Food allergy
Food allergy, characterized by an adverse immunological response to specific food allergens, is a growing public health problem with an increasing prevalence worldwide in recent decades [1]. Food allergy is estimated to affect nearly 10% of the population worldwide, approximately 5–8% of children and 1–4% of adults [2, 3]. According to the data from the European Academy of Allergy and Clinical Immunology (EAACI), the number of food allergy in Europe has doubled in the last decade [4]. At the same time there has been a significant increase in interventions related to anaphylaxis [4]. There is a considerable geographical variation in the food allergens in different regions, reflecting regional dietary patterns. For example, peanut allergy is more common in Western countries [5]. Recent data show a 3.5-fold increase in peanut allergy over the last two decades, reaching 1.4–2.0% in Europe and the USA [5]. The increase in peanut allergy may also be due to Ara h1 exposure from increased CO2 emissions [6]. The ECAP study conducted in Poland has shown a significant and dynamic increase in the incidence of allergic diseases, including food allergy, in children compared to the previous decade [7]. Studies of food allergy outcomes suggest that children with milk protein allergy often have a positive outlook and are likely to develop tolerance to the allergen naturally over time. Allergy to peanuts and tree nuts, however, is more likely to persist from childhood into adulthood [8]. Meta-analysis data have shown that the prevalence of food allergy in Europe increased from 2.6% between 2000 and 2012 to 3.5% between 2012 and 2021, as determined by a clinical history or positive food challenge tests (OFC or DBPCFC) [9].
The reason for the increased incidence of food allergy is complex, and the most likely factors include changes in dietary habits, increased consumption of highly processed foods, frequent use of supplements, antibiotics, proton pump inhibitors (PPIs), and non-steroidal anti-inflammatory drugs (NSAIDs), as well as climate changes, urbanization, and pollution [1, 8, 10]. Early exposure to allergens is also known to be a factor contributing to the increased incidence of allergic diseases [11]. The primary route of exposure to food allergens is through the digestive system, which breaks down food into a form that the body can absorb for energy and growth. However, exposure to allergens can also occur by other routes such as skin contact or inhalation, particularly in occupational settings such as the food industry [12]. The clinical presentation of food allergy is complicated by the variety of symptoms that can affect all organs and systems. Symptoms include skin rash, hives, angioedema, pollen-food allergy syndrome, nasal congestion, wheezing, coughing, abdominal pain, abdominal cramps, nausea, vomiting, diarrhea, etc. [13]. The most severe and potentially fatal reaction in food allergy is anaphylaxis, an immediate, life-threatening hypersensitivity reaction that usually occurs within minutes to hours after exposure [14]. It is characterized by skin symptoms, a sudden drop in blood pressure, difficulty breathing, and possible loss of consciousness. Recent data have shown an increased prevalence of anaphylaxis, particularly caused by drugs and food [14, 15].
Some food proteins are more likely to cause anaphylactic reactions [13]. The Food and Drug Administration (FDA) has compiled a list of the most allergenic foods, called the Big Eight, which includes milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, and soybeans [16]. The United States officially acknowledged sesame as the 9th major food allergen through the enactment of the Food Allergy Safety, Treatment, Education, and Research (FASTER) Act on April 23, 2021 [16]. Data show that approximately 90% of food allergy in the United States are caused by these allergens [17]. All these allergens must be listed on the food label if they are present [16]. In addition, the allergenic potential depends on the form of the food consumed and the thermal processing (freezing, boiling, cooking, roasting, pasteurization). Roasting can even significantly increase the allergenic potential of peanuts [18]. Thermostable allergens such as ovomucoid, casein, tree nut, peanut, prolamin storage proteins of cereal seeds, cause the food to retain allergenic properties even after heat treatment [19]. It should be noted that certain protein families are highly cross-reactive [19].
