This was the first of several chats I had with Dr. Peter K. Smith, whose “False Alarm Hypothesis” is a novel explanation for the explosion of food allergies over the past couple of generations. Unfortunately for his fellow Australians, it is the chemistry of that sear on their beloved barbecue, among many other cooking techniques, that puts the immune system on high alert for allergic reactions because the chemistry signals that dying cells must be eliminated. Junk food lovers, beware. Pete is going share these and other insights with our conference attendees Thanks to New York Medical College for their support.– Henry Ehrlich
A supposition or proposed explanation made on the basis of limited evidence as a starting point for further investigation.
For many years, the allergy epidemic has been blamed on the “hygiene hypothesis”–also known as the “pound of dirt theory,” the “farm effect,” and probably many others that add up to the idea that we have removed so many accustomed bacteria and microbes from our environment that our immune systems, lacking their natural prey, go looking for new targets. My own criticism is that it mostly seemed to revolve around how people respond to the word hygiene—from hand sanitizer to overuse of antibiotics. A true hypothesis is testable. The farm effect seems to work with asthma–see our new piece on the Amish study here. But we need a new one for food allergies.
Now we have one. “The False Alarm Hypothesis” comes to us from Dr. Peter K. Smith, Professor of Medicine at Griffith University in Australia, and three co-authors who work at Mount Sinai in New York, Madhan Masilamani, PhD, as well as Dr. Hugh Sampson, and Dr. Xiu-Min Li (both contributors to this website). A few years ago, Dr. Li told me that food allergies and other immune disorders arise from confusion of innate immunity and acquired immunity. A healthy immune system will attack things like cold viruses automatically. They don’t have to learn new skills. Acquired immunity allows the system to respond earlier instead of having to go through a full cycle of inflammation, fever, and other unpleasantness.
Another thing we do without coaching is eliminate cells dying a non-programmed death. After damage from a bruise or a cut, our bodies recognize that cells are dying and get rid of them before they fester and poison us. The cells release molecules called alarmins, which mobilize a response from various protective cells.
Other things chemically mimic that triggering effect and they are found in many common foods. They are called “advanced glycation end products” (AGEs), which bind to their own high-affinity receptors (RAGE) on cells, the way IgE binds to high-affinity receptors on mast cells. They create a chemical SWAT team that isolates and expels the cells before they can infect the surrounding tissue. But when food is the culprit instead of dying tissue, chaos can ensue. When the cat trips your home alarm, you don’t want SWAT to answer the call.
Unfortunately, the things we do to make foods taste better aggravate the problem. It’s that sear on a good steak or the crisp brown skin on a roast chicken, the result of the “Maillard reaction” that caramelizes the natural sugars into something more tasty. It’s roasting peanuts (boiling them makes them less allergenic). Microwaving raw milk for a minute increases AGEs 5-fold and three minutes 86-fold. Fructose, which has become the industrial sweetener of choice over the past generation, is a massive source of AGEs.
We reached out to Dr. Smith to find out more:
AAC: Thanks, Dr. Smith, for taking time with our readers. To start I’d like to ask some questions on how science gets done. First, where did the idea come from? Australia has some of the highest rates of allergies and asthma in the world, and Australians are noted for being avid barbequers. Was there a connection?
PKS: Thanks Henry – actually double thanks: first for the opportunity to discuss this with your readers and secondly, for what you are doing to reach out and explain many aspects of allergy to the wider community. Like you, I am not totally happy with the hygiene, vitamin D and microbiota stories. I think they hold part of the key, but do not explain a several hundred-fold increase in food allergy in the last 2-3 decades in young children. Yes we barbeque and consume sugars to excess in Australia and we have the highest rates of food allergy in the world. We live in a land of milk, honey, steak and “glycotoxins”. The connection actually came to me 4 years ago when looking at plant compounds that modify skin inflammation and I found publications that linked glycation and ageing (and this was accelerated in diabetics). High AGE diets accelerated ageing and diabetic damage (and also several other inflammatory conditions). Dietary AGEs could also mimic cell damage signals (they have a promiscuous receptor). I plotted epidemiological data with dietary patterns and then sought reviews on how AGEs and tissue alarmins work to stimulate the immune system. The more we looked, the more the story was strengthened. It integrates in very well with current theories.
