Researchers have found a possible link between the gut microbiome in infants and development of allergies

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A team of researchers affiliated with several institutions in Korea and Australia have found a possible link between the gut microbiome in infants and development of allergies.

In their paper published in the journal Science Advances, the group describes their study of a certain antibody response in young mice and what they found.

Food allergies have been widely reported in the past few years, particularly in children.

Scientists have been taking a closer look at the causes of the seemingly sudden rise in the number of people who are allergic to certain foods.

In this new effort, the researchers looked into the possibility of a connection between food allergies and the gut biome.


Allergic diseases, include heterogeneous inflammatory pathologies such as respiratory and food allergies (FA), which are characterized by an immunological response with T lymphocytes producing IL-4, IL-5, and IL-13 and low production of IFN-γ (Th2) (1) and others producing IL-9 and IL-10 (Th9) (2) as the main effector T cells. They promote the induction of other effector cells involved in allergic inflammation, such as mast cells, basophils, and eosinophils (1). These diseases have dramatically increased in prevalence over the last few decades (36) and recent research points to a central role of the microbiota (78). It is well established that the microbiome can modulate the immune response, from cellular development to organ and tissue formation (9) exerting its effects through multiple interactions with both the innate and acquired branches of the immune system. In the late 80s, Dr. Strachan proposed what is now referred to as the “hygiene-hypothesis” (10), in which changes in environment and nutrition produce a dysbiosis in the skin, gut, or lung microbiome inducing qualitative and quantitative changes in composition and metabolic activity (1112). Furthermore, it was proposed that a lower incidence of infection in early childhood, which may be associated with low microbiota diversity, could explain the increase in prevalence of atopic diseases (13). It should be pointed out that the hygiene hypothesis has not been found to apply to individual hygiene [no relation between personal or home cleanliness and increased risk of asthma or allergy has been found (14)], but to independent host factors such as number of older siblings, contact with pets and rural versus urban living, all of which have been shown to affect microbiome composition and the development of immunologic tolerance (15). Today, the use of bacterial culture-independent tools such as next-generation sequencing to identify different microbes has permitted the investigation of complex populations and their roles in health and disease. Here, we review the potential role of the skin, respiratory, and gastrointestinal tract (GIT) microbiomes in allergic diseases.Go to:

Microbiome

The term “microbiome” refers to the microorganisms that live on or inside another organism.

They interact with each other and with their host and can be classified as beneficial (symbiotic) or dangerous (pathogenic) (16).

Microbiome in humans can account for 90% of the cells by a ratio of 10:1 (17).

New studies point out that the number of bacteria in the body is of the same order as the number of human cells (18).

Most of these microorganisms inhabit the gut.

The microbiome effectively adds a huge amount of genes to the human genome, potentially increasing it up to 200 times (19).

As a result, the composition of the human microbiome could be important in the context of health or disease.

They interact with each other and with their host and can be classified as beneficial (symbiotic) or dangerous (pathogenic) (16).

Microbiome in humans can account for 90% of the cells by a ratio of 10:1 (17).

New studies point out that the number of bacteria in the body is of the same order as the number of human cells (18).

Most of these microorganisms inhabit the gut.

The microbiome effectively adds a huge amount of genes to the human genome, potentially increasing it up to 200 times (19).

As a result, the composition of the human microbiome could be important in the context of health or disease.

Microbiome in humans can account for 90% of the cells by a ratio of 10:1 (17).

New studies point out that the number of bacteria in the body is of the same order as the number of human cells (18).

Most of these microorganisms inhabit the gut.

The microbiome effectively adds a huge amount of genes to the human genome, potentially increasing it up to 200 times (19).

As a result, the composition of the human microbiome could be important in the context of health or disease.

Human Gut Microbiome and Implications in Food Allergy

The GIT has a very important immune function in developing either effector or tolerant responses to different antigens by balancing the activities of Th1 and Th2 cells as well as regulating Th17 and T regulatory (Treg) cells in the lamina propria (2023).

