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Microbes, metabolism and autoimmunity
Ramnik Xavier, Massachusetts General Hospital, Boston, USA
Friday, Sept. 29, 2017 · 9:06 a.m. · 56m 03s
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ah
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so what if there are hundreds but invitation and what i try to do in the next um
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thirty to forty minutes is to give you an overview of the marker by on and try to make some connections to human help
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so we've all seen this observation where well the incidence of infectious
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diseases that continued to decrease there's been a clear spike
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in various immune disorders from allergy to auto immune disease
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where clearly the foundational principle of all these diseases is being uncontrolled inflammation
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and as we look at any of these diseases and its distribution across the globe there is clear correlation with
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so she cannot mix and the absence of the presence
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of hygiene hygiene hypothesis which i'll try to address
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but my focus today is gonna be mainly on the dot michael by on
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and how it relates to how the micro by ms assemble during help
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how it contributes to a disease um in various stages i'm going
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to use allergy an auto immune disease as two examples
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but before i get there are two principles so we've known for a long time that
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there are many factors that contribute to how the got micro by ms estimate
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clearly age is an important role in our data that in a minute but clearly it's the
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dot architecture that plays the most critical role in assembling who's there and what it means
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clearly we have had many perturbations in our life so for example antibiotics without a
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lot about the body mass index and its effect on the market by um
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clearly diet and lifestyle clearly highly stressed upon by many speakers
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yesterday clearly affect how this michael by ms assemble
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and host genetics which just talk to play an important role more recent studies have suggested
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that this in fact places small role in how did that michael by mister sample
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there is clearly a dynamic or sort of the state of active um
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set points that assemble you wonder to look at the microbial ecology
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how the dock battery is maintained family on the line immune response
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and clearly as you can see here as these two states
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change in fact the micro by um undergoes peaks and valleys
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that keeps trying to reset how this is a sample
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so what are the principles of that that might provide clearly many studies boating humans and mice
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over the first thousand days of life in humans have gone on to show that the micro by
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um clearly is important in how the new coastal
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immune system much she was assembles and doubles
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and this for six month period is a critical window in which the michael
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by men micro by an exporter influences how the immune system is set
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despite the got playing an important role in what we eat and how
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we absorb minute koreans we still understand very little on how
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food substances like battery breakdown products us sen standards all
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so clearly the signals that control micro by responses and diet
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that impact sort of the concepts of the mean tolerance and break down us do poorly understood
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and so we need to understand more of these sensing mechanisms if
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you have to sort of but understand how this crosstalk between
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the marker bile and they got the symbols on the same principles i think apply to the scan another body sites
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evolution has taught us that clearly there a certain volume off exams
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for example in the actually typing online for example in t.
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l. uh polymorphism status controlled by the in response
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so many of these features yeah not only control how the immune system
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develops but also with time we began to appreciate microbial products
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also signal to many of these receptors are now talking about it
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so ready to get started in two thousand and nine working which ah smoke by
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really interested in how these microbial products the shot chain fatty acids a sense in the body
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used an integrated regional makes approach unidentified g. p. r. forty three as one other
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sectors that sense shot chain fatty acids and plays an important role in controlling
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be sure home yes cases of insulin sensitivity where they've been the at
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the post issue labour must so and more recently that that
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so clearly us highly produce much obliged punch signals to g. p. l. forty
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three and the time that mean other we suppose that have been identified
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that play a role in sensing accessible died an energy metabolism
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so we know that we take a start using complex forms these on the go
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baby is break non reactions mediated by that michael by um
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resulting in the production of short chain fatty acids
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over time we've learned that these molecules play an important role in regulating how t. cells respond
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how we make imminent lobby name and how it affects many of the other side of kind responses
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so the first question we asked was how do these structure in fatty acids signal
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so i had to stop and back another said previously shown that the into spinal stem cell
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in fact he's inhibited by due traits or short chain fatty acid
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that's made at high levels in fact restrains ought restricts how the stem cell functions
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the best evidence for this comes from looking at zebra finch so
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these are um uh organisms that lack the creep like structures
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where the stem cell compartment in zebra fish is highly sensitive to be great
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we've also known better you trade like the other sergeant fatty acids
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after the metropolis my host cells too many breakdown products
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and as i told you in addition to g. p. r. forty three there been other
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receptor types that have been identified but potentially sense these short chain fatty yes it's
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so we joined white side we asked a very simple question is if you pray that affects the short stem cells
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or is it breakdown products of butte rate that control
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stem cell activity and what's the coffee signalling pathway
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not been going to details but being able to show that h. that inhibition in
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fact is the one that morse crow closely correlates with stem cell proliferation
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and in a series of chemical reactions bevy simplified view trait
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a step at a time to get down to the most minimal unit abuse great
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the activity of the stem cell activities in fact defined and limited to due to it so none of
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the breakdown products signal it you need the intact you trade to signal through shot chain fatty acids
