Countersignature Food Allergy Chart Made Easy

Countersignature food allergy chart

hello everyone and welcome my name is Carrie Michalski and I am the director of education here at Fair I am delighted to be your moderator for today's discussion around food allergies and the microbiome but before we get started I just want to go over a few quick things please note that for maintaining a quality recording all attendees are going to be muted throughout the presentation however this is definitely not going to stop you from joining in on the discussion today everyone should see a zoom toolbar it's going to be in black and at the bottom of your screen specifically in this toolbar you'll see a little Q&A button you can use this to communicate directly with me please do let me know if you're having any technical difficulties and I'll do my best to help out but most importantly you can use this feature to ask questions we've built in some time at the end of the discussion for a few moderated questions so please feel free to send them my way at any time throughout the presentation time permits at the end I will pass them along to our presenter so now without further ado I'm delighted to introduce today's presenter dr. Wayne Schaeffler dr. Schreffler is the division chief of pediatric allergy and immunology the director of Susie allergy Center and principal investigator for the center of immune ology and amatory diseases at Mass General Brigham he is an associate professor of pediatrics at Harvard Medical School and an associate member of the Broad Institute food allergy science initiative at this time it is my pleasure to turn the presentation over to dr. Schaffer thanks Kerry and hello everyone Kerry promises me that I'm not just talking to myself that there is an audience out there it's my pleasure to be here today in this series of presentations from fair on this topic that I hope you'll be interested in and you're not just to or to do anything else so I have a few disclosures highlighted are the most relevant in particular Madhu a clinical trial with vedanta Biosciences that I'll touch on looking at a bio therapeutic in peanut allergy my other disclosure is that I really am this guy in current form and I'm more serious note just wanna you know under sort of nod to the fact that of course we're doing all all these things in these ways under circumstances that are not ideal and not of our choosing I hope everyone is staying safe and sane during this time and I'm glad we can join together in this way and look forward to and we couldn't do these things in other forms again so by way of overview I'm gonna start by talking a little bit about you know kind of the basics of food allergy I know this will be familiar to most of this group but I think it's important to set up you know sort of what are the early studies that kind of led to thinking about you know micro it's relevant at Bossier and factor in food energy and other allergic disease show a little bit of data actually from cohort studies that indirectly suggest a role for the microbiome usually because they are associations that are two things that are known to affect the microbiome and then really try to build a case based on current data and this is really data you know coming principally from other groups on the importance of the microbiome by association by functional studies and ultimately by intervention studies many of which are just now in progress and then talk a little bit if we have time about you know why this matters and what the future may bring is this really where the money is should we be focused on prevention secondary prevention or treatment what does that mean and then leave some time at the end for your questions so on no doubt familiar to this group is the fact that allergic disease along with other immune-mediated diseases it's been increasing in prevalence over the last several decades and that's really been a rate that far exceeds what's possible for explanations other than that there are changes in our environment and in particular in the more recent decades it actually even appears that some forms of food allergy including food allergy are in we sing at rates that are faster than respiratory allergy which seems to have more plateaued furthermore that's even particularly true among the youngest kids suggesting that we haven't sort of reached a peak we haven't reached our our first wave yet in the prevalence of this most likely this is data from Australia showing that in the youngest cohort that were followed there was a five fold increase in the decades between the basically the first half of the 2000s and that's led to some cohorts having really remarkably prevalent even single food allergies such as this estimation by Jay Lieberman of more than 4% peanut allergy in one cohort or the most probably definitive at this point epidemiological look at food allergy prevalence funded I think at least in part by fair by Ruchi Gupta showing using a variety of criteria for strictness of food allergy diagnosis but coming up with an overall estimate approaching 10% of food allergy in the US population so a really remarkable rate no doubt familiar to many of you let me just silence this phone so that increased prevalence of course has driven increased disease burden and these are data showing IDI a presentation driven by food allergy with peanut leading the way has caused it as a leading cause of anaphylaxis and so the increased prevalence is also of course increasing reactions that are being seen in the emergency room and most people credit David Stratton with sort of first articulating what came to be known as the hygiene hypothesis in this essentially opinion piece in the British Medical Journal in 1989 addressing you know sort of the hypotheses about this post-industrial revolution epidemic as he phrased it of allergic disease and it wasn't for folks that food allergy on the time he was really looking at allergic disease broadly mostly with an eye toward respiratory disease and he suggested that you know this this past century of declining family size and improvements in sanitation and personal cleanliness reduced the opportunity for cross infection and young families and really proposed that it was the reduction in