Immune dysfunction in allergic diseases such as asthma and atopy seems to be related to differences in the function and composition of the gut microbiome (24).

The gut microbiome constitutes a highly complex ecosystem which includes eukaryotic fungi, viruses, and some archaea, although bacteria are the most prominent components (25).

Its composition is generally formed during the first 3 years of life (26); however, recent work has suggested that its colonization may begin in utero (27), contrary to the widely held dogma of the fetus as a sterile environment.

Despite its early formation, its composition is highly dynamic and dependent on host-associated factors such as age, diet, and environmental conditions (262831) with the major phyla being Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria.

The gut microbiome is not homogeneous throughout the GIT, showing higher diversity in the oral cavity and intestine, and lower diversity in the stomach, mainly because of the acid environment (32).

Aerobic species are mainly located in the upper small intestine and anaerobic species in the colon (33).

Most antigens in the GIT come from dietary factors and gut microbiota, both of which can affect immune tolerance being the promotion of Treg cells to these dietary factors crucial to avoid an immune response to dietary antigens (34).

Alterations in GIT bacterial levels or diversity (dysbiosis) can disrupt mucosal immunological tolerance, leading to allergic diseases including FA (35) and even asthma (3638).

Moreover, low IgA levels at the intestinal surface barrier can also contribute to FA. In fact, low microbiota levels and IgA appear to be related: gut microbiota can stimulate dendritic cells (DCs) in the Peyer’s patches (digestive type of mucosa lymphoid-associated tissue) to activate B cells, leading to specific IgA antibodies production through class switching (39).

This stimulation may occur through the production by members of the microbiome of metabolites, such as short chain fatty acids (SCFAs).

Thus, the immune tolerance network in the intestinal lumen can be considered to include the gut microbiota, their metabolic products, dietary factors, epithelial cells, DCs, IgA antibodies, and regulatory T cells (Figure ​(Figure1).

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Figure 1
Interaction between gut microbiota and immune system. Gut microbiota metabolites and dietary factors constitute the main antigen load of the gastrointestinal tract. Macrophages (CXCR1+) and dendritic cells (DCs) are stimulated and T regulatory (Treg) cells are activated by metabolic products such as short chain fatty acid (SCFA). Follicular T cells activate B cells inducing the production of IgA antibodies.

Several factors associated with dysbiosis may influence FA, such as cesarean versus vaginal delivery (40), low versus rich fiber diet (41), breastfeeding (42), and/or early-life-antibiotic exposure, all of which affect bacterial load and diversity.

Once thought to be almost sterile, the esophagus has been shown to comprise around 300 bacteria species. Significant differences in the microbial composition of children with active esophageal inflammation caused by eosinophilic esophagitis compared with controls have been reported (43). Importantly, both the degree of inflammation and the treatment regimen seem to impact the esophageal microbiota (43).

Human Lung Microbiome and Implications in Respiratory Allergy

As with the esophagus and fetus, the lung has long been thought of as sterile; however, recent evidence has shown it to harbor various bacteria phyla, including Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria, even in healthy subjects (44).

Similar to the gut, the lung microbiome changes rapidly in the first years of life, before beginning to stabilize (4546).

Colonization occurs gradually in healthy children, starting with Staphylococcus or Corynebacterium, followed by Moraxella or Alloiococcus (46).

A breakdown in the development of the commensal population can lead to dysregulation of the IgE–basophil axis, with elevated serum IgE concentrations and increased of circulating basophil populations as has been described in murine models of allergic airway disease (47).

Importantly, this link was found to be B-cell intrinsic and dependent on the MYD88 pathway.

Moreover, the lung microbiome may also play a role in driving asthma endotype polarization, by adjusting the balance between Th2 and Th17 patterns. Enterococcus faecalis can suppress Th17 immunity and symptoms of allergic airway disease, and thus it has even been considered a potential therapeutic agent for both asthma and Th17 immunity (48).

Differences in levels and diversity of the lung microbiome have been found between healthy people and patients with asthma and allergic diseases, with an increase of Proteobacteria in the latter; moreover, their presence has been linked to increased severity of asthma probably through the upregulation of Th17-related genes (4950).