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in had invaded h. that to maintain this stem cell phone use
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spaces so that's the first concept i like the once
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the second is i think we can learn as i told you
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base of geographical distribution of allergy and auto immune disease
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but i think we can also learn the fundamental principles of
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nutrition science by looking at the global distribution and
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in this case i'd like to highlight but will hop up population are raised in conditions of broad standing
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which would suggest that there might be features after
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got that promote or restrict absorption of nutrients
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and this could potentially function through you have to be identified receptor systems
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that could be potentially exploited in the context of disease and how
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so could be use these this unit types that are distributed throughout the
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globe to better understand how the principles of nutrient absorption take place
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so the best example with this study by developer another's
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ready look at the nutrition in taking enough fossil
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and in the western world and showed that depending on your take on died
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which in theory of legumes and vegetables you clearly alter the microphone
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so do these microbes make microbial products that sick no differently in the kids in book
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in advance so compared to the kids in the western world yet to be started
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a second example with this disease call environmental and property
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which is a disease that's linked to poor sanitation
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these children end up with the shark microbe eliza they don't get these long processes
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and they have effects in value function how the group is assembled and then you can also system develops
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that again i think there's a unique opportunity to identify what are the
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sensing mechanisms to the diet and the microbes in this altered state
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and can we learn from that so that we can then maximise on knowledge of how
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new trends and micro nutrient madcap lights microbes and microbial might happen like suspense
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so that'll be going in the field so we just completed an atlas of
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the got ready map that that that's single cell resolution so be
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hopefully we'll describe many different types of that material cells in many different types opinion cells
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and the hope is that at single cell resolution one might be able to identify
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how new koreans then you pretty much have a lights microbes
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and mike probably on the cabinets signal demand can help
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the broad approach that be taken in the lab is always followed
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a very simple principle the people they started the population studies
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we then use the population information to get to groups of patients with disease
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or out and then always ended up focusing on the individual patient
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over time we've gone from human genetics some rock descriptions the findings
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that need asians the same thing with the micro bile
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and then more recently how does the environment influence how genetics and the
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market by on contribute to how i'm gonna give you two examples
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the first example is this core part of children that we started in finland so these are forty children
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as you can see twenty of them never saw single antibiotic in the first two years of light
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these twenty kids but something like nine to fifteen courses of antibiotics in the first two years of life
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and this was because they had upper respiratory tract infections or
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yeah infections indications but which antibiotics are not required
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yeah the unique opportunity for this whole part was that they've got my combined samples
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monthly for three years so we could look at how perturbations such as antibiotics
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or to that micro by um during that critical period of first year or so
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but then how does you reset the micro by m. next potentially you want to buy an antibody perturbation
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obviously the weakness of this study was that there were too many courses
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of antibiotics one after the other so we couldn't at times
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blame one ninety battery to the michael hi distributions are at times yet
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to look at the aggregate effect of many might anti markets
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but we learned some important things the first is that as others have shown in
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a healthy child ah the micro by um has a certain trajectories work or
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we know that back friday stock at a very high abundance and continue to increase over three years of light
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the introductory a. c. a. the defeat those stockpile but then go down at the age of three years
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whereas others like the lack knows on the remain up outside of the box that
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might have a lot shorter in fatty acids increase with time over three years
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but this cohort also allowed us to do was to look at if events all the time
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because up until this call for most of the studies that have been done was single time points so cross
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sectional studies during child development that said my combine is associated with the fact that the b. and c.
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the first observation but there are studies that previously shown that if you
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were born by the designer but you had the appearance and that's
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why these very early in life and you had essentially new stream plot
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that that friday's pacific blue band over three years of life
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and if you happen to be borne by c. section back fridays appeared later in life suggesting that this
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assembly of the microbial ecology in that that could have positive and
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negative effects in immune system development and potentially open disease
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but what this court told us was that there was in fact about twenty percent of kids
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i want my vaginal but who also had the same my combine distribution as a
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kid bound by c. section so clearly value of starving kids all the time
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the second observation was that there was a number of studies previously that shown
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that the abundance of be futile bacteria the milk living organisms correlated breastfeeding
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the answer is not true you in fact in c. for different happens of this video appearance and disappearance
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with the exposure or the um treatment i mean it with a take no products are not so clearly that maybe
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an intrinsic genetic clock that determines when beefy dose come
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and disappear dependent or independent of your milk intake
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what are the other lessons we learn from the score so clearly antibiotics had bad effects
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one certain bacteria so clearly showing that they create population bottlenecks
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at strain levels for these organisms i'm showing you one example so the much talked about australia for
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fourteen it lasted isn't that the most affected cluster if you take antibiotics early in life
