU DIG DOWN LOOK AT THE BIOCHEMISTRY THE WAY THE GUT MICROBIOME CAN INTERACT AND REGULATE THE IMMUNE SYSTEM, IF THAT REGULATION IS NOT OCCURRING, THEN YOU GET INFLAMMATION. PLAWSH THANK YOU. [APPLAUSE]>>THANK YOU. ARE THERE THERAPEUTIC ASPECTS INVOLVED WITH –>>WELL, ONE THING WE’VE BEEN THINKING IS ADD SERRING MD
ADMINISTERING
MDP TO PATIENTS, AND WE ARE COLLABORATING WITH PEOPLE AT JOHNS HOPKINS TO CREATE NANOPARTICLES THAT — MDP, ACTUALLY GIVE IT TO PATIENTS AND INDUCE REGULATORY RESPONSES, BUT ONLY IN THOSE PATIENTS, YOU DON’T HAVE THE POLYMORPHISM AND CAN’T RESPOND TO MDP. SO IN THE 95% OF PATIENTS WITH CROHN’S DISEASE, WHO CAN RESPOND TO NOD2, HAD WOULD BE EFFECTIVE THERAPY.>>SO WHY DO CROHN’S DISEASE PATIENTS GET GRAN LOMAS AN GRAN
LOW GRAN L
OMA AND NOT GET OVERT — INFLAMMATION.>>THAT’S A GOOD QUESTION AND I THINK IT RELATES TO THE FACT THAT YOU GET A LOT OF ACTIVATION OF MACROPHAGES OF THIS DISEASE, WHEREAS IN ULCERATIVE COLITIS, WHICH IS — IT’S MORE OF A SUPERFICIAL INFLAMMATION AFFECTING EPITHELIAL CELLS, YOU DON’T GET THAT MUCH ACTIVATION OF MA ROW PHAGES.>>YOU WOULD IMPLY THAT THE SAME MECHANISM IS ACTIVE IN ULCERATIVE COLITIS?>>OH, YES. ULCERATIVE COLITIS IS A VERY DIFFERENT KIND OF MECHANISM. BUT I WOULD IMPLY THAT WHAT’S HAPPENING HERE IS ACTIVATION OF MACROPHAGES AND DENDRITIC CELLS.>> — POLYMORPHISM –>>WAIT A MINUTE. GO AHEAD.>>SO IT LOOKS LIKE YOU LET PEOPLE USE WEIGHT JUST TO TRACK IF THE COLITIS — OR NOT OR INFLAMMATORY BOWEL DISEASE. ARE THERE ANY KIND OF BIOCHEMICAL MARKERS FOR THAT?>>FOR THE ANIMALS OR HUMANS?>>LET’S START WITH ANIMALS. PLAWSH>>WELL, THERE’S NO SPECIFIC BIOCHEMICAL MARKERS. THE INFLAMMATION IS RATHER NONSPECIFIC.>>IS THE PRESENCE OF THE POLYMORPHISMS ASSOCIATED WITH CROHN’S DISEASE, IS THAT SUFFICIENT?>>NO, IT ISN’T SUFFICIENT, BECAUSE — IN FACT, MOST PATIENTS WHO HAVE THE
POLYMOREMORE OFISM DON’T HAVE THE DISEASE. SO THIS IS THE CASE WITH MOST POLYMORPHISMS. THERE ARE OVER 150 POLYMORPHISMS THAT HAVE BEEN ASSOCIATED WITH INFLAMMATORY BOWEL DISEASE. 150 TO 200. HAS TO BE COMBINED WITH OTHER ABNORMALITIES. SO WHAT DO WE KNOW ABOUT THE PAISH WHPATIENT WHO HAS AN ACUTE
EPISODE AND THEN GOES IN TO A PROLONGED REMISSION FOR YEARS AND YEARS, CAN YOU ACTUALLY MECHANISTIC MECHANISTICALLY SEE WHAT’S GOING ON THERE?>>WELL, IT COULD BE THAT FOR INSTANCE HIS DEVELOPMENT OF REGULATORY CELLS, IL10, SO THAT THE RESPONSE IS ACTUALLY — CAN BE SORT OF POLYMORPHIC IN A SENSE. YOU CAN ALSO INDUCE REGULATORY CELLS. WE SHOW IN CERTAIN STRAINS — DEFICIENCY COULD ACTUALLY BE PROTECTIVE BECAUSE AT CERTAIN STAGES OF THE KEYS, YOU HAVE MORE REGULATORY CELLS.>>I SEE. ARE THERE ANY OTHER QUESTIONS? IF NOT, THANK YOU VERY MUCH. WONDERFUL. [APPLAUSE]

3 thoughts on “Demystifying Medicine 2016: The Intestinal Microbiome and Inflammatory Bowel Disease

  1. These talks are so valuable to us not in the USA. Please have more of these. Thank you for all the information.

  2. 15:33
    I though this sounded fishy .
    She lied , it is a subliminal dairy industry advertisement .
    Ilya Mechnikov – Facts
    """" studies of starfish larvae, in 1882 he pointed to phagocytosis as one of the immune system's ways of operating. """
    https://www.nobelprize.org/nobel_prizes/medicine/laureates/1908/mechnikov-facts.html

  3. Please continue posting these very informative videos. Really enjoy watching and learning from them. This video in particular because it hits home for me dealing with Crohn’s disease.

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