By Dr. Eva Untersmayr
Food allergy researchers worldwide have been trying for years to figure out why foods that should be nutritious may cause potentially life-threatening reactions in food-allergic patients. Decades of research have been devoted to identifying characteristics of proteins responsible for allergic reactions and predicting the allergenic potential of novel food compounds. However, there is another and equally important element to evaluate. That is the stability of these proteins during preparation and ultimately gastrointestinal digestion. Testing is based on the concept that to trigger food allergies, the proteins must be capable of resisting the harsh conditions of cooking and the digestive tract to reach the immune induction site in the intestine without being broken down.
In the laboratory, food allergens must be characterized by experiments simulating the gastrointestinal enzymatic protein degradation. In these assays proteins of interest are incubated with gastrointestinal enzymes responsible for allergen fragmentation. First there is the interaction with gastric proteases. Thereafter, proteins are incubated with enzymes released by the pancreas to simulate the intestinal digestion resulting in the formation of small mono- and dipeptides. In our bodies, these peptides are taken up by the cells that line the gastrointestinal tract and deliver nutrition to our tissues. It should be noted that a number of important food allergens are readily degraded after brief incubation with the first enzymes responsible for the protein digestion, the gastric proteases. After a single minute of gastric digestion, important fish allergens have their capacity to bind to allergy-inducing IgE antibodies extensively reduced.
Under normal conditions, high acidity–low pH–is responsible for activating the main enzyme for fragmenting proteins in the stomach. The partially digested acidic food—called chyme—then arrives in the upper part of the small intestine, the duodenum, triggering the release of enzymes from the pancreas.
However, in situations of high pH–low acid production in the stomach, also called hypoacidity, these enzymes do not become activated. Gastric hypoacidity is not a rare condition. It is found both in newborns and infants in the first two years of life, and also in older patients. For small children, this leaves a window of opportunity for sensitization to complex proteins. For their part, more than half of patients older than 60 have reduced gastric acid production, which may account for many complaints from grandparents after a holiday dinner, or general loss of appetite as food just “sits there” instead of passing through comfortably. This discomfort may be aggravated when they medicate themselves for “heartburn” by taking over-the-counter antacids or prescription acid-suppressive medication for dyspeptic disorders such as gastritis, ulcer and reflux. These may include Sucralfate, H2 receptor blockers, and proton pump inhibitors (PPIs) as well as antacids, all of which lead to less gastric acidity. In experiments, this state of hypoacidity allows the food allergens to remain stable. They are not fragmented as they would be with greater acidity.
This raised the question: what this could mean for the food allergy potential in patients being treated with acid-suppressive drugs?
My research partners and I became interested in this question more or less by coincidence as we diagnosed a previously non-allergic patient who became severely food allergic to Beluga caviar. As researchers, we were very lucky. Because the allergen was so special, even after several years the patient was able to remember quite vividly his first, symptom-free ingestion at a party. When he ate caviar for the second time several months later he experienced severe symptoms with need for hospitalization, and then again after several years had passed after eating with a salad with a trace of the Beluga roe. This history made it easy to zero in on the allergen.
During follow-up and diagnosis, the patient recalled that he was on acid-suppressive medication that first time. As we investigated and characterized the novel food allergen in Beluga caviar we saw that it is usually completely digested by gastric enzymes very quickly. However, when we simulated hypoacidic conditions, the protein remained stable. So we concluded that when he ate it the first time, the sustained elevation of the gastric pH by the prolonged antacid drug intake might have caused sensitization and development of caviar allergy.
In studies following this first case we confirmed our hypothesis. In several preclinical studies with mice, we observed the development of food allergy, evidenced by high IgE antibodies, positive skin tests, positive provocation tests, and influx of inflammatory cells. In all these studies we used important but highly digestible food allergens such as milk, fish, celery and so on, given orally but accompanied by treatment with acid-suppressing medications. Without the antacids the food allergens were tolerated perfectly. However, our clinical studies of adult patients indicated a definite connection between intake of anti-ulcer drugs and food specific IgE induction leading to the development of food allergies.1-3
We were also interested in situations where food-specific IgE is already present. In food-allergic adult patients we found that gastric digestion had a direct influence on the amounts of food proteins they could tolerate. This effect was not only observed in skin testing with digested and undigested allergens, but also in double-blind placebo-controlled food challenges (DBPCFC), which are considered to be the gold standard for food-allergy diagnosis. The fish-allergic patients tolerated up to 30-fold higher dosages of fish allergen if the proteins were degraded by gastric enzymes.4 We therefore concluded that gastric digestion plays an important protective role in prevention of food allergy development and also in reactivity by already-food-allergic patients.5,6 In addition, recent research papers published by other groups are further supporting our hypothesis and report connection between gastric acid-suppression and allergy in pediatric patients as well.8-10 Besides the growing evidence between the link of impaired gastric digestion and the risk of developing food allergy or reacting for those already allergic, there is also an apparent link between gastric acidity and protection from infectious agents like bacteria.
All these studies indicate that the health of the gastrointestinal digestive system and its ability to degrade proteins varies widely between individuals, depending on the acidity of the gastric environment. Also in the same individual, depending on overall health, medication and other factors, levels of reactivity might vary at particular times. This could account for the severity of reactions in the same patient, making the difference between, say swollen lips in one food allergen exposure, and catastrophic loss of blood pressure and respiratory distress in another.