infection or infectious disease exposure that set the immune tone that made it permissive for developing allergies in over the last couple of decades since that was first articulated this is really evolved to what is most often called the microbial diversity hypothesis or the first friends hypothesis to more broadly recognize that a lot of early life exposures beginning in utero including mode of delivery maternal diet perhaps maternal antibiotic exposure early feeding practices exposure to antibiotics early in life contact with animals or older siblings or in daycare other kids all influenced immune health and that's thought to be primarily mediated by the microbiome whether that's gut or airway or skin and we'll talk mostly about the gut and it's led to the idea that we ought to be doing more of this more close contact with farm animals but I hasten to add that that's not the only relevant exposure difference that we need to keep in mind and in fact keep in context when we think about the risks associated with the microbiome especially when it comes down to sort of making recommendations when I came out of training 20 years ago the advice I was thought to give to patients was avoid since and including and it was the astute observation of investigators in London and Israel that early introduction was associated with protection and subsequently shown by a randomized controlled trial funded by the NIH and fair and others to prove that point so I wanted to find a few terms for us most of them will be familiar so I'm not the microbiome is just that some of microbes and their genomic elements in a particular environment again we could be talking about the gut the skin the airway and it's now appreciated that bacteria and that got far outnumber human cells and have a major impact but less appreciated and no doubt important is the microbiome and other spaces short chain fatty acids like butyrate and acetate these are key metabolites already understood with pretty good evidence to have a direct effect on immunity and relevant to food allergy it is thought this is a specialized group of t-cells or regulatory t-cells with some apology for all this jargon here so these are called roar gamma t-positive Fox p3 positive regulatory t-cells these are cells that are thought to be key players specifically induced by microbiota in the gut and key and suppressing allergic inflammation probiotics or microorganisms that we may intentionally take for their beneficial effects prebiotics or the food that may fuel them dysbiosis is then just a state of imbalance in a microbial ecosystem again could be gut skin or elsewhere so in parallel with our increasing understanding of the role of microbiome and Health has been sort of the rise of what we might call the tolerance paradigm in food allergy so this is from a review by Harold runs from a couple years ago in which we understand you know kind of the normal state of immune and got health to be food proteins recognized in the absence of inflammation trafficked through the gut epithelium which is just a single cell layer wide and sampled by Sentinel specialized cells that are responsible for inducing tolerance in normal Editions not only to food antigens but to the normal bacteria that some of which have you know a fairly close contact with our own immune system left out of the review but I'm adding in here is the role of the healthy bacteria and maintaining this state and in particular the role of butyrate and other short chain fatty-acids which have been shown to have direct impacts on the development or differentiation as the jargon term of these regulatory t-cells and in contrast with allergic disease hypothesized to be in part due to dysbiosis a situation is set up where there are factors often called alarm ins that alter the state of these Sentinel cells and ultimately the T cells to promote an allergic inflammatory type of T cell in favor of and suppressing of the regulatory T cells and it's these cells or subsets of them more precisely that create the conditions that drive the antibody secreting cells called B cells to make IgE and IgE of course that arms mast cells and other effector cells to cause the symptoms and problems that we know of with allergies so what about these cohort studies that indirectly suggest a role well they've touched on and revealed factors like the following some of which were in that kind of overview cartoon prenatal maternal exposure to pets mode of delivery with c-section being associated with risk growing up in a rural environment or more importantly having close contact with animals including pets or your older brother will probably do just fine as well so here's data looking specifically at Association to caesarean mode of delivery this is one that's been sort of you know not always reproduced perhaps having something to do with the underlying prevalence of the disease in the population being studied but overall in this meta-analysis from 2008 of several studies all of which include at least some measure of food allergy again one of the tricky things about interpreting this literature is that the way food allergy is defined can vary and not necessarily be as rigorous as we I always like but overall associated cesarean mode of delivery with a 30% increased risk of food allergy and really as you can see generally early in life but kind of across the pediatric age range so to give you a sense of that impact that's really the equivalent of for every 33 kids born by cesarean section you'd anticipate one more that has food allergy than would otherwise have the study in Murdoch Children's in Melbourne Australia led by Katie Allen and our John complan looking specifically at egg allergy and they failed to find in this study that was published after that meta-analysis any association with mode of delivery and now this is in a setting in Australia where similar to the u.s. they have high rates the food allergy they did identify protective factors that we've already mentioned and in particular again you're an older sibling or a dog were associated with us fairly strong half the rate of egg allergy in this cohort but I do want to highlight that in comparison they also looked at early feeding and found that if egg introduction was delayed