A life-threatening risk for food-allergic patients is the accidental ingestion of allergenic foods [20]. The constant awareness of risk causes persistent anxiety, significantly reduces quality of life, and seriously impacts social and family life. Unintentional ingestion can occur due to cross-contamination during food preparation or the presence of hidden allergens in processed foods, among other factors [3]. The impact of food allergy on a patient’s life extends beyond physical symptoms and health risks. Constant vigilance in avoiding allergenic foods, coupled with the fear of another allergic reaction, can lead to anxiety, stress, and a reduced sense of freedom in daily life [3]. Patients with a history of anaphylaxis must be provided with a life-saving kit, which requires them to carry epinephrine (adrenaline), a life-saving medication that is crucial in the treatment of anaphylaxis [4]. Education and awareness play a crucial role in managing food allergy. Patients and their caregivers should be aware of the allergens they need to avoid, how to read food labels effectively, and what to do in case of an allergic reaction [21]. Although many diagnostic tests are available, diagnosing food allergy remains complex and time-consuming [7]. We currently use skin prick tests (SPT) with allergen extracts, prick-to-prick tests with native allergens, specific IgE assessment for food allergens, component-resolved diagnostics, basophil activation test (BAT), mast cell activation test (MAT), elimination diet and oral provocation tests [4, 7, 22]. The gold standard remains double-blind, placebo-controlled, food challenge (DBPCFC) [23]. A very important part of the diagnostic plan is the history, but it has limited evidentiary value, especially when symptoms are non-specific, have been present for a long time, involve allergy to multiple foods or cross-reactions with other food and/or inhalant allergens, and in cases where co-factors are involved. In some cases, it is impossible to determine the triggering factor of allergic reactions. Considering the reduction in quality of life of patients, the burden of symptoms and the unpredictable nature of their clinical manifestation, there is no doubt that the issue of food allergy requires further research into its etiology, diagnosis, treatment and prevention.
Microbiota specification and factors influencing microbiota composition
The human gut is home to a vast and varied ecosystem of microbes, with over 100 trillion microorganisms present, which makes the colon one of the most densely populated microbial environments on Earth [24]. The gut microbiome has an extensive genetic capacity, with over 3 million genes and the ability to produce thousands of metabolites [25]. In comparison, the human genome contains only around 23,000 genes [24, 26]. It constitutes a complex ecosystem, consisting mainly of bacteria, but also includes archaea, viruses, fungi, and other microorganisms [10]. The gut microbiota plays a crucial role in human health through various mechanisms, including nutrient metabolism, protection against pathogens, development and regulation of the immune system, and modulation of host physiology [25]. The composition of the gut microbiota is influenced by several factors, including diet, lifestyle, antibiotic use, and environmental exposures. Firmicutes and Bacteroidetes are the most prominent bacterial phyla found in the gut [24, 27]. Other phyla, such as Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia are also present but in lower abundance [24]. Among the fungi, Candida, Saccharomyces, Malassezia, and Cladosporium are commonly found in the gut [28, 29]. The gut microbiota performs multiple vital functions, including food fermentation, nutrient extraction, energy metabolism, and immune system development [25, 30]. Microbiota contributes to these processes by possessing versatile metabolic genes, which provide unique enzymes and biochemical pathways that aid in food digestion and energy production [30]. In addition, the production and metabolism of essential compounds, such as vitamins, amino acids, and lipids are highly dependent on the composition and activity of the gut microbiota [25, 31]. The gut microbiota interacts with the immune system by producing antimicrobial compounds and participating in the development of the intestinal mucosa and immune response [25]. Colonization of the gut microbiota begins at birth and is influenced by various factors, such as the mode of delivery (vaginal vs. cesarean section), feeding practices (breastfeeding vs. formula feeding), maternal microbiota, and environmental exposure [10]. During early life, the gut microbiota rapidly diversifies and becomes more complex [10]. This critical period of microbiota development is believed to have long-lasting effects on the immune system and overall health. A substantial amount of evidence highlights the significant role of human microbiota in the development and regulation of the immune system [30]. Insufficient microbial diversity in early life has been suggested to contribute to the onset and severity of immune-mediated diseases.
Diet is a fundamental determinant of the types of microorganisms that dominate the gut [32, 33]. A diet rich in plant-based foods, mainly fruits, vegetables, whole grains, legumes, nuts, and seeds promotes the growth of beneficial bacteria and a more diverse microbiota [33, 34]. The metabolism of dietary components by gut microbes, including fiber, contributes to the complex interactions within the gut and has significant effects on the health and functioning of the host [27]. Dietary fiber, an indigestible component of food, consists of various carbohydrates that differ in solubility, viscosity, and susceptibility to fermentation [34]. In general, fiber can be divided into four main groups: non-starch polysaccharides (NSPs), resistant oligosaccharides, resistant starch and lignin associated with dietary fiber polysaccharides [34]. These properties determine the fermentability of fiber and its availability to microorganisms. NSPs are the most abundant form of dietary fiber and include cellulose, hemicellulose, and pectins [34, 35]. NSPs are found in the cell walls of plants and provide structural support. They vary in solubility and are not digested in the small intestine, meaning they pass through largely intact. This adds bulk to the stool and promotes regular bowel movements. The microbial fermentation of NSPs begins in the large intestine [36].
Resistant oligosaccharides are a type of fiber that resists digestion and absorption in the small intestine. They include fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), xylo-oligosaccharides (XOS), and inulin [34]. These fibers are broken down by gut bacteria in the large intestine through fermentation. This process produces short-chain fatty acids (SCFAs), which provide energy to colonic cells and offer various health benefits [37]. The anti-obesity, anti-inflammatory, immunoregulatory, cardiovascular-protective, neuroprotective, hepatoprotective, and anticancer effects of SCFAs have been observed [37, 38].