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so you shut down many of those strains that have been implicated in assembling to deregulate pretty cells
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you also see the appearance of antibiotics resistance cheats clearly you can see here
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yes porsche to uh benson in like structure i mean everybody clearly
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and uses the expression of a beta latin is resistance she
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but more importantly what you end up losing is your diversity
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but more importantly in the organisms that are found in
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lower buttons so that's not the high abundance organisms
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that are affected it's the organisms that i found in low abandons and this
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strains that affected as a result of this repeated exposure to antibiotics
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so summarising the first principle that told the delivery more has a long term effect on the micro by um
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antibiotics in his effect strains that different strains that
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altered and more importantly you have the rest
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giving in expanding antibiotic resistance genes in the school so much for children but about adults
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so they do this um we've embarked on the study in the netherlands badly enrolled
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something like two thousand to adults in the age of ten to the age of seventy
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the whole idea here this can you now look at the adults micro bile
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as it develops in the scoreboard the plan is to follow the scoreboard overtime probably for the next ten years
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and at the same time we get and number of immunological essays of you get sixty
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different masses how the mileage those work out of the regulatory t. cells what
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how to be innate immune system control in the presence or absence of the market by and then
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cost could be connect the micro by on two sided kind responses in the cell to court
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so is there a rule set point in this so called l. p. about that we could build on
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so to do this really took life from these uh help
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individuals stimulated in the various known bacteria mostly pathogens
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and the shapes like the crime responses over time over a seven day period
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so you could begin to ask is the other side the kind signature that's associated with certain micro mines
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i'm not gonna going to a lot of detail out but if you look at the cop principle quite nets we could identify
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that aside kind responses say for example to fungal infections
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was clearly dependent on your that michael my
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in about ten percent of individuals so you could see a gradient outside
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a kind responses that up predetermined in the state of hell
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so this is even before you get any perturbation that could have important influences so
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it's likely to be basic community of people who are high tea and it produces
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this is no together for produces eyesight kite expertise is as i said uh kind
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by produces that are going to be dependent on the black market by
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again without going into details will be able to identify certain backed bacterial packs are that associated
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with the ability to make sidelines while one mile sixty and i felt fine into
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you have to highlight to work them out these the real species
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these are species that lead but see tammy note nuisance
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so they'd sleep silent placid often using like molecules yeah by
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making the mucus layer a little bit more or less
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clearly this but microbes play an important role in in different gamma
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response in that that so this is again in healthy people
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so i've given it to examples starting with a core part of children and then a core part of
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what else to tell you how the micro by one might influence help over time what about disease
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so the example that are gonna highlight today is that you have an unique opportunity to study a thousand children
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when and rolled into a study in finland in estonian russia
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the whole idea was these that gives you a high risk
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allergy an opinion disease because of the underlying actually status
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and the big able to follow the micro by um and leave at three is again the value of unwanted you sample
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to start it's clearly been known to many years that he's in finland have
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a very high risk of type one diabetes compatible child born in russia
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the same is true for various put allergies suggesting that this micro by um i've but
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uh the first year of my mike tell us something about the susceptibility is
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again i'm showing you a stream plot then if you focusing on finland here in russia here saying finland you see
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these backslide e. t.'s appear really nice and have a strong band over the first two years of life
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that is in the russian kids to start with it as much lower but they had big band of acting of bacteria
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so we did sixteen s. unmet original makes and ask what's different but what about
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the functional implications of this different community structures in the first year of life
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obviously in any type of uh analyses you find any different
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ah ways that are potentially or to it as a result of the microphone
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i'm being present or absent but the hard way that give us caught our attention was
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this poppy admit today by synthesis or like will probably second right by synthesis
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that was different because of the microbial community in the finished gets compared to the russian gets
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so we went and looked at the strange that but different between the fins on the restrooms
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and isolated eleven of them and as you can see here so again i'm
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illustrating the same principle if you happen to be born in russia
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more stuff your l. p. s. synthesis or l. p. s. like product comes them you call that
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whereas if you happen to be born in finland before like contributes but now
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you can see the major contribution is from these other planes trains
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suggesting that that could be some basic principle differences between the community
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structures between these two people i mean these two kids
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so be purified o. p. s. n. each one of these eleven strains and ask
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how do they engage throwing plummet re signalling that it's how they make cider kinds
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as expected equal i made lots of n. f. kappa beholder probably implement beside lines
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that s. the highly abandoned actually the species that i found
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in the finished gets failed to engage the spot it's
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suggesting that they may be making a different type of l. p. s. compared to
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the sixty such an l. p. s. that is made by the russian kits
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and the entrees true so be purified these um l. p. s. like molecules
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people lie as expected nexus six is such a an l. p. s.
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that as the l. p. s. that comes from the back to riley species makes a four and five is such an l. p. s.
