Food allergies could reverse by targeting gut bacteria


Every three minutes, a food-related allergic reaction sends someone to the emergency room in the U.S. Currently, the only way to prevent a reaction is for people with food allergies to completely avoid the food to which they are allergic.

Researchers are actively seeking new treatments to prevent or reverse food allergies in patients.

Recent insights about the microbiome – the complex ecosystem of microorganisms that live in the gut and other body sites – have suggested that an altered gut microbiome may play a pivotal role in the development of food allergies.

A new study, led by investigators from Brigham and Women’s Hospital and Boston Children’s Hospital, identifies the species of bacteria in the human infant gut that protect against food allergies, finding changes associated with the development of food allergies and an altered immune response.

In preclinical studies in a mouse model of food allergy, the team found that giving an