Resistant starch is a type of fiber that resists digestion in the small intestine. It is found in foods such as legumes, whole grains, and cooked potatoes [34]. Resistant starch is also fermentable by gut bacteria in the large intestine, producing SCFAs, which promote the growth of beneficial bacteria and may have a positive effect on colon function [33]. Lignin is a complex compound found in the cell walls of plants. It is the only component of dietary fiber that is not a carbohydrate [34]. Lignin is generally insoluble in water and resistant to fermentation by gut bacteria. It adds bulk to the stool and promotes regular bowel movements [39].
Overall, dietary fiber plays a crucial role in maintaining an efficient digestive system and promoting overall health. It helps regulate bowel movements, prevents constipation, and can help control blood sugar levels and reduce cholesterol levels [27, 33]. To obtain the benefits of dietary fiber, it is important to consume a variety of fiber-rich foods, including fruits, vegetables, whole grains, legumes, and nuts [39].
The basis for understanding the impact of the microbiota on our health is that through the process of fermentation, the microbiota enables the assimilation of dietary fiber and other substances in food that cannot be digested by humans [25, 27]. Bacteria possess a variety of enzymes that enable them to ferment dietary fiber, producing SCFAs among other by-products [34, 40]. SCFAs are the best-known metabolites of bacterial fermentation and include acetate (C2), propionate (C3), and butyrate (C4) [26, 34]. They represent 90–95% of total colonic SCFAs and play a crucial role in maintaining an effective intestinal epithelial barrier. They also influence the host’s immune system by binding to G protein-coupled receptors (GPCRs) [30, 34]. The gut microbiota also generates small amounts of valerate (C5), caproate (C6), and branched-chain fatty acids (BCFAs), particularly iso-valeric acid and iso-butyric acid, through the fermentation of amino acids [41].
Historical changes in fiber consumption have been associated with an increased prevalence of allergic disorders, as metabolites derived from fiber play an important role in immune cell decision-making processes. On the other hand, diets rich in processed foods, saturated fats, and added sugars can lead to an imbalance in the microbial community and reduce microbial diversity [30]. A high-fat, low-fiber diet and obesity have been associated with unfavorable changes in gut microbiota composition and metabolic activity [34]. A recent meta-analysis found that consumption of fiber-rich foods, such as nuts, led to a significant increase in key microbial groups, including Clostridium, Dialister, Lachnospira, and Roseburia, which play an important role in gut health [34]. Fiber intake or SCFAs supplementation in experimental models has been shown to protect against colitis, arthritis, viral infections, allergic inflammation, and food allergies [34]. Other factors that influence microbiota composition include the use of antibiotics, supplements, PPIs, and NSAIDs, which significantly disrupt the balance of intestinal bacteria and lead to dysbiosis [42, 43]. Antibiotics can significantly reduce important beneficial anaerobic bacteria, such as Bifidobacteria, Lactobacilli, Bacteroides, and Clostridia. Just 7 days of antibiotic treatment can result in a 25% decrease in microbial diversity, with a drop from 29 to 12 core taxa. Moreover, antibiotic-resistant Bacteroidetes may increase by 2.5 times. This reduction in microbial diversity due to antibiotics can also lead to decreased production of SCFAs [43]. Environmental factors such as stress, sleep patterns, exercise, exposure to pollutants, and breastfeeding also play an important role. Variations in the composition of the gut microbiome have been observed in infants before weaning, with differences noted between those who are breastfed and those who are formula-fed. Breastfed infants typically have a microbiome primarily composed of Lactobacilli and Prevotella, while formula-fed infants tend to exhibit a more diverse microbial community dominated by Enterococci, Enterobacteria, Bacteroides, Clostridia, and Streptococci [43]. It should also be noted that methods of food preservation, such as heat treatment, pasteurization, or pascalization, reduce the diversity of microbiota provided to the intestine through food. In traditional and minimally processed foods, beneficial naturally present bacteria can contribute to the gut microbiota through horizontal gene transfer, allowing the exchange of genetic material between different bacteria [44]. However, modern food processing techniques often eliminate or reduce the presence of these beneficial bacteria, limiting the potential for gene transfer and potentially compromising the resilience and functionality of the gut microbiota [45].