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the four and five years size chanel yes lines the t. l. awful receptor but cannot signal
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so an important component of immune education does not take place in the first year of like
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the six site is such an l. p. s. binds that you'll have full receptor and activates the park
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so very simple observation on the longitudinal cohort of children but focusing on the first year of like
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obviously the review was asked us to do this experiment to the mall seventeen even though i was
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not very keen to stay focused on human experiments they insisted
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on a mouse experiments if you use the not nice
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and we fed the l. p. s. that came from the russian gets
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the polite yes and that delay the progression of type one diabetes
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that has to be diarrhoea l. p. s. that came from the finish gets in fact accelerated the progression it up yes
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so in the third example that given your very simple concept that there is great
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value to understanding the microphone in help in that first year of life
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and by studying longitudinal sampling one might begin to understand what
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are the principles of the immune education in the
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first year of life that may it's set us later on the diseases such as allergy an opinion disease
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so where can we go from here but about other diseases again to summarise i've told you
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that that that micro by ms affected by genetics how you born yeah you lady
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it's kind of hygiene died nutrition and exposure to
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antibiotics and we have many perturbations in that
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so what about a disease like internet about disease not uh not immune disease not
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uh not allergic disease but talk to be an or to implement a disease
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so to do this we but actually several years ago barely be
00:22:48
able to study five hundred children were referred to that physicians
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does this child had clones disease so these are kids who had abdominal
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pain and g. i. leading so they had not yet been diagnosed
00:23:01
with crowns disease and it meant to i guess going prodigies to ask could this be crowns disease
00:23:07
we've been lucky because we were able to get all the files specimens this for these kids but treated
00:23:13
what did we learn clearly double bonds that like standard in his big problems disease
00:23:19
and but that but depleted in kids with crowns disease so this is before they got treatment
00:23:24
and again if you look at the so called cross p. d. always the ones that make regulatory t. cells
00:23:30
markedly depleted um before they got before the the treated suggesting that that could
00:23:36
be an early microbial event that in fact it's the balancing these children
00:23:42
again we've looked at certain up without come back to this later clearly associated with many
00:23:47
of these battles and be functionally validated that these partners in fact are important
00:23:53
that if we go from here we just completed a study
00:23:56
that we've studied ninety individuals with newly diagnosed implement about
00:24:00
disease we have the sample them micro by him every two weeks but yet so we could look at
00:24:06
how do drugs affect the micro by um how can be identified predictors of
00:24:11
disease play yeah so that if one were going to be able
00:24:13
to treat them we might be able to sort of avoid unnecessary immune
00:24:17
suppressing drugs if we could identify this much early in life
00:24:22
so we've measured lots of different measurements on the goal is to sort
00:24:26
of put this together but i'd like to highlight one for principle
00:24:30
so with metal genome x. so the ram knows my sentences partly
00:24:35
to know that that and many different tax uh that can
00:24:39
can contribute to ram knows my synthesis so this is a metabolic
00:24:42
pathway that is important in maintaining that battery of function
00:24:47
but if you do matter transport don't mix in fact that only five of these that yet transcribed
00:24:52
so only five of the many bacteria that bias sensor statistic really are
00:24:57
functionally important so that if one were to start thinking about intervention
00:25:02
you would only focus on these five strains not on
00:25:05
this large twenty also strains so and unique opportunity
00:25:11
one of the weaknesses with the micro by one is that we tend to study the micro by um in isolation
00:25:16
i'd like to emphasise that it's important to study the micro by um in the context of the human holes
00:25:22
so the approach we've taken is the exploited alone in some human genetics
00:25:27
and started to ask the question how do these changes in microbiology
00:25:31
contribute to changes in how the the ease my combine changes in fact effect
00:25:37
the vulnerable park ways as a result of human genetics so can be identified microbes
00:25:43
that walter kind of cell function innate immunity adaptive immunity and so forth
00:25:48
um with the idea that we'll be able to with this new poll what
00:25:52
put together a map that could be used to from our market discovery
00:25:57
to identify who is going to fly with disease before they end up
00:26:01
going to a physician and hopefully many starting points but downstream analysis
