Cathryn Nagler│Food Allergies and the Gut Microbiome

By Adem Lewis / in , , , , , /

So how many of you either has a food allergy or knows someone who has a food allergy? Yeah, lots of hands. So when I was a kid, my brothers and I ate peanut butter and jelly almost every day for lunch. By the time my kids got to elementary school, their classrooms were peanut free and food allergies have become an enormous problem in the US and other developed countries it’s now estimated that 15 million Americans suffer from food allergies some of these are life-threatening, so it seems to present as 2 types of diseases One of the presentations involves a food allergy that develops between ages 2-5 and resolves on its own And the other is a lifelong, life-threatening allergic response to food that can send someone to the emergency room every 3 minutes in the US. So we now have 2 children in every classroom with food allergies how do we account for this kind of change in just a generation? That’s the question that we’re trying to tackle. And our hypothesis is that it’s due to changes in what we call the microbiota That is, all of the bacteria that live in and on our bodies so in the video, you might remember when I mentioned that we are 99% microbial there are trillions of bacteria living in our intestines that are, as yet, very poorly understood and control many physiological processes and have a particular impact on the development and function of the immune system. So we’re suggesting that what’s happened, what’s caused this generational change is lifestyle practices that have changed the composition of these bacteria. So what are some of these? They’re depicted here. The biggest offender, by far, is antibiotic use. It’s estimated that children in the United States have 6 courses of antibiotics before they’re 2 years old most of them for viral infections, for which antibiotics serve no purpose we also have extensive exposure to antibiotics sub-clinically so you may not know that for 50 years farmers have had a practice where they’ve given their livestock subclinical doses of antibiotics because they knew that that made the livestock fatter and more valuable. And some have suggested that we’ve done that same experiment to ourselves, and that’s what’s driving the epidemic of obesity in this country. So I should mention that we study particularly food allergy, but food allergy is appearing as part of a constellation of diseases that are sometimes called The Diseases of Western Lifestyle and they include inflammatory bowel disease, obesity, food allergy, diabetes, autism, asthma, all of which are increasing in parallel. Another major offender is diet. So we’ve co-evolved with our microbiota over millennia. And as we’ve heard a little bit about, our ancestors were not consuming McDonalds. So the diet has changed, and our bacteria eat what we eat. And their food source has changed in a way that’s changed them, seemingly for the worse. We’ve also eliminated previously common enteropathogens vaccination had reduced exposure to infectious disease, has also changed the composition or our microbiome. And here I want to be very clear that I’m not in any way suggesting that vaccination is not the greatest public health success story in history. But what I am suggesting is that you know that being infected with something elicits a very different response than receiving a vaccine against it. The immune system sees them in two different ways. And finally, caesarian birth and formula feedings, and I want to take a little bit of time with that. So we’re sterile prior to birth, and the co-evolved strategy is vaginal delivery. That’s how we get our founder microbiota. And the microbiota that we inherit from our mothers’ vaginal tract has a relationship that evolves over time, over an ecological succession between the mother and the mother’s interaction with the baby and breast-feeding. That whole naturally evolved interaction is disturbed by caesarean section birth. And it’s been shown that babies born by C-section are instead, their initial founder bacteria can be tracked to the skin of their mother or their care-giver. Caesarean birth associated with higher risk of allergic disease, higher susceptibility to pathogens. Early childhood is what we study as the window of opportunity. This is when all of the changes in the immune system are taking place, And when it’s most susceptible to intervention, but also most susceptible to damage. And the bacterial populations are changing rapidly, they’re very unstable but over time, each individual develops their own unique microbiota that possibly changes again when they become elderly. The bacteria that live in our gut have also a very important role in digesting our food so many of the common dietary fibers that we ingest are in fact insoluble to us without help from these bacteria that ferment them into products that are essential for our health. Prominent among these are the short chain fatty acids and we’re particularly interested in one of these called buterate that serves as a critical energy source for the epithelial cells that line our digestive tract and also has other functions for the immune system. So how do we begin to address a problem of understanding with bacterial populations are important for regulating allergic responses to food? We’re lucky that here in the University of Chicago we have access to state of the art germ-free mouse facilities. So germ free mouse means that we can raise mice so that they’re never exposed to any bacteria at all. They live inside these bubbles, so these white things hanging down, these are actually gloves these are the fingers of the gloves So in order to work with the mice that are living in here for their entire lives, you have to stick your hands through these gloves and manipulate the mice within these cages. That system allows us to select bacterial populations that we can introduce into the mice specifically, and look at how those bacterial populations interact with the immune system But as I mentioned, we know very little about the microbiota as yet. So how to approach this? What we decided to do was we divided the whole world of intestinal bacteria, and these are thousands of different species, many of which are obligate anaerobes that means that they can’t grow when they are exposed to oxygen. So they can’t be cultured in test-tubes, and we know them mostly by their genetic information, by their sequences. So what we decided to do was to compare… so this is a depiction of the epithelial surface to compare the bacteria that live in association with the mucous layer to bacteria that are free-floating with the digestive food. And see if we could get some insight into which of those populations might be important. And in the course of those studies, we did identify a particular population of mucosa-associated bacteria called the clostridia that protected against allergic sensitization to food. And what we found that it does is that it regulates the function of the epithelial lining of our digestive tract in a way that increases the production of mucous and increases the production of natural antibiotics, antimicrobial peptides so it has a barrier protective effect. So then we wanted to apply this to the development of novel therapeutics to prevent or treat food allergy. So to begin to do that, we collaborated with a group in Italy that had done a large-scale study examining dietary management of children with cow’s milk allergy. And what our collaborator did was to compare: so these are children that come into his clinic with cow’s milk allergy, and he put them on to different formulas, to see what was most effective at managing their disease, and what he found was that when he gave them a formula that was supplemented with a conventional probiotic, lactobacillis g. g. so this is the probiotic bacteria that’s present all through Whole Foods, and that is contained in yogurt, He found that those children had a greater rate of acquisition of tolerance to cow’s milk after 12 months of treatment. So he gave us fecal samples from children that received this diet, and also that received the diet without L.G.G. And what we found was that the children that had cow’s milk allergy, this is at 4 months of age had a bacterial population that looked entirely different from that in the healthy children. It had more diversity, it looked like the bacterial population of adults. As if it had gone through its maturation at warp speed. And that was very surprising to us, and we found what’s showing you here is that is was more diverse and even though the amount of bacteria present was the same. Particularly what we noticed when we compared samples before and after treatment is that the children that received the formula that was associated with the acquisition of tolerance had high levels of buteiric acid, that short chain fatty acid that I told you was important for intestinal health that’s produced by the fermentation of dietary fiber They had much more of that detectable in their feces, and after treatment. So this leads to a picture, this is a schematic that was published in Nature and Scientific American last year, which suggests that there are populations of bacteria including the Clostridia, or another bacteria called fecal bacteria Prausnitzii that act to digest dietary fiber and produce buterate to increase populations of immune system cells I also told you about this barrier protective cytokine L22 and all of this is important for maintaining a healthy barrier an intact mucous layer. But in the absence of what this author called the bacterial peace-keepers, you have a depleted mucous layer more access of toxins and foods into the body, into the circulation, more chance for disease. So how can we use this information to begin to develop treatments for food allergy? The way we decided to approach this was to take the fecal material from healthy infants or from allergic infants, and put them into these germ free mice. And then sensitize them with the cow’s milk protein, so the idea being that these mice would be non-allergic they’d be protected. And these mice would become allergic. And we got this really mind-boggling result. So what I’m showing you here is that here in red are the mice that are colonized with the healthy infant’s bacteria. Here in grey are the mice that are colonized with the allergic infant’s bacteria. And what we’re looking at is a change in core body temperature, so when somebody goes into anaphylaxis, their core body temperature drops And I think you can readily appreciate, if your core body temperature drops 8 degrees that’s a big problem. And these mice are dying of anaphylaxis. So what’s amazing here is that all we’ve given to the mice is the fecal material of those infants. And we’ve recapitulated the clinical phenotype so we found, then, in a topic microbiome, a microbiome that creates an allergic response. And I emphasize that all we’re giving to these mice, what’s killing them, is milk protein. That’s all. So this, then, gives us a platform that we can use to screen potential therapeutics and we formed a company on campus to do this, and some of the candidates are mixtures of bacteria that are identified by our sequence analysis a pre-biotic dietary fibers, that is, fibers that have been selected specifically to expand buterate-producing Clostridia working in conjunction with a carbohydrate chemist, and finally nano-formulations of buterate working with the collaborator at the Institute for Molecular Engineering So I’ll just end by thanking all of the people and funding sources that have contributed to this work. [applause] [Q:…a long range potential use of what you did with the mice applicable to newborns who are born by caesarean section as a way of preventing them from getting allergy? So one particular strategy that other people are pursuing, not us, is to actually take vaginal swabs from mothers of caesarean babies, and use that to inoculate inoculate the baby’s mouth, as they might have been had they been delivered vaginally. Because the children that are coming into our study have already got this altered microbiota at 4 months of age, it’s already too late. So that’s one approach that other groups are taking to address that issue. [Q: are there any results from that?] Very small studies so far shows that it has some efficacy colonizing those babies with the vaginal microbiota, but it’s a very small scale so far. [Q: thank you.]