Dysbiosis as a potential trigger for food allergy
Dysbiosis refers to an imbalance or disruption in the composition and function of the gut microbiota. It has been linked to various health conditions, including gastrointestinal disorders, metabolic diseases, autoimmune disorders, and allergies. Microbiota imbalance has been proposed as a potential trigger for the development of allergy due to alterations in immune responses [10]. Several studies in both mice and humans have shown that increased permeability of the intestinal barrier is linked to food allergy. This compromised barrier function allows allergenic substances, such as dietary proteins, toxins, and microbial by-products, to cross the intestinal lining. Once these molecules pass through, they can interact with immune cells located in the gut-associated lymphoid tissue (GALT), potentially triggering immune responses that lead to allergic reactions [42].
Dysbiosis may affect the immune response to food antigens, compromising immune regulation and tolerance to allergenic proteins [30]. The presence or absence of specific bacterial species, alterations in microbial metabolites, and disrupted microbial-host interactions can skew the immune response toward an allergic phenotype [46]. Recent research has demonstrated that introducing gut microbiota from individuals with food allergy into germ-free mice can make the mice more susceptible to developing food allergy [47]. Conversely, germ-free mice that were colonized with bacteria from healthy infants, but not from those with food allergy, were protected from anaphylactic reactions to a cow’s milk allergen [47].
Moreover, dysbiosis can compromise the integrity of the gut barrier, allowing allergens to translocate into the bloodstream and trigger immune response [48]. This disruption in the gut barrier function is thought to contribute to the development of food allergy.
Studies have shown that people with food allergy tend to have different gut microbiota profiles than non-allergic individuals [48]. Healthy gut microbiota has been shown to prevent the onset of food allergy by enhancing the integrity of the intestinal barrier and promoting the development of specific immune cells, such as RORγt+- and Foxp3+-expressing regulatory T cells (Tregs), which are crucial for maintaining immune tolerance [47, 49].
In another study, researchers used a twin study design to explore differences in fecal microbiota and metabolites between twins, where one had a food allergy and the other did not [47, 50]. Because monozygotic twins share both their early environment and genetic background, this approach helps reduce confounding factors, making it easier to pinpoint how microbiota variations relate to food allergy [47, 50]. The researchers examined 18 twin pairs, aged between 6 months and 58 years, including 13 pairs where one twin had food allergy and the other did not, and 5 pairs where both were affected. Using 16S rRNA sequencing, they identified 64 distinct operational taxonomic units (OTUs), with 62 being more prevalent in the healthy twins and 2 in the allergic twins. The majority of OTUs that were abundant in healthy individuals belonged to the Clostridia class, specifically from the Lachnospiraceae and Ruminococcaceae families. Interestingly, the Lachnospiraceae family has been linked to protection against milk allergy in mice colonized with microbiota from healthy humans [47].
These differences include lower diversity, alterations in bacterial abundances, and an imbalance in beneficial versus harmful bacterial populations. Additionally, reduced production of microbial metabolites such as SCFAs has been observed in individuals with food allergy [46, 48].
The exact mechanisms underlying the relationship between dysbiosis, and food allergy are still under investigation. However, interventions aimed at modulating the gut microbiota, such as diet modifications, administration of prebiotics, probiotics, postbiotics or in some cases fecal microbiota transplantation should be investigated further.
Summary and concluding remarks
Recent research has highlighted the potential role of gut microbiota dysbiosis in the pathogenesis of food allergy, suggesting that alterations in gut microbiota composition and function may influence immune responses and contribute to immune dysregulation, adverse reactions to food and allergic sensitization. Diet plays a crucial role in shaping the gut microbiota, with fiber and plant-based foods promoting the growth of beneficial bacteria and a more diverse microbiota. Imbalances in bacterial populations, reduced microbial diversity, decreased production of metabolites such as SCFAs, and impaired intestinal barrier function may contribute to immune dysregulation and allergic sensitization. Individuals with food allergy have been shown to have different gut microbiota profiles compared to non-allergic individuals, highlighting the potential role of the gut microbiota in the pathogenesis of food allergy. Further research is needed to elucidate the mechanisms underlying the relationship between dysbiosis and food allergy and to investigate potential therapeutic approaches targeting the gut microbiota. Future studies should focus on the effects of dietary interventions, prebiotics, probiotics, postbiotics, and potentially fecal microbiota transplantation on modulating the gut microbiota and restoring immune tolerance in individuals with food allergy. Additionally, genetic microbiome studies and metabolomics may provide further insights into the role of the gut microbiota in the development and severity of food allergy. By targeting the gut microbiota through dietary and lifestyle modifications, there may be potential to reduce the development and severity of food allergy. Further research in this area holds great promise for improving the quality of life for individuals with food allergy and advancing our understanding of the complex interactions between the gut microbiota and the immune system in the context of allergic disease. In the emerging field of personalized medicine, modifying the gut microbiome offers a promising approach to tailor diagnosis and treatment for patients with food allergy, with the potential for more individualized and effective therapeutic strategies.