00:26:07
obviously the micro binders complicated and i go in the lab
00:26:11
is to understand how these microbes working details of the
00:26:15
in collaboration with the broad instead i mean with i might with i. b. m. they're gonna try to study
00:26:19
every single gene in the microbe and try to do the structural maps speech one of these genes
00:26:26
obviously very interested in the determinants about common isolation and
00:26:30
how it relates to h. m. o. utilise asian
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and then hopefully we'll be able to identify important at the tops
00:26:37
that in fact control adaptive immunity in the developing child
00:26:43
another area of interest is how fickle microbe i'm
00:26:47
transplants might tell us about microbial ecology
00:26:51
so we've been in a unique position where are we been able to study eighty six healthy don't and so
00:26:57
these are the super don't as that contributed to twenty five thousand people might remind transplants in the us
00:27:05
them all come from eighty six don't and then as you can see some
00:27:07
of them give samples all that many gays throughout the two year period
00:27:13
you isolate started isolating every single back in the support onus on the idea is to sort of know the
00:27:19
edgy gnomes know what they make and so forth with the idea that we can begin to understand
00:27:24
how we might build the basic principles of the building blocks of what's in and fickle my
00:27:29
combine transplant so that we could define smaller communities in the context of health and disease
00:27:37
i like when bites highlighting some of the functions potential intervention points with the micro mart
00:27:42
so what i told you is that that difference is set to the ladies have
00:27:46
focused mostly on what a new disease this is also true for allergy
00:27:52
we've also told you that in the case of the trade betrayed itself is important in maintaining stem cell
00:27:59
but that could be other might have uh like that or by actives that i've made by put breakdown products
00:28:05
of bacterial breakdown products that offer them a catalyst in that that so that they could have different effects
00:28:12
in a classic example where are individuals who exports to meg foreman
00:28:17
so what brought that regulates your blog should the balance
00:28:21
within two days of treating these individuals with mat forming you brought about the change in the microphone clearly
00:28:28
having a very acute effect on glucose on your spaces and the microphone and two of these buttons
00:28:35
um at commands yeah and as a as a non backed uh in fact grew much faster in the presence of next one
00:28:43
so suggesting that that could be both positive and negative effects
00:28:48
on xena buyout takes a breakdown products it drives and how the microbial ecology is maintained
00:28:55
so what we'd like to do is begin to ask the question whether it
00:28:59
be food substances albrecht non products of fruits microbes are them microbial products
00:29:04
how to assemble the dot micro bile and how they might communicate with the holes
00:29:10
in the last ten years many labs have contributed to run
00:29:13
number of receptor systems that sends these breakdown products
00:29:18
and that means some very elegant examples we have an example yeah the
00:29:22
um product holding on the goes metabolism by bacterial enzyme called part c.
00:29:29
to make him all t. m. a. n. t. m. a. gets up to diced in the labour
00:29:34
and in fact he anyway levels that correlated with mister that's just a rocket disease
00:29:40
so steve hayes and i there's table to identify uninhibited is enzyme
00:29:44
and clearly could show that there is a correlation with the accumulation of these make apple like
00:29:49
with disease ways but more importantly one could also correct that phenotype by affecting a bacterial enzymes
00:29:58
we've spent a lot of time lapse
00:30:05
sorry
00:30:26
yep
00:30:29
won't allow me to
00:30:37
uh_huh
00:30:41
so popular that you spend a lot of time recently to understand how trip the fan is not having like
00:30:46
this so if you look at the literature trip the fan is broken down thing that's in south bay
00:30:51
but in a series of experiments we've been able to identify that in fact
00:30:54
ripper fan is broken down too many other indoor break down on us
00:30:59
on these products appear how in patients with renal disease out you'll be me eyes control
00:31:04
they had and intimately properties the function as potentially h. i. agonies
00:31:09
and we will report shockley that they are not work for the fan might
00:31:13
have uh like that in fact sense to g. p. c. has that
00:31:18
so we were interested in understanding how this might be control and but
00:31:21
i'm gonna tell you the story about that to stop the caucus
00:31:26
so do this we asked a very simple question so if you took so we know that the new
00:31:31
sin is important not the mucus lane that that is an important role in battery of function
00:31:36
and so we've interested in trying to identify bacterial
00:31:40
enzymes that potentially break down you since
00:31:44
or bacterial and transporters that could potentially transport news and breakdown products
00:31:50
the chain will do in the lab to the computational approach to identify
00:31:55
i've yeah these enzymes in transport is that we can identify
00:31:59
and then draw these individual bacteria in had no musing
00:32:04
on high news in um how to system to show that these bacteria in fact live on using products
00:32:11
and you can see here the positive control recommend sanderson philly yeah clearly
00:32:16
loves new saying would be able to identify some normal organisms
00:32:20
we took these buttons one at a time and put them into minds and asked in my dues of inflammation
00:32:27
could these bibles that maintain a healthy mucus layer maintained that yep
00:32:32
and as you can see here then you fed my sleep yep that's departments
00:32:36
or sally i now with chemical injury model bayes no damage to that
00:32:42
suggesting that base but could potentially that's something good that protects you from material injury
00:32:50
we then went on to by looking at um sequencing strange that belong
00:32:55
to the baptist rapid papas resell yeah family identified two strains that