Unfortunately, there is evidence that patients and doctors are trading long-term health for short-term comfort. In Europe, and I suspect elsewhere, the sales figures of acid-suppressive drugs are continuously on the rise and they are being used for long periods of time. Moreover, several investigations indicated that up to 60% of pharmaceutical gastric acid-suppression is initiated inappropriately during hospitalization.
Without any question there are clinical situations where patients have to take acid-suppressive medication. But it might be worthwhile to be skeptical and to discuss this issue with a trusted physician. Above all, self-medication and prescription-free intake of these potent drugs is not a good idea. They can be very helpful for relieving symptoms of digestive disorders, but there are certainly side effects that should be considered. We should also be very careful as we evaluate new applications for antacid drugs. Because of my work investigating the role of digestion in food allergies, I am concerned at anecdotal reports of antacid use to suppress vomiting during oral immunotherapy. I feel that because the concomitant use of antacids with ingestion of allergenic proteins may induce food allergy to begin with, their regular use with proven allergens could make digestive systems even more vulnerable.
In general, physicians should review the patients’ medication at every consultation to reduce inappropriate long-term usage of acid-suppressive drugs. This could prevent side effects, dangerous interactions between medication and save money from overall health care expenditures. For mild symptoms, physicians could recommend life style changes such as light diet or avoiding coffee, alcohol or cigarette smoke. It should never be forgotten that the gastrointestinal digestion not only is crucial for fueling the body, and defending against infectious agents, it has an additional protective gate-keeping function turning intact, potentially allergenic proteins into well-tolerated nutrients. Tampering with it is not a great idea.
1. Untersmayr E, Schöll I, Swoboda I, Beil WJ, Förster-Waldl E, Walter F, Riemer A, Kraml G, Kinaciyan T, Spitzauer S, Boltz-Nitulescu G, Scheiner O, Jensen-Jarolim E. Antacid medication inhibits digestion of dietary proteins and causes food allergy: a fish allergy model in BALB/c mice. J Allergy Clin Immunol. 2003 Sep;112(3):616-23.
2. Schöll I, Untersmayr E, Bakos N, Roth-Walter F, Gleiss A, Boltz-Nitulescu G, Scheiner O, Jensen-Jarolim E. Antiulcer drugs promote oral sensitization and hypersensitivity to hazelnut allergens in BALB/c mice and humans. Am J Clin Nutr. 2005 Jan;81(1):154-60.
3. Untersmayr E, Bakos N, Schöll I, Kundi M, Roth-Walter F, Szalai K, Riemer AB, Ankersmit HJ, Scheiner O, Boltz-Nitulescu G, Jensen-Jarolim E. Anti-ulcer drugs promote IgE formation toward dietary antigens in adult patients. FASEB J. 2005 Apr;19(6):656-8. Epub 2005 Jan 25.
4. Untersmayr E, Vestergaard H, Malling HJ, Jensen LB, Platzer MH, Boltz-Nitulescu G, Scheiner O, Skov PS, Jensen-Jarolim E, Poulsen LK. Incomplete digestion of codfish represents a risk factor for anaphylaxis in patients with allergy. J Allergy Clin Immunol. 2007 Mar;119(3):711-7. Epub 2007 Jan 9.
5. Untersmayr E, Jensen-Jarolim E. The role of protein digestibility and antacids on food allergy outcomes. J Allergy Clin Immunol. 2008 Jun;121(6):1301-8; quiz 1309-10. doi: 10.1016/j.jaci.2008.04.025. Review.
6. Pali-Schöll I, Jensen-Jarolim E. Anti-acid medication as a risk factor for food allergy. Allergy. 2011 Apr;66(4):469-77.
7. Dehlink E, Yen E, Leichtner AM, Hait EJ, Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study. Clin Exp Allergy. 2009 Feb;39(2):246-53.
8. Ramírez E, Cabañas R, Laserna LS, Fiandor A, Tong H, Prior N, Calderón O, Medrano N, Bobolea I, Frías J, Quirce S. Proton pump inhibitors are associated with hypersensitivity reactions to drugs in hospitalized patients: a nested case-control in a retrospective cohort study. Clin Exp Allergy. 2013 Mar;43(3):344-52.
9. DeMuth K, Stecenko A, Sullivan K, Fitzpatrick A. Relationship between treatment with antacid medication and the prevalence of food allergy in children. Allergy Asthma Proc. 2013 May-Jun;34(3):227-32.
Eva Untersmayr, MD, PhD, is Associate Professor and head of the Gastrointestinal immunology research group at Department of Pathophysiology and Allergy Research at the Medical University of Vienna. She is an Immunologist especially interested in the connection between digestion, food allergy and the immune system of the gastrointestinal tract. Her work was continuously funded by several grants of the Austrian Science Fund and the Austria National bank. Following her medical studies, Dr. Untersmayr also trained as an acupuncturist in Austria.
Elaine Burton says
Very interesting article — thank you for writing it. Years ago I was plagued with periodic episodes of severe/widespread hives, and one of the medications my G.P. recommended was the antacid Pepcid AC (famotidine) in addition to Benadryl, though neither medicine seemed to make a difference — I would typically be covered for 1-2 full days. Then again, I now know my G.P. wasn’t recommending nearly enough Benadryl. At any rate, perhaps famotidine for hives in atopic individuals isn’t such a hot idea.