3 thoughts on “Cathryn Nagler│Food Allergies and the Gut Microbiome

  1. Most food allergies come from foods that are used in the manufacture of confectionery and other processed foods. For example, chocolate/biscuit factories have huge machines that daily process large amounts of dairy, nuts, wheat and even eggs (usually powdered). The proteins from these foods stick to the machines. When the machines are cleaned, chemicals are used, traces of which remain on the machines (because nobody's going to immerse the whole machine in vat after vat of water to make sure every bit of chemical has been removed). The next time food is processed in the machines, traces of these cleaning chemicals go into the processed food. People eat this food together with the chemical which their T-cells recognise as hazardous. Over time, as they keep eating the contaminated food, their T-cells start to recognise not only the chemicals as hazardous but also the food that came with them, e.g. nuts, seeds, dairy, wheat, eggs, etc. It's the same for people who use shampoos, soaps or other products that have both chemicals as well as almond oil or coconut oil or avocado extract in them. The body will become intolerant of these foods over time.

    The way to fix the problem is to re-introduce the foodstuff back into the gut with the aid of a food the person is highly tolerant of in conjunction with a bit of clean dirt or other probiotic element that can act as a chaperone. So for example, if you're allergic to almonds, you have to eat a tiny bit of almond in conjunction with another food your body likes as well as a high amount of good bacteria, such as that found in pro-biotics or soil. Your body, which has been wary of the almonds on their own, will be more ready to accept them in the company of compounds it trusts and that are good for it. Think of it like a lover who has broken your heart. If they show up at your door surrounded by all your close friends and family begging you to just hear them out for a few minutes and your family was saying the same, you are more likely to relent than if they showed up by themselves. Over time, with this treatment, the allergy could be cured.

Leave a Reply

Your email address will not be published. Required fields are marked *