past the first year of life that was associated with almost a five-fold increase in egg allergy so I think we want to keep these effect sizes in mind this is substantial and significant half the rate by having a dog or you know 25 percent lower rate by in a family a child born into a family with siblings but not as strong as the effect of early feeding here in Boston we also have an infant cohort that we've been following for the past several years this is called the G map cohort this is a healthy newborn study starting from the first week of life and following them through actually now to 18 years with additional funding looking specifically for food allergy outcomes and we focused first on one of the early manifestations of food allergy which is called allergic prokta colitis we didn't find an association with motor delivery or Perry nodal or maternal antibiotic exposure but we did see an association with feed once again and in particular a finding that again is suggestive of a role for microbiome which was that the formula fed kids strictly formula fed kids had the highest risk and any amount of breast milk particularly when mixed with some of the culprit allergen milk in this case in the form of formula was associated with lower risk of developing this form of food allergy a form of food allergy which by the way is associated with subsequent risk for developing IgE mediated oncology so you can see these kids that had ap as infants were six times or two times more likely to have some forms of food allergy later moving on then to sort of build the case more directly of the link between the microbiome and food allergies specifically cependant the pandava niche with cecilia berry amount sign and I have this really nice review that was just published in December I highly recommend it to you kind of outlining the process by which investigators in the field move from initial observation studies whether it's in human populations or in animal models essentially pinning them between those with or without the disease state in our case obviously food allergy or in the mouse susceptibility to food allergy progressing them to functional studies so actual experiments what are investigators can manipulate the system to get stronger evidence in this hierarchy and finally moving on to interventions and this is of course the main goal right this is where we want to get is to the point that we could develop therapeutics either of microbes themselves or with defined factors that would promote the health of the microbiome generally so looking at one of these early association studies this is actually from one of the first rounds of the consortium for food allergy research that's the major NIH funded consortium that studies food allergy and these kids were actually recruited more than ten years ago and this was published fairly recently this was 500 kids recruited between 3 and 16 months of age and identified as having a geology or positive skin test - egg or not and then followed for resolution in the case of a geology they found not surprisingly as an association with atopic dermatitis and the risks of egg allergy that's been widely reported and that's a strong association you can see 9% of the egg allergic had no eczema versus only 1% in the controls so the microbial association that they found in reported in this paper is shown here they found in case of egg allergy and egg sensitization disproportionate hits in Clostridium family members the Clostridium bacteria are those that contains for forming fermenting bacteria many members of which can elaborate short chain fatty acids including butyrate that has the effects that we showed before this is now an association study from - Lodge attila at Boston Children's Hospital home of food allergy these animals have a genetic mutation that renders them susceptible to developing food allergy spontaneously but they develop as as shown in his paper a dysbiosis that even when transferred to healthy animals can cause them to be susceptible to food allergy as well and again what dominates this list probably a little hard to see on the screen are members of the Australia family both in terms of more or lesser abundance and that's because there's diversity within this family as will come - coming back to human studies this is again bicep inda at Mount Sinai looking at milk allergy what she found in this cohort was no association I should clarify I'm sorry these are kids with milk allergy looking at whether or not they have persistent milk allergy at 8 or whether that allergy has resolved by the time they reach 8 years of age so it's a little different than just did they develop the allergy or not but what she found again and this is a consistent theme if you're not getting it already is the strong associations with member of the clostridia family in this case is sufficient or resolution of allergy so looking now at some functional data this is from a follow-up paper again by two law Chile's group at Boston Children's they recruited 56 infants with a food allergy defined as at least one of the major food allergies match them to about a hundred controls and sampled them throughout early life up to two and a half years of age they did what's called 16s sequencing to define the microbes so there's that's a relatively low resolution but the advance year in part was higher resolution identification of bacteria that are associated with disease and they also did functional studies by doing fecal transplantation from affected or healthy human patients in two of the animal model and once again the striking finding here lactose appreciate being also from the Clostridium family other cross rydia family members associated with either risk or subsequent protection and this is really the highlight of this paper is that they showed that transfer of bacteria into animals shown here at the top when done from healthy controls was protective but when transferred from food allergic humans was not protective in comparison to the control here in the dark black this shows the drop in temperature which is indicative of a severe allergic reaction in the animal model in another study published almost back-to-back by a group led by Katherine ziggler in Chicago she looked at for infants