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By Madelaine Leitman

An estimated 220 million people worldwide suffer from food allergies, in which seemingly harmless food encounters can send people of all ages to the emergency room. Allergic reactions exhibit a wide range of manifestations, spanning from itching, swelling, nausea, and vomiting to the most severe symptom, anaphylaxis. More than 50% of people with food allergies have experienced at least one anaphylactic reaction, characterized by the constriction of airways due to swelling, causing difficulty breathing or even death. These adverse reactions can often be traced back to eight types of food that are responsible for around 90% of all reactions. These culprits include eggs, milk and dairy, peanuts, tree nuts, shellfish, fish, wheat, and soy.

“In the case of food allergies, benign substances are mistaken as pathogenic.”

Food allergy is an abnormal immune system response to antigens, certain molecules found in some foods which can be proteins, complex sugars or fat. Such antigens, which lie on the surface of cells, including plants and microbes that allow the immune system to recognize whether or not a particular exposure is harmful ( or “non-self”) or benign (“self”). The immune system of healthy individuals can distinguish between harmful and harmless “non-self” antigens with the help of specific receptors. In other words, a healthy and “well trained” immune system is able to distinguish healthy vs. toxic foreign entities based on various patterns that distinguish the two in order to decide when an immune response is warranted. In the case of food allergies, benign substances are mistaken as pathogenic. When the immune system encounters one of these substances, or an allergen, it initiates the production of a specific antibody, immunoglobulin E (IgE). An antibody is a specialized immune system protein that is trained to recognize specific antigens deemed as harmful, then each subsequent encounter with such allergen will initiate an immune response to expel or neutralize the threat. This process involves the release of mediators, such as histamine and cytokines, which are responsible for the inflammatory symptoms of allergic reactions. During inflammation, blood vessels in the affected area dilate to increase blood flow which leads to reddening of the tissue and increase their leakiness leading to swelling. In the case of exposure to a pathogen, these immune and tissue responses allows for the containment of pathogens at the site of infection and promotes the healing process. In the case of a benign allergen, the same responses can cause severe allergic reactions.

This leads to the question– how may everyday foods we eat lead to an inappropriate immune response? A prominent theory is that the answer lies in the gut microbiota, which is comprised of bacteria, viruses, and fungi that have a symbiotic relationship with each other and with their human host. These microbes live within the intestinal tract, which represents the largest surface area between a person and the external environment, approximately the size of a basketball court. Therefore, the gut has an important role in acting as a biological and physical barrier between the external environment and the body’s internal systems, including the gut associated immune system.

“A balanced microbiome, known as eubiosis, promotes immune tolerance, which means that the immune system is less likely to overreact to harmless substances like food antigens.”

To start, the biological barrier of the gut consists of the gut microbiota who protect against pathogen colonization and overgrowth through spatial and nutritional competition. The gastrointestinal tract is the ecosystem for trillions of microorganisms, so the competitive microbial-microbial interactions can reject the colonization by ingested pathogens, especially when the microbiota is balanced. A balanced microbiome, known as eubiosis, promotes immune tolerance, which means that the immune system is less likely to overreact to harmless substances like food antigens. However, the opposite is true for individuals with gut dysbiosis, an imbalance in the microbiota. This was seen in a study, where gut dysbiosis preceded the onset of food allergy, and the diversity of gut microbiota of those with allergies differed significantly from nonallergic controls. Specifically, children with food allergies had fewer Bacteroidetes, Bifidobacterium, and Lactobacillus colonies.

In addition to the barrier made up by the gut microbes, the physical barrier consists of a layer of tightly coupled cells that prevent toxins from the digestive tract from entering the bloodstream and surrounding tissues. This layer influences immune system activity, controlling immune system receptors and cytokine release. Each epithelial cell is connected to the next by specialized structures called tight junctions, which are characterized by selective permeability, meaning that only specific molecules are allowed to pass through while harmful substances and microorganisms are prevented from leaving the gut. When the integrity of the tight junctions is compromised, which has been referred to as a “leaky gut”, larger molecules, including allergenic proteins, can leak from the digestive tract into the bloodstream. Basically, leaky gut syndrome is when the “bad” bacteria create lesions in the wall that separates the gut from the bloodstream, allowing food toxins and pathogens to leak through. This increased permeability leads to increased immune responses, which is what is occurring during an allergic reaction. While the exact causes of leaky gut are being studied, several factors contribute to its development, such as processed, low fiber diets, chronic stress, medications, exposure to environmental toxins, and infections.

“During early life, the composition of gut microbes is especially malleable, so disturbances during this time may have a great impact.”

During early life, the composition of gut microbes is especially malleable, so disturbances during this time may have a great impact. While food allergies can develop at any age, most appear during this same time – early childhood. In fact, food allergies impact 6-8% of children younger than 5 years of age, compared to about 3-4% of adults. A theory as to why so many people tend to “outgrow” their food allergies is that as the gut microbiome matures and stabilizes, it plays a role in promoting tolerance to certain allergens. While food allergy prevalence tends to decrease from childhood to adulthood, we have seen an overall increase in food allergy prevalence across the board in the last 2 to 3 decades. The hygiene hypothesis suggests that reduced exposure to infectious agents and microbes during early childhood could lead to an increased risk of asthma, autoimmune disease, and allergies later in life. Early life microbial exposure helps train the immune system to differentiate between harmful and harmless bacteria. Over recent decades, enhanced sanitation practices and a significant surge in antibiotic usage have contributed to the reduced microbial exposure experienced by individuals, which temporally aligns with the rise of food allergies.

Still, many questions remain as there is no uniform diagnostic criteria for food allergies, and the only effective treatment is strict elimination of the food that causes the reaction. However it is clear that the gut microbiome plays a vital role in human health, including the development and management of food allergies via the gut-immune connection. Geared with the knowledge that colonization by a “healthy” microbiome is a key determinant in immune system maturation, we can prioritize eubiosis through diet, conservative antibiotic use, supplementation with probiotics and prebiotics, and more.

Madelaine Leitman is an undergraduate student at UCLA, with a major in Computational and Systems Biology. Her passion for her ongoing research at the Goodman-Luskin Microbiome Center is fueled by her strong belief that the brain gut microbiome system plays a crucial role in overall wellbeing and health. Her ultimate goal is to contribute valuable insights to the scientific community and disseminate knowledge to the wider public. Beyond her academic pursuits, she enjoys traveling, running, practicing yoga, and playing volleyball.