00:32:59
contained by synthetic gene class to that as one strain that lack that by synthetic
00:33:04
gene class that we do these bags and identify the products to make
00:33:09
so they make too derivative subscript the fan metabolism that appear to be important in maintaining that yep
00:33:17
and if you go back and look at samples in patients with inflammatory bowel disease
00:33:22
in fact more put these in semantic program some market be depleted
00:33:26
and even known for a long time news in depletion is one of the early or
00:33:30
not of internet about disease so we've been able to connected by a breakdown product
00:33:36
i didn't use in help and potentially that your function and without going into details
00:33:41
we've been able to match what these molecules to do so they clearly
00:33:46
make news in choosing right enhance the barrier they
00:33:49
shut down inflammation they up regulated production about
00:33:52
them and their work through a program of enough and i've too since it's it's
00:33:58
so i think there is not unique opportunity of learning from microbes in help potentially identifying by
00:34:06
a synthetic machinery and their products that could potentially influence how help and refuses men thing
00:34:12
that number of examples clearly they are molecules the n. aside in mind that stands to the p. c. r.'s
00:34:19
the single repeats that sends to the c. d. one the receptor program and then breakdown
00:34:24
products uh by last stage that stands through the effects are family of molecules
00:34:31
two and i would like to give you one example of how we might be able to intervene with our current knowledge
00:34:38
so if we take patient inflammatory bowel disease with the best
00:34:42
available drives only about forty percent of patients respond
00:34:47
if you follow these patients to the end of the first year now only twenty percent response
00:34:53
so if there was a unique opportunity to ask can we identify microbial features in the individuals
00:35:00
who respond to this brought the dallas in there and stay responses for one yeah
00:35:06
compared to the individuals to respond for three months and then lose response
00:35:11
with the hope that if you can identify factors that lead to loss of response
00:35:16
maybe this could be an early entry point where we could potentially replete
00:35:20
the missing buttons so that you can extend the duration of response
00:35:25
and i think the same principle could be applied to
00:35:29
nutrition sciences to maintaining principles of that l. install
00:35:34
so not replace the entire micro by um bit that speaker michael mime transplant
00:35:39
but the more sort of focus and define replace the missing organisms
00:35:45
so what action on the question and it was it took hundred individuals before they started treatment and look at
00:35:51
the micro by um we also did lots of immunological studies to figure out what immune system changes
00:35:57
and try to boss can become the other ones to respond to the dragon stay responses that well mine's
00:36:03
compared to the ones who respond and lose response with the idea that we could correct the missing box
00:36:10
so if you look at it you can clearly see that as individuals to stain remission haven't large amount
00:36:16
of this was a brilliant lorenz whereas those who use remission ham are depletion in these openings
00:36:23
so suggesting that it's likely that we'll be able to identify similar bacteria that we could
00:36:29
potentially correct yeah by extending the duration of the drought that is known to work
00:36:36
and we'll be able to identify something like someone different
00:36:39
strains that are depleted in this fourteen hundred individuals
00:36:43
that potentially could be used as a starting point for replacement
00:36:47
therapy because in a drought that's already actually approved
00:36:52
obviously but each person smoker not made a difference and then whether you had disease
00:36:56
activity also minute disciplines so i could be a combination of michael by on
00:37:01
uh by market discovery and something that in combination would be
00:37:06
used as an entry point at their peak it's
00:37:10
so what i told him so i told you that early life microbe lamb exposure is
00:37:14
important it determines whether the uh susceptible to diseases like asthma allergy autoimmune disease
00:37:22
i told you that there are distinct microbial signatures in diseases like intimately by disease
00:37:27
type one diabetes and i expect this to be defined for many other diseases i
00:37:32
mean there's clearly value by looking at them long term all the time
00:37:37
i'm an interesting study that we just started on is to look at the market mime in the framing
00:37:42
impact study that can be can be identify microbial features that tell you something about metabolic out
00:37:50
we can exploit the differences in the global or the geographic distribution
00:37:57
of broad features dizzy speeches to better understand how microbes died and that
00:38:03
breakdown products uh sensed a then you and your to be discovered
00:38:08
set the systems that we can and have a so that we can make it more efficient fun you koreans
00:38:13
you korean signs as to what that uh but more importantly how the micro by might signal up
00:38:20
happy holidays real value to longitudinal sampling and not relying on a
00:38:24
single entry point to study health and disease because you
00:38:28
could miss trajectories that are important in immune education and so forth
00:38:34
i'm not spoken to you about ah efforts to map that that that
00:38:38
single so resolution so that we'll know every single cell type
00:38:41
that response to these products and how one might be able to explain
00:38:45
that intonation what on the market by inside and the outside
00:38:49
and then i ended up with showing you one example in the case of intellect really cassie the breakdown product up rip the fan
00:38:56
how it might function you may the help and how these factories in fact depleted
00:39:02
in patients with inflammatory bowel disease suggesting that this could be an entry point
00:39:07
but i've also made everyone's life a little bit more complicated i've told you that if
00:39:12
you can't micro biotech a it may be associated with predisposition to disease w.