with milk allergy compared to four age-matched non-allergic controls they were sampled only once during infancy similar level of resolution in terms of identifying the bacteria specifically and again with functional studies of transplantation from human to the mouse and again what she found were hits predominantly within a subtype of the Austrailia family called lactose-free CA and very specifically and confirmed by protection in the animal model again this is the temperature drop in the control animals they have severe anaphylaxis here in red are the protected animals getting this single species of lactose free CA demonstrating protection in in this model and giving us hope that that might be therapeutically helpful so what about therapeutic trials so there are a few that have been published looking at probiotics for cow's milk allergy predominantly in cow's milk allergy in these studies is inclusive really of that range of milk allergy including the allergic practical itis kids that I showed before in infancy that's really a dominant form of milk allergy these investigators looked at 119 119 rather infants with cow's milk allergy I'm given some common bro probiotics at the time the lactobacillus and Bifidobacterium it did not accelerate tolerance however the same group looked at 55 infants and when combined with a very digested or hydrolyzed cow's milk formula like Nutramigen and given a different strain of lactobacillus called rhamnosus GG or LG g for short they did show evidence of earlier resolution and a follow-up study to that looking at 220 infants with the same resolution or the same intervention rather also showed a higher rates of resolution landfall root three years of age and by this age many of those kids we are talking about IgE mediated milk allergy now this is been initially somewhat curious because a functional aspect of LGG hasn't really been clear but what these investigators did also show by picking out a subset of the patients in both arms of the study and evaluating four metabolites that there were associated changes in the frequency of butyrate producing organisms that were induced by giving out so LGG may have a secondary effect on the overall microbial community in this case and that's what renders out the benefit now LGG has also been looked at as a treatment to established peanut or lima it's a peanut allergy when used as an adjective and this is work of many Mimi tangs also at Murdock Children's in Melbourne and the highlight from follow-up studies so far on that is that at four years 67% of the active intervention arm were consuming peanut whereas only 4% of the placebo were the limitation of this study is that it didn't separate out peanut OIT from LGG it was a control group with placebo versus group with LGG combined with peanut OIT she is now conducting a larger follow-up study that does have an arm isolating oh I T and so we look forward to seeing those data to other clinical trials that I want to mention here in Boston and I'm proud to sort of take this opportunity to also say that we've been selected by fair to be one of the ten discovery centers in the country and it's a it's really a perfect example of what fair is trying to do by bringing groups together that we submitted a Boston wide Discovery Center application so both Mass General and Brigham along with Boston children are part of this consortium and these two trials are led by members within that group myself here at Mass General in collaboration with Vedanta and Reema Rashid is doing a fecal transplant study at Boston Children's so I'll give a little bit of information about the rationale and study design for the trial that we're doing with Vedanta in case it's of interest so again this is really predicated on the observations from several years ago now that this is a group of bacteria that contains species and strains that have potent capacity for inducing regulatory t-cells specifically these ror gamma t-cells that I mentioned in the introduction here's a list of the strains shown and here is shown induction in various and it's now been reduced to fewer strains but various components from clostridia in inducing Fox p3 positive regulatory t-cells here's the study design that's now underway the study is actively recruiting and we're looking at multiple arms including the combination of this bio therapeutic with oh I T versus OIT alone and looking at whether initial treatment with the antibiotic vancomycin which is known to help colonize these bacteria is necessary for the therapeutic effect so wait surely this god is not the only game in town right so I just wanted to highlight for a moment at least in a little bit of time we have work from other groups looking at the skin and I had the pleasure of being in a form much like this one remotely only it was 9 a.m. local time in London 3 a.m. here with George judwaa who was a leader of the leap study and in that cohort they've done further analysis the leap study in case you are not familiar is the intervention trial that showed in high-risk individuals that peanut ingestion was protective they have found subsequently that eczema severity and its duration and even to some extent what parts the body are affected is a strong risk factor for developing peanut allergy and the high-risk population and that staff appears to play have an important association with that and suggest that there's a role for that so a lot to learn here and this is not the only group to find this association and there are already interventive looking at it as a a modality that could be hopefully risk reducing him early in life there we go so in addition there's a lot of really exciting you know basic work being done trying to unravel the complex sensing mechanisms that are present in the gut with you know specialized epithelium cells immune cells neurons all playing an active role sensing both bioactive compounds from food as well as metabolites that are generated from the microbiome there's a lot of effort characterizing dysbiosis and specifically you know analyzing for which organisms might be associated with non IgE forms of food allergy including aap as I mentioned but also F PI's and eosinophils esophagitis there's a lot of interest in the role of the microbiome