The Gut Microbiome and Allergic Diseases

• The human body houses a diverse and dynamic gut microbiome, which in its essence is a process.

  • This process involves a complex community of bacteria, viruses, fungi as well as parasites.

• The microbial population is influenced by the development of the host.

• It participates in a sequence of immune and metabolic activities, is variable and dependent on many stimuli.

• An infant has a different composition of the intestinal microflora than an adult.^[1]

  • Factors determining it include, among others, past infections, antibiotic therapy, stress and diet.^[1:1]
  • The latter factor, among many other processes, affects the interaction between the microbiome and epigenetics.^[1:2]
    • Epigenetic modification is one of the mechanisms associated with the development of diseases in response to a modified gut microbiome.^[1:3]
  • Genetics itself also plays an important role in shaping the composition of the gut microbiome.^[1:4]

• The gut microbiome is associated with the course and occurrence of many diseases and ailments.

• A diverse and dynamic microbial population influences, among other things, the occurrence of autoimmune disorders, cancer, infectious diseases or allergies in humans.

• Cohort studies have shown significant differences in the composition of the microbiome in healthy people compared to those affected by food allergies.

• It has been proven that the development of food allergies is one of the consequences of dysbiosis.^[1:5]

• There is a consistency of the gut microflora with the human immune system, as evidenced by processes like regulation of immune functions and inhibition of pro-inflammatory factors by the bacterial community.

• The microbiome plays a role in the development of asthma and atopic eczema.

• The microbiome ecosystem, composed of trillions of microorganisms, has a significant impact on the human body during both homeostasis and disease.

• The microbiome participates in many physiological functions such as neutralizing toxins and pathogens, producing vitamins, maintaining intestinal cells and obtaining energy from food.

• Human health depends on microbiome composition and function.

• Food allergies can significantly reduce the standard of living of patients.

• There is no established cure for treating or preventing food allergies.

• Pathogenesis of food allergies is mostly based on immunoglobulin E (IgE)-mediated reactions.

• Allergic symptoms appear within minutes, and they consist of rash, fever, redness, diarrhea, vomiting and swelling.

• Severe food allergies may lead to life-threatening anaphylaxis.

• Symptoms of food allergies are conditioned by the degranulation of basophils and mast cells.

  • Degranulation occurs as a result of the binding of IgE to high-affinity IgE receptor(FcRI) (Figure 1).

• IgE secretion is dependent on Th2 lymphocytes that produce IL-4.

• It is this interleukin that B cells need to form the IgE isotype.

• In addition, it is important to remember the key function of Treg cells, which can stop the generation of Th2 immunity and the production of IgE.

• Food allergies are likely caused by dysregulation in IgE synthesis.^[1:6]

  • Germ-free mice, or mice treated with antibiotics became increasingly more susceptible to peanut allergy, while showing increased levels of peanut-specific IgE compared to the control groups.^[1:7]

• The mucosal surface in the digestive tract is constantly exposed to trillions of bacteria with which it forms a symbiotic relationship.^[1:8]

• The number of bacterial cells far exceeds the number of human cells, which is why maintaining symbiosis is crucial for the proper regulation of the immune response.^[1:9]

• Short-chain fatty acids (SCFAs) are one example of metabolites produced by the microbiota that are crucial in promoting oral tolerance and barrier integrity to decrease pathogenic reactions to consumed meals.^[1:10]

• Dietary fiber is the substrate for subsequent production of SCFAs.^[1:11]

• SCFAs are essential metabolites in the regulation of intestinal Treg cell differentiation and, in addition, cause increased secretion of IL-10.^[1:12]

• SCFAs are epithelial barrier enhancers by controlling goblet cell mucus secretion and IL-22 production by ILC3.^[1:13]

• The production of SCFAs by microbes inhabiting the gut helps in prevention of developing food allergies, therefore dysbiosis in gut microbiome can increase the risk of developing food allergies.^[1:14]

• The first few years after birth are crucial in preventing food allergies.^[1:15]

• Microbiome colonization is fully completed by the end of the first month, and later changes are observed usually when the infant’s diet is introduced to new food groups [16]. Roduit et al. discovered that the variety of food consumed in the first year of life has a counter-proportional effect on the development of food allergies [17]. Research provided by Du Toit et al. supports the hypothesis that infants should be introduced to allergens as fast as possible. In this study, 640 infants at 4–11 months of age that have been already diagnosed with at least one allergy, were randomly assigned to a group where they were either consuming or avoiding peanuts until 60 months of age. Results confirmed that early introduction to the allergen in high-risk patients, had a great chance of decreasing the risk of development of food allergy targeted toward peanut allergy [18]. Another important factor to take into consideration is “hygiene hypothesis”. Once again, in this aspect everything starts in infancy. The term “hygiene hypothesis” was first used in 1989, when David Strachan linked the exposure to the microorganism with development of the immune system in childhood [19]. First studies that were researching this hypothesis were done in Europe and resulted in promising findings. Children living in the farm areas were exposed to much more microbes than children in city areas. This exposure to microbes, positively influenced development of the allergy in children brought up in farm areas. Apart from the exposure to microbes, the mode of delivery, family size, diet, antibiotic exposure and exposure to furry animals also play important roles. All those factors lie under the “hygiene hypothesis” umbrella term, and they are playing a crucial role in composition of microbiome and development of food allergies [20].

The gut microbiome has modulatory properties when it comes to development of food allergies.

• Food allergy immunotherapy.