AAC: I am also intrigued by the combination of authors. How did you end up working with a team almost 10,000 miles away?
PKS: Professor Sampson has always been generous with his time, knowledge and friendship. I am intrigued by innate immune responses and how threat signals are propagated. Many of the components of Professor Li’s Chinese herb mixtures have actions on cellular ion channels and we have discussed these for the last 3-4 years. Two years ago when developing the False Alarm Hypothesis – we identified that some plant compounds including isoflavones could block peanut allergy occurring in an animal model. These actually reduce the formation of AGEs. This work was already being done by Dr. Masilamani, and Professors Sampson and Li. They were just not aware of the AGE-RAGE axis yet. It makes great sense to work with people who have established models and are the best in the world and we are continuing to do lab work in this area – I have been over there a few times and we try to have Skype meetings every fortnight. The world is a very small place with IT (and planes) these days.
AAC: Could you describe as simply as possible the basics of how AGEs transform the various cells, both in utero and in newborns. I am particularly interested in the permeability of the digestive system.
PKS: AGEs bind to the same receptor as a couple of key cell damage products (S100 proteins and another called HMGB1) – called the RAGE receptor. This is a key activation switch for the early immune response. It activates the mast cells (a key cell in allergic response and tissue defense) within 20 seconds and this activity is maintained for up to 60 minutes. If there is further stimulation – these cells go on and make products with amplify the response. Dendritic cells (problem spotting cells) require RAGE stimulation to mature and present the problem’s chemical signal to T cells. They start secreting HMGB1 to enhance T cell responses. Others have shown allergic T cells responses are blunted in the absence of RAGE signaling. We hypothesize that alarmins are being copied by our western diet.
The newborn is somewhat of a “blank canvas” immunologically. There are genetic and antenatal environmental stimuli and evidence that maternal IgG passes in utero and via breast milk to influence early immune responses. It is up to the baby to develop tolerance. AGEs can cause tissue inflammation as part of an innate danger response. We need to do work looking specifically at skin and GI permeability and AGEs. Diabetes is a naturally occurring high endogenous AGE producing state – and in late pregnancy, diabetes is associated with increased eczema and food sensitization in infancy. AGEs also pass through in utero and in breast milk. Methygloxal from cigarette smoke is a great example of an AGE that widely disperses through all tissues.
AAC: Since all living tissue is subject to unprogrammed cell death, I am guessing that all parts of the body would be susceptible to respond to false alarms, given the right receptors (RAGE) and exposure to AGEs. Is this correct and does it account for systemic reactions to allergen exposure—aka anaphylaxis?
PKS: Yes – diabetes affects multiple organs– kidney, blood vessels–and disease is also distributed around the body: atherosclerosis, cataracts, skin ageing, Parkinson’s disease and Alzheimer’s. We do have an enzyme called glyoxolase 1 that reduces as we get older – making us more susceptible to damage. This raises the question – why do we not get more allergies with age? I think the acquisition of tolerance helps explain that. We hypothesize that with higher RAGE stimulation – the body looks for the reason why and may falsely react to foods that are present. Genetic and environmental risk factors are likely to feed in. Higher AGE pattern diets have been linked to asthma, rhinitis, and eczema and these are known amplifiers of systemic anaphylaxis responses.
AAC: Do you think mothers with allergies themselves have to be more careful about AGEs? Do you think families with no history of allergies can be pushed in that direction through excessive consumption of AGEs?
PKS: I think we have to stress that this is still a hypothesis. We published this hypothesis and the most relevant data to discuss it. We expect people question it, challenge it, include it in consideration of their analyses of food allergy risk factors, allergies in general, and then look at modifying it. I think we are a good 5 years away from making dietary recommendations. Fortunately, the worse case scenario of this advice is to suggest eating fresh fruit and vegetables, do not fry or microwave meat, use fresh herbs and spices with cooking, reduce excess free sugars you eat, do not over-eat, exercise, don’t smoke, sleep well and try to reduce stress. Make sure you are not vitamin D deficient. All of these appear to influence AGEs or the RAGE receptor. These are pretty common public health messages anyway.