Early colonization with Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae has been associated with recurrent wheezing and asthma (45465152).

Importantly, as well as bacteria, viruses will also influence asthma development, as has been demonstrated with human rhinovirus infections of the nasopharynx in early-life (46).

In addition, other associations such as helminths may be protective for asthma, as helminth infections have been shown to increase the microbiota diversity (53).

Associations have been found between the composition of the lung and gut microbiome and the risk of respiratory allergic disease development (54) indicating that both gut and lung mucosa may function as a single organ, sharing immunological functions (44).

Skin Microbiome and Cutaneous Allergic Diseases

Bacterial dysbiosis is associated with chronic inflammatory disorders of the skin, such as atopic dermatitis (AD) and psoriasis (55).

The composition of the skin microbiota depends on the body site samples (56).

The relevance of AD, often associated with other allergic diseases, has significantly increased in the last few decades. Outgrowths of Staphylococcus and reductions of other communities like Streptococcus or Propionibacterium species correlate with AD flares (57). On the other hand, skin commensal Acinetobacter species have been reported to protect against allergic sensitization and inflammation, playing an important role in tuning the balance of Th1, Th2, and anti-inflammatory responses to environmental allergens (58).

Interestingly, studies of cutaneous allergic diseases have found an association with gut microbiome dysbiosis (59), although the underlying mechanisms are still unclear. An initial study of 90 patients with established AD found enrichment for Faecalibacterium prausnitzii and decreased levels of SCFAs in the gut (60).

Therefore, we can summarize that changes in environment and diet produce dysbiosis in gut, skin, and/or lung microbiome inducing qualitative and quantitative changes in the microbiota which directly affect the immunological mechanisms implicated in the prevention of allergic diseases (Figure ​(Figure2).

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Figure 2
Dysbiosis induce qualitative and quantitative changes in the microbiota that directly affect immunological mechanisms leading to allergic diseases.

The research started after some team members noticed that lab mice raised in a sterile environment (who also had no gut microbiome) expressed higher levels of immunoglobulin E (IgE) when they matured enough to start eating solid food.

Prior research has shown that IgE is a mediator that plays a role during an allergic response – when allergens are detected, IgEs send out signals alerting other parts of the immune system, which in turn release chemicals that result in inflammation, a major allergy symptom.

To find out why the sterile mice were producing more of the antibodies, the researchers separated a group of mice into two sub-groups – one group was fed a normal diet while the other was put on a special diet designed not to provoke the immune system.

They report that the mice who ate the normal diet developed a normal immune response, while those on the special diet did not.

Suspecting that the lack of a normal healthy gut microbiome could be linked to an immune response triggered by certain foods, the team tried delaying the introduction of normal food for those mice on the special diet.

Possible link found between gut microbiome in infants and development of allergies
Food antigens drive spontaneous IgE elevation in the absence of commensal microbiota. Studies with germ-free (GF) mice fed an elemental (antigen-free) diet (designated as antigen-free mice) revealed that spontaneous IgE elevation in GF and antibiotics-treated mice is driven by food antigens through the generation of IL-4-producing TFH cells in gut-associated lymphoid tissues, Peyer’s patches and mesenteric lymph nodes (MLNs). Early life is highly favorable for TFH cell generation in response to food antigens. Credit: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea

They report that doing so led to less of an increase in IgE production.

A closer look showed that T follicular helper cells were involved in the heightened immune response.

Such cells are generally more prevalent in young mice (and children).

The researchers claim this is why children are more prone to allergic episodes than adults.

The researchers also found that if they let the diet-restricted mice mingle with the mice on a normal diet, the restricted mice stopped producing high numbers of T follicular helpers and IgE numbers fell.

More information: Sung-Wook Hong et al. Food antigens drive spontaneous IgE elevation in the absence of commensal microbiota, Science Advances (2019). DOI: 10.1126/sciadv.aaw1507

Journal information:Science Advances

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