  • By modifying the immune system, the therapy hopes to permanently stop the body’s reactivity to dietary allergies.
  • This involves increasing regulatory B cells, which release IL-10, and converting allergen-specific Th2 lymphocytes into Treg cells, which generate IL-10.
  • These modifications lead to a diminished sensitivity to allergen triggers and a decrease in Th2 inflammation.
  • There are three proposed ways of introduction the food allergy immunotherapy, including the oral, sublingual and transdermal route.
  • For now, the oral route seems to be the most effective, despite having the most side effects.

• Pharmacological treatments, apart from known adrenaline and antihistamine drugs, one of the biotechnological drugs – omalizumab, seems to be gaining interest as an anti-IgE monoclonal antibody.

• Prebiotics and probiotics are also considered as helpful, however results from multiple studies are non-homogeneous and further research is needed to establish their full potential.

• Asthma is the most prevalent chronic disease among children.

• In the United States alone, in 2020, 7.8% of the population was diagnosed with asthma, with women being more susceptible than men according to CDC data.

• Breathing difficulties in asthma are caused by the constriction of the airways due to spasms and a rise in bronchial secretions, which can be reversed and brought on by allergens or hypersensitivity.

• Allergic asthma often manifests when a patient is exposed to allergens and tends to develop in early stages of life, while non-allergic asthma usually occurs later in life.

• The gut-lung axis plays a significant role in asthma development, with dysbiosis or other factors potentially contributing to its onset.^[1:16]

• Atopic eczema, which may otherwise be called atopic inflammation, is a disease that affects young children, in particular, with most cases reported in affluent societies.

• The cause of this condition is a disruption of the protective barrier, that is the epidermis and an allergy involving immunoglobulin E.

• The skin lesions are mostly characterized by itching, leaks and papules, which increases the chances of bacterial or viral infections.

• More than 80% of people who develop atopic eczema, later struggle with allergic diseases such as allergic asthma or rhinitis.

• The etiology of atopic eczema is not completely understood and involves both environmental, genetic and allergenic factors.^[1:17]

  • Scientists have begun to look for a link between the disease and changes occurring in the gut microbiome.^[1:18]

• Studies have confirmed the correlation between the occurrence of atopic eczema and changes in the gut microbiome.^[1:19]

• A study comparing the gut bacteria between healthy infants and infants who developed atopic eczema showed that the infants with atopic eczema had bacteria that were not present in the control group, and vice versa.

• Allergic diseases are linked to the diversity of the gut microbiota.

• Infants with atopic eczema have reduced microflora.

  • A significant difference was observed in the presence of Proteobacteria. This microorganism is courted by Gram-negative bacteria with a built-in endotoxin that induces the immune system through T-helper type 1 cells (Th1).
  • There is an increase in IL-12 and dendritic cells, this process favors the occurrence of atopic eczema.
  • There was a significant reduction in Ruminococcaceae bacteria compared to the control group.
  • These bacteria also activate cells of the immune system and stimulate IL-6, among other things.

• There is a lower colonization of Bifidobacterium in children with atopic eczema.

• Those exposed to atopic eczema have a significantly higher number of Enterococci.

• Children with atopic eczema are not deficient in aerobic bacteria such as Lactobacillus.

• There is a significantly higher Campylobacter colonization in children with atopic eczema compared to healthy controls.

  • This relationship may be due to the fact that this bacterium can damage the epithelium, facilitating the passage of Escherichia coli, which can induce colitis/inflammation.

• The opposite observation was made for Roseburia, a bacterium that has a positive effect on protecting the colon, so its decreased numbers can also lead to inflammation and atopic eczema.

• The number of Escherichia coli is correlated with the presence of IgE.

  • Children suffering with atopic eczema have significantly more of these bacteria than the control group.
  • Through the ability to produce Lipopolysaccharide (LPS), this bacterium is virulent, can cause inflammation, increase the permeability of membranes, allowing the penetration of non-threatening antigens, which can cause an excessive immune response and may reduce the number of beneficial bacteria.

• There is a clear relationship between the intestinal microbiota and the occurrence of atopic eczema.

  • This is especially true for differences in the number of types of bacteria, especially the Gram-negative Enterobacteriaceae family and the Gram-positive Ruminococcaceae.
  • These bacteria largely contribute to the activation of the immune system, which increases the likelihood of the appearance of eczema.

The plant-based diet is based mainly on plants such as vegetables, fruits, seeds, oils and so on. Notably, the plant-based diet has a lot of benefits which influence on our health by reducing cholesterol or saturated fatty acids.

• Gut flora plays a crucial role in nutrient metabolism and maintaining immunomodulation.
• Gut flora consists mainly of a set of bacteria which are responsible for controlling digestion and absorbing vital nutrients from foods which are necessary for the health.
• A plant-based diet especially vegan diet, contains more bacteria in gut flora, therefore the gut flora may have more desirable metabolites and other ingredients which will be able to prevent the inflammation.
• Children that regularly eat fruits and vegetables, have decreased chances of developing asthma.
• The consumption of fruits and vegetables may relieve some symptoms of allergic asthma.
• Consuming a plant-based diet may have a significantly reduction in risk of developing allergic asthma.
• Fruits and vegetables contain health-promoting flavonoids, containing antioxidants, which work by inhibiting pro-inflammatory cytokines and influence on not only gut microbiota, but also other cells.
• Some of antioxidants such as vitamin C or E are able to prevent development of oxidative stress and lipid peroxidation which are involved in cellular damage and initiating an excessive cytokine response.
• In the case of atopic dermatitis, there is an overproduction of free oxygen radicals, which causes the development of oxidative stress and intensification of inflammation.
• Plant-based diet can prevent the formation of free radicals because antioxidants are able to inhibit free radicals thereby decreasing the inflammation process in the cells.
• Ther is a direct impact of the composition of the microbiota on the development of various types of allergic diseases.