00:39:18
to tell you something about no response to projects and
00:39:22
that it could potentially make inclination and no inclination
00:39:26
but i think the added important value is that now we know the components
00:39:30
it's always easier to build a system however complicated it is if we know the individual players
00:39:37
so that one can begin to put together the right assembly to make create help with this disease and that seems to
00:39:45
and the principle that we'd like to get to is can be now move
00:39:48
away from the classical thinking about pro by objects in you know
00:39:54
to defining the next generation up robotics that could be
00:39:58
a combination of bacteria and bacteria and that's
00:40:01
but i think it's important that this be done in the context of the host response
00:40:07
studying bacteria by itself is not gonna make it any better
00:40:13
at the same time i want to tell you that my combine should be taught in that should not be part in isolation
00:40:19
always communicating with the host with a either got the skin or the long
00:40:25
i think we need to move away from the folks single
00:40:28
about hypotheses any disorders that relate to new question
00:40:33
inflammation allergy and opinionated it is likely that it's not many buttons
00:40:39
many systems that uh all to that contribute to help with this disease
00:40:45
i'd like it is i'd like to propose that we need to move away from the good and the bad but because the
00:40:50
bad but could be good in a different setting as long as it has the right set of interacting part once
00:40:58
but i think we also need to pay attention that not everything
00:41:02
in human health and disease is associated with the market by
00:41:06
it's likely that people now you all diseases by many plating the michael by um but i think we'll learn
00:41:13
some fundamental principles in helping disease by studying how the
00:41:17
micro byron interacts with the human cost thank you
00:41:30
yeah
00:41:33
just for
00:41:39
hi
00:41:45
okay so i think uh a short questions got actually thank yous yes from us
00:41:54
and i see why in the rationed finland steady resting in
00:41:59
the for the i particularly this one or i
00:42:03
sure am ed obviously on the other hand much later
00:42:09
end and even in the in comparison that the
00:42:12
a universally versus other western children or massive difference
00:42:17
is that you simply imply was related i
00:42:21
so i i i mean is there right in our only kicks in a later stage
00:42:27
or is it just press thinking and and other sorts of your inferences are equivalent
00:42:33
yes i think the point i was trying to make is that the bands really in line
00:42:38
would it be breastfeeding or die plays an important role in setting state i mean say setting the rios
00:42:46
it's not the only thing that contribute to finish was is the russian kids um
00:42:52
obviously the social dynamics and the environment daily been is very different
00:42:58
the russian kids uh mostly out enough i mean area they make a
00:43:02
lot more contact with up to activities us to finish his
00:43:06
leaving concrete colours with a little bit so that could be
00:43:11
uh multiple inputs you know thinking what i was trying to stress is that
00:43:18
any complex system unless we can break it down this is great
00:43:23
measurable units are going to identify what are some of the uh the bands that one
00:43:30
yeah
00:43:32
yeah
00:43:34
uh oh i just thought i
00:43:42
ooh ooh ooh ooh ooh ooh ooh it's i go for it but it's not
00:43:53
oh oh i love it when i was a but it sure on one side
00:44:01
oh i see i see what you're all about
00:44:06
on the other side i i
00:44:10
ooh ooh ooh ooh yes it's it's
00:44:17
well actually it's like that but it's you or your well i would like to ask you is
00:44:24
so you what you should do you propose to ah you
00:44:29
just make sure it's well i sure i start
00:44:36
understanding why not
00:44:41
so that's that's a lot so alex i gotta realise it's it's
00:44:50
but i got that out of that sort i it's yours let's see what's seriously i use the topic
00:45:00
that's a serious it was i it currently has the because
00:45:08
yeah ah yeah yeah so i i'm not not at all proposing that
00:45:16
you yeah yeah features you know is there should be a all of us i
00:45:24
i actually you were asked to ensure that i i i a if you
00:45:33
to put it on what i make remote you
00:45:37
but ah that the also for if you use for
00:45:41
the file you are also what diseases now
00:45:46
just one you see that you stop you what is it up there
00:45:52
i it so that is that it it what you should do we wanna know what's which he also you use
00:45:59
yeah it's that well that is now ah it's got this up well
00:46:05
now that we're courses without i use that to get through
00:46:12
actually now that we see that i will uh
00:46:19
that's what i do is i e. u. i. it's that for which is
00:46:25
what what's that for sure why a useful for us
00:46:30
you really you show that you rule sell it so i i
00:46:37
i uh i i still i would ah see who it should at least
00:46:45
because you know all all to us that you sure that is too slow
00:46:50
it's off the analytical work which is that i i go that route
00:46:56
zero to prove that that's childless i you know that's all
00:47:03
so what is that so how do you use they you're right to
00:47:07
its to add two and here is on its side ah it's
00:47:12
yeah and i realise that i mean i it just now let's use a a a three
00:47:19
right but i i don't know i find i it
00:47:24
yeah or or uh it's
00:47:29
what does it cost
00:47:33
or are you sure we with regards to what i'm responses to colin encrypted fan
00:47:43
i had absolutely no interest replete encrypted or not only
00:47:47
what i was what i was referring to what i was referring to is that
00:47:52
the breakdown products that trip to fan or the breakdown products that calling
00:47:56
could be entry points to better understand some of the bad effects of these men tablets and
00:48:03
i'll i'll give you one example that um so we've now collected very nice data that
00:48:10
anti depressants only working some people