in shaping the immune repertoire to begin with so Sarita Patil in our group is very interested in how your initial microbial makeup will influence the B cells that develop and are present at the time that foods are being introduced and whether that helps to shape the subsequent immune response for good or ill the impact of oh I T itself on microbiome in other words does giving peanut oh i T or other food OIT influenced the microbiome differentially between people and could that be an important association and ultimately mechanism of differences in outcomes and and many more things to come so I want to move on to sort of you know whether or not that Willy Sutton rule applies fear where is the money the most obvious intervention would seem to be one that's most likely to address this tolerance paradigm and that might suggest that you know rather than doing studies like we have underway now that look at older kids maybe we need to be looking earlier in life with these kinds of interventions some horse studies are but the FDA doesn't always allow us to start with new things on the youngest among us for good reason but do we need to think about you know on the likely role of regulatory cells in prevention and secondary prevention meaning and high-risk kids versus in treatment or could it be the treatment is just important there are data this comes from Coronado slams several years ago looking at t-cells from peanut allergy patients that had undergone oral immunotherapy and showing evidence for the importance of these regulatory t-cells that I've mentioned repeatedly these Fox b3 positive t-cells what's shown here is the relative accessibility and indirectly the expression of Fox b3v in T cells and that it's you know most available and on in patients who do well versus those who don't and there's another group you know again from several years ago showing consistent data with this that Fox b3 cells are induced during oral immunotherapy both of these studies relied on methods that have been replaced with newer ones where um cells need to be expanded in vitro first and subsequent studies have you know sort of not replicated that finding so here from the same group in Stanford they found instead using a more sophisticated single-cell technique that rather than induction of regulatory cells good outcomes seem to be associated with the absence of effector or really allergenic team cells and with they're kind of being turned off or energized as the jargon term and Eric Wong Bray in Seattle at Benaroya also really showed that the major effective oral immunotherapy appeared to be to suppress the th2 cells without finding evidence of really inducing regulatory cells and that's been shown by others as well and so our group has been look this also in a peanut oral immunotherapy trial and collaboration that's been facilitated by Fosse and we find at a single style t-cell level a variety of phenotypes really an impressive diversity of different T cell types that are specific to peanut allergen that are expanded during treatment and that when evaluating for the type of t-cell that's most predictive of outcomes in oral immunotherapy which consistent with other data are suppressed that may have more to do with other phenotypes that are expanded at the beginning of treatment and we can't forget also a very important effect of you know therapy for inducing antibodies and and so it's really a question I think of whether the T reg tolerance model is the one that's most relevant for something like oh I T in patients with established disease even though it appears to be quite relevant early on or with prevention so I'm looking forward to questions we've got plenty of time I want to thank those that have been collaborating and from whom we've had research support I'll highlight a couple of investigators here among our collaborators Sarita Patil and Rob Anthony who have received funding from fair which were grateful for I look forward to questions awesome wonderful thank you dr. zeppler we have a lot of folks joining us so I just want to say hi to all of our attendees thank you for being here and I will jump right in and do my best kind of answer everyone's question or at least suggested it so we had a few come in that were you know kind of just around you know improving the microbiome or improving your gut like how do you do that you know someone I think it was Emily was saying you know as a mother what can she do it is there advice that you can give as far as you know maybe exposing her child to healthy bacteria even I mean she'd be taking her kids to the farm or playing a dog or is there certain food though if you could just speak generally just kind of on ways that maybe parents could help improve you know their children's microbiome our gut bacteria so one thing so far and away my favorite presentation picture I ever use is the boy pig kiss so I you know I do think that among the things that we can sort of do more important I think than you know sort of recommending specific probiotics right now which I think you know the evidence is still coming in and it's it feels a little premature to me is supporting health by diet so we do know for example that the bacteria that are good at fermenting fiber into short chain fatty acid need fuel to do that and it's very plausible that one of the major changes in our modern lifestyle is the reduction in fiber in most of our diets and therefore giving less substrate less prebiotic for the healthy bacteria to you know create the metabolites that promote good immune health so I think it starts really with a really good diet the other thing I guess I feel compelled to add and that I've tried to sort of make the point of mentioning throughout is the effect sizes for all of these things as important it is as it is to understand this because it gives us more insight into immunity in the context of food allergy and I believe the more basic level we understand will lead to new interventions the effect sizes for many of these things like being born into a house with an older sibling are modest in comparison to things that you can control early in life like not delaying the introduction of food allergens probably like controlling the skin well with aggressive and appropriate