AAC: You mention the rise of food allergies in conjunction with the fast food industry. I am particularly struck by your observation that candy and soft drinks used to be occasional treats and are now everyday items for kids (and adults). Why does fructose, also found in fruit juice, which is supposed to be good for us, make such a difference? What does McDonalds have to do with the food allergy epidemic?
PKS: McDonalds is not the cause; it just is an indicator of the foods consumed and patterns of eating (too much in calories, less fiber, more fried foods and more sugar). Fructose consumption – as pointed out in the paper – has risen several hundred fold in the last 30 years. This sugar is a fast track substrate to a nasty AGE called methygloxal. Having more fructose than we can deal with results in more AGEs being made. When did eating candy and having soda every day become normal? Cheaper fructose as a sweetener may have something to do with certain crops being subsidized commodities, particularly corn. Fiber in foods helps us excrete some dietary and bacterial AGEs. Orange juice (fresh) actually seemed to be protective for asthma in US children. However, juice as a food actually does not make much sense – it gives a rush of fruit sugars without all the chewing to stimulate salivary and digestive enzymes or the time it takes to consume intact fiber and provide satiety. Try eating 1 raw carrot – this will fill you more than 3 that are juiced and your fructose rise will be far less and drop again with a single chewed carrot. It is the spikes that cause more AGEs to be formed. Our bodies just have not evolved to process the levels of sugar and ultra-heated meats we see in contemporary diets. Our dietary and lifestyle trends have diverged from evolution and we think our bodies are responding to them as if we are in crisis. Alarms (and alarmins) go off and the troops arrive.
AAC: One characteristic of a useful hypothesis is that it should be testable. It’s the difference between a circumstantial case and an evidentiary case. It appears to me that evidence can be gathered to support the False Alarm, such as the experiment on mice without the receptor. What are the next steps?
PKS: Yes – there are knock out mice – they do not develop as strong allergic inhalant allergy responses. As mentioned, some plant compounds that reduce AGEs being formed have been shown to reduce peanut allergy. We are developing in-vivo and in-vitro models. We do need a solid funding injection to cover research.
AAC: Everyone who spends time with food allergy mothers hears the question, “what did I do wrong?” Does your hypothesis give them one more thing to regret? What would the basics be of a low AGE diet?
PKS: The Mediterranean diet and Asian traditional diets are really quite low AGE diets. The have lots of herbs and spices – fresh is better. If you want meat – marinate it in lemon, garlic and herbs – and slow cook. Use fresh vegetables. Bacon is really high in AGE as are grilled cheese and French fries. If you want the browning as flavoring, do this with the occasional vegetable rather than meat (hold back on the fries though). Use your microwave for vegetables rather than high-protein foods. Reheating in the microwave amplifies AGE formation. Avoid soft drinks and snacking on candy. Rice is a great food to feed children. It is low glycaemic and has some anti-inflammatory compounds. I would love to see more of this instead of apple juice in infants’ diets. Bad bacteria produce more AGEs – and there is also convergence of signaling with RAGE and Toll receptors to signal threat. The RAGE receptor tends to increase if vitamin D is low, and it also coincides with being overweight, if you are stressed, do not sleep well, or are not exercising.
Life balance is also about context and the journey. Enjoy it all, including food, but now armed with knowledge (and a hypothesis) – eat sensibly. When I share a meal with an AGE expert I notice that many do eat meats, but not in large amounts, not char-grilled and they mix it with herbs, spices and fiber (not French fries). They tend not to finish off meals with a large dessert. We all should enjoy treats but not every day – (or several times a day).
AAC: Thank you very much for your time.
PKS: Pleasure. I hope this invokes discussion and more research. If this provokes any funding interest, please direct it towards Professor Li at Mt Sinai in New York and I hope this can progress answers sooner in their world-leading, established food allergy models.
Pete Smith is a Professor in Clinical Medicine at Griffith University in Queensland Australia. He trained in Pediatrics and did his PhD in molecular immunology at Flinders University South Australia and has worked as a Senior Lecturer at the Institute of Child Health London and an Honorary Consultant in Allergy at Great Ormond St Hospital London. He consults in Clinical Medicine in Southport Queensland and is Medical Director of Allergy Medical Group in Brisbane and Sydney. Current research includes AGEs and allergy, molecular ion channels in hypersensitivity and allergy, molecular activation pathways in allergic rhinitis and clinical studies in food allergy and rhinitis.