00:48:15
yes it doesn't work you know is oh no i'm not ah yeah i i think you're missing the point so the
00:48:31
no
00:48:34
oh that i'm trying to say is that the i was focusing on the people who don't respond to antidepressants
00:48:40
and the individuals who don't respond to antidepressants have early evidence
00:48:45
that there is a micro by room that loves gab
00:48:48
the big break down the by availability of the active molecules so that it cannot work
00:48:55
so there you have a loving organisms all yeah yeah been allergic signal into words
00:49:02
in the dark so there is the potential that in some of these individuals
00:49:07
that you could find out the ones that don't respond to it right
00:49:12
and try to improve the response rates i'm not trying to kick things off the shelf
00:49:18
i'm trying to find ways of already approved if the arabs work will help a lot of population
00:49:27
and then with regards to obviously how um microphone on microbial mat
00:49:32
kinda like this therapeutics could be applied in human out
00:49:38
i think i need to talk to the people in this room i i don't think i have the expertise
00:49:42
to define the regulatory steps that are required to
00:49:47
um understand how these could be implemented
00:49:50
but i think the blah to implement some of these inhuman help is likely to be a lot lower
00:50:00
sure wish or
00:50:02
we're not actually no memory retention for your raw
00:50:07
green sorry right it's a row of
00:50:12
memory issues seems to result and that's really what do the first ones or
00:50:20
how did remember the others has a whole ah courses time function train like what is this
00:50:29
and your horse even worse listen you're a real so it's a combination of both
00:50:36
um there's been very nice work done by laura who plan on those
00:50:39
at the southwestern rather been able to show that memory men's
00:50:43
hind quarter not only the bacteria but then it's systems like the
00:50:48
clock genes play an important role in maintaining that memory response
00:50:56
sure
00:50:58
first i want to thank you for this uh really explore the screen what can
00:51:05
you don't like take messages but you're not going for one much good
00:51:09
but you don't fully understand the reaction of oh
00:51:17
maybe holding on the question of which just don't do we actually know
00:51:23
we're ideally we would want to deliver any
00:51:27
of them to manipulate microbial home alone
00:51:30
with just one person on trial and the other any of them to understand
00:51:34
that particular aspect to improve the system system which of
00:51:40
i i think the possibilities are that the that could be
00:51:45
certain events that up primarily mediated in the small bow and arrow
00:51:49
part supplements that could be maintained in the cold and
00:51:52
and depending on where these community changes take place one would potentially have
00:51:58
to deliver to that side now obviously i think that um
00:52:04
lots of activity in sort of finding ways to deliver microbes to the dump
00:52:08
so that they don't get broken down by bile acids and got acid and so forth writing be um i think but i'm
00:52:15
my intention today was not to say that my crime is ready
00:52:19
for therapeutics my intention today was to tell you that
00:52:23
that are important principles that one needs to learn about
00:52:26
how the micro mime communicates with the immune system
00:52:30
but they've been they've got on the skin and how the marker
00:52:33
mime positively and negatively affects died and i clicked on it
00:52:37
so that one might get into this field with some understanding rather than
00:52:44
um some of the broad approaches that have been taken now
00:52:48
good
00:52:52
one week one testicle percentage when you she would you know you could i
00:52:59
well uh just you should always use or uh i mean it's impossible that you don't find
00:53:06
the launch we fix omitted that's true because you see
00:53:10
all reduced to use use one sort of people
00:53:15
you make one more comment at the beginning that there might only will be
00:53:21
a very small uh i'm a i'm a fake own glued genetic predisposition
00:53:28
oh i'm i've won excel to which views to duplicate would coke in into it
00:53:35
may fall completely different interferes to do one with which beach the long
00:53:44
people will looking for fifty euros for who use while and you see six used
00:53:49
which views the tissues we'll we'll muscle shoals walk into the lawnmower tricks
00:53:57
it in the short must be had it it was not current there was no show
00:54:02
of reaction that all of those cells and actually looked into the wrong the rich
00:54:08
do you want to living cells it tasted all even still takes a few what you
00:54:15
actually played from the little so you want to call it too much weeks
00:54:20
so the actual so long about which is the only thing that the
00:54:24
that you might see with you you could oh i just thought
00:54:28
so my question no using you sure any seem quite good nutrition what
00:54:34
to it'll which makes the cogent actual remote x. p. from scripture
00:54:41
yeah so i may i don't know the answer so i mean i think the so one of the challenges with
00:54:46
ah linking human genetics to the micro miami so clearly there is an influence so there is
00:54:53
been a couple papers that have been published suggesting that certain percentage of the micro by means dependent on
00:55:00
your ah on the line genetic variants and i think that's true but my hunch is that
00:55:07
that genetic contribution to the micro by on may not be the same in every single disease state
00:55:14
so it could be more important in metabolism obesity matters less important
00:55:21
in what they mean disease and so forth so i think one needs to
00:55:25
spend a little bit more time to sort of get closer to
00:55:31
genetic mutation effect and how come and to do
00:55:35
that one needs unfortunately very very large cohorts
00:55:39
uh because the fact of the genetics is very small or the other i would be very simple we all push but you know
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