treatment of eczema and things like that but to not dodged the question entirely you know I do think that we're you know our society tends to overuse antibiotics even though that doesn't jump out as a strong risk association in a limited number of studies that we've seen so far I think it makes sense to be prudent about that I think it makes sense you know to you know enjoy sort of being in nature and having contact with you know the microbial diversity that's around us these are the things that are known to associate with improved microbial diversity and you know ecosystems in our gut and elsewhere wonderful thank you and kind of picking up on that you know and it's pretty the current topic and a couple of people are just around the use of antibacterials and you know they they recognize that presently you know we're all using so much like hand sanitizer all the time disinfectant other answer materials you know because of this pandemic that were in and the corona virus you know then we're just wondering maybe you could speculate or not you know will this have an impact you know on our microbiomes or maybe even in the picture do you think we could possibly see it spike in food allergies just kind of if you could speak to that a little yeah I mean this reminds me in a way of you know um this balance that we're trying to achieve always and for example you know not advocating that you do not speak medical care and use antibiotics when they're clearly indicated I'm not advocating that you alter your child's you know vaccination schedule and I'm not advocating not taking you know appropriate CDC you know guidelines right now with kovat and that's because we're finding a balance right between various risks and benefits always as we do every day in life I think that these factors as I've sort of tried to allude to in the comparison of treatment studies versus prevention studies are likely important at a very early window in immune development so I have to say I don't really worry about you know that preschool you know age kid who is using you know more hand sanitizer right now as part of you know the family's strategy to minimize risk for the whole household due to kovat I you know I can't speculate on whether you know epidemiologists will be able to tease out an impact from essentially this massive natural experiment that we're all going through right now but if a signal is seen I would I you know I would guess that it would be really in kids who are experiencing their first months and you know a couple years of life during this time but again I want to emphasize the relative effect size I think that one thing that gets lost often especially in sort of the public media type coverage of this whole area in general is that there are likely to be many things that are more impactful including in that at-risk young child like making sure you know they're on a feeding schedule not excluding the major allergens taking good care of their skin then the relatively modest effects that might be due to the increased use of hand sanitizer wonderful thank you so much that's a great answer and and just to jump a little bit and I know you you spoke about it throughout your presentation but a couple people brought up just speaker transplant again you know and wondering about will it be I don't even know if mainstream is more of the world but words are term but would it be you know or do you think it'll be available kind of as a treatment moving forward you know to possibly reverse food allergies or food sensitivities so if you could just maybe talk about that a little bit more and maybe worth where the science and research is emerging or kind of next steps you see that going into the future around the topic of just fecal transplant in general yeah I mean so I think part of it it's that willie sutton question right is that where the money is is established to see it's going to be reversible from these interventions both ones that are defined microbial consortium versus you know an undefined fecal transplants with a big difference with fecal transplant right is that you're collecting donor material from healthy individuals you're sort of essentially diversifying your portfolio you're taking the approach of saying I'm not confident I know you know which are the beneficial bacteria they're gonna make the most difference I'm gonna transfer this entire community from someone that's healthy and it you know and the good news is that appears to be quite safe there have been you know very rare reports of bad outcomes but those have been immune deficient individuals and you know I think fmt may well find a place in the treatment kind of options I suspect it's more likely to be with time as its shown to be safe earlier in life but who knows I mean that's essentially why we run these experiments I mean I'm very excited about the trial we're doing right now with clay Danza even though I can't help but wonder if it might be more effective in younger age groups I think the same thing applies to fmt or any sort of you know microbial intervention like that thank you it really is fascinating and we are so grateful for the work that you and others are doing it's so important so thank you for that kind of moving on we had a couple questions and you talked a little bit about oh I see our earlier in the presentation just around that and kind of just in general you know how how Ont for food allergies may impact the microbiome and kind of vice versa how does the microbiome impact the success of oh I see we have an attendee here Stephanie and she was kind of interested in learning you know how the microbiome of patients who are going on undergoing ong may respond differently and does the daily presence of an allergen you know possibly caused some low-lying inflammation and then can the microbiome be you know perhaps manipulated to reduce that inflammation so just any kind of correlation with the two would be great yeah so I agree this is a fascinating area and a you know a great question that unfortunately don't have a lot of data to speak to yet so early you know oral immunotherapy trials or even subsequent you know large scale like the phase three clinical trial that's led to the approval of befores you have not looked at the impact on the microbiome some studies you know subsequent to that recently completed or in progress are beginning to look there are some fascinating possibilities there are there's a group in McMaster that's shown there are you know microbial community members in the gut that can very efficiently digest peanut proteins and actually utilize that send me selectively you know so they really thrive on that as a food source and presumably you know blossom or bloom you know during something like OIT and so one wonders if you know your relative abundance of organisms like that at the beginning might influence oh I T outcomes because with more rapid digestion you might be presenting the immune system to more essentially hydrolyzed protein similar to the study design I mentioned where the extensively hydrolyzed protein in you know was given to milk allergic kids so you know I think it is a really interesting area and unfortunately we just don't have a lot of data yet but they'll be more data to come wonderful thank you dr. Shepherds a couple questions come in and we specifically asked are there any studies of adult micro vials of allergic people so a couple people have just kind of wanted to know if there if there if there's any studies or information related to adults you know and I guess the second part of that would be you know are there specific recommendations for a certain probiotic or diet or different you know lifestyle choices for adults versus children other than you know sort of the high fiber you know which is good for you in a lot of ways again remember that the associations even at that kind of first level of evidence just the epidemiology alone tracking with increased rates of allergic disease corresponding to quote-unquote westernized lifestyle that doesn't just track with food allergy attracts with other immune diseases and so there are a lot of reasons to you know suggest that we all should be consuming you know higher amounts of fiber and I you know I'm not ready to make a recommendation now but I can't help but wonder you know if the when we have better knowledge of which you know specific Australia species and strains are you know key for elaborating short chain fatty-acids you know that seems very plausible is the kind of thing that would probably be good at least in some measure for all of us but we just don't have the data yet there are studies that are looking at adult dysbiosis and there are interventions for example our own with Vedanta on the v4 one six that includes specifically the adults and so there will be data forthcoming um there are the placebo arms as well right so all of those individuals will have microbiome analyzed over time so some of this question and the previous one you know we'll have more data in the coming years but it's premature in my opinion to start offering you know specific recommendations other than you know maybe that young milk allergic kid and the data from LGG there's at least you know a couple of relatively significant powered trials that show you know evidence of the benefit there but not so far that I know of for adults okay thank you that does give us hope so so appreciate that another another kind of bucket of questions that we that we received were around kind of the skin microbiome and best ways to maintain proper micro balance on our skin and and and specifically I'll just ask one of our attendees here with us asked if you could please explain you know a little bit again why is it important to control eczema with regards to food allergies you know if the X was less uncontrolled does that mean it could perhaps lead you know to worse food allergies I think a few people were just acting if there is also you know a relationship between you know the mic our microbiome in our thoughts and then also on her skin if you could talk a little bit about that sure yeah I I didn't put more in the talk about this because a lot of it is fairly preliminary and I wanted to make sure there was plenty of time for the question period but I'm glad someone asks because it's very clear that skin inflammation is this a very significant risk factor for food allergies all food allergies it's been seen specifically for peanut milk to my knowledge of rheology you know when it's been addressed eczema almost always comes up as a significant risk association early in life and part of that is you know what's led to something called the dual exposure hypothesis so in particular in the absence of concomitant or concurrent exposure to the allergen via the mouth in other words in the gut skin exposure when it's inflamed is thought to be a major driver of allergic inflammation many of the sort of pro allergenic alarming signals that I mentioned in the cartoon contrasting healthy and allergic GI tract also are operative in the skin there are some differences but you know those alarm and cytokines play a role there as well and there is evidence of t-cell subsets that can traffic from between the skin and the gut in other words oh you know allergy induced in the skin might also then exacerbate inflammation the GI tract and lead to subsequent or you know kind of in a feed-forward way more sensitization to more foods the role of the microbiome and and so this has been I mentioned the leap study but multiple studies have shown looking at severity of eczema duration of the eczema all of these things even there's like a dose effect in addition to just seeing association which is a nice sort of signal but investigators rely on to kind of you know get more weight to a specific hypothesis so um the role of the microbiome is less well understood there is certainly known for a long time in individuals with eczema or even individuals who have mutations that predispose to eczema but have relatively uninflated skin a greater tendency to be colonized or even frankly infected with staph aureus and staff in work that Don Leung a national Jewish in Denver and others have done has a myriad ways of inducing so-called type 2 inflammation or allergic inflammation some of the and enterotoxins it produces had this effect and there is at least one study I know of Paul Bryce was still at Northwestern he and a Marine anne-marie sing showed that there was a higher rate of staph aureus colonisation in the GI tract in those kids as well suggesting that there might be a role for staff in the gut also so colonization of staff on the skin leading to increased amounts of staff in the GI tract contributing to allergic inflammation so there are now interventions some of which have been disappointing already looking at barrier cream and bathing but some still under way and it's the devil is in the details so there's been some positive data recently on ceramide containing topicals just presented in London at the European Academy meeting well virtually in London and whether or not they mediate at least some of their effects via the microbiome or whether it's just pure sort of compensating for a poor skin barrier is unclear but I would be frankly quite surprised if we don't find that there is an important role for the microbiome the skin is immunologically very dynamic there is a tension and balance just as there is at other interfaces between you know inside of us on the outside world of the immune system and the microbial community elaboration of antibacterial peptides at the surface of the skin that influence the microbial community and can be altered with eczema so there's it's a it's definitely a minefield you know or maybe a wheat field would be a better metaphor but an area of active investigation wonderful thank you that was extremely helpful we have so many questions and not so much time so I think last just a few more and thank you so much dr. Shepherd for your time and we have attendees who are extremely engaged so thank you to all of you just to adjust a next bucket of questions and we have we have obviously of a lot of mothers you know that that our mom was fair and then he never loved expecting mothers and mothers that are pregnant and I think the question that's come up a few different ways was just around the mother's microbiome you know during pregnancy and any influence you know that that may have on the baby's microbiome and that likelihood to have food allergy so and if you can speak just generally about that a little bit there haven't been studies looking specifically at probiotic interventions during pregnancy with an outcome of food allergies specifically at least not that I'm aware of there have been a couple looking at eczema as an outcome and there have been also interventional studies of probiotics beginning in pregnancy that have looked at airway disease most of these studies the intervention begins in pregnancy but then also continues in early life some of them looked just at the maternal time period and they're sort of a mixed bag so some have shown protective effects on eczema as outcome very tempting to speculate that if you're having a positive impact on eczema you may have a positive impact on food allergy but it wasn't really specifically addressed this was in Scandinavia or rates of food allergy or a little bit lower and on the airway disease at least you know as it's sort of fixed a little bit later in life when you really know whether or not a child is going to have asthma the data been largely you know negative they haven't found least the probiotics they've been looked at you know haven't been shown to be protective so similar to the situation we're in with respect to advice for expecting moms on diet we're you know we're still waiting for better data on whether we know for sure maternal consumption is protective and but most of us lean in that direction and we're still waiting for better data on the microbiome and and one of the real complexities which I hope has come across in the patron is you know you know until we better understand from the Association functional and then interventional trial kind of paradigm which organisms are really the ones that have the effects we want it's it's even difficult to kind of interpret the literature so you know a given probiotic study obviously you know may have no bearing on your hypothesis you know generation when you're thinking about a different set of organisms so very interesting though that you know this small chain fatty acid pathway does seem to come up over and over and over and again and whenever you sort of you know trying to make these decisions as a family and you're talking to your doctor and you're reading I would urge you to look for the things that really stand out as being reproducible and also keep your eye on the effect size lest you you know drive yourself crazy worrying about everything and you know with time we'll know more and we'll have better and better answers wonderful thank you and and we did have a couple questions come in about future studies and I think you know just everyone is so excited about what's on the horizon and and lastly if I just if I may ask you know you mentioned just talking to your doctor if people are hungry for more information are there some resources that you can maybe point some of our some of our attendees do to kind of learn more um yeah so there are I mean the food allergy org site you know is a great place to start for a lot of advice and you can also you know um look at the clinical won't work there and likely find a care center you know relatively near you there are dozens of them that now you know Ferris helped to stand up with this latest iteration of the network the American Academy of asthma allergy and immunology so-called quod AI forays and I org is also a great resource if you're looking for you know a referral the last sleek area if I can I just want to plug you know one way that everyone out there can kind of contribute to you know our shared knowledge and learning over time is highlighted here on this slide the fair registry so consider you know participating in that and the intention long-term is for that to also be you know a source of two-way communication wonderful I can't thank you enough dr. Schaeffler this was fascinating and exciting and I like everyone joining conjoining today you know I'll speak on their behalf we'll just say thank you for bringing this to our attention you know in the world of food allergies and the different innovation and possible treatments that are coming down the pipeline so thank you to our attendees and thank you doctor for joining us this afternoon my pleasure Kerry and everyone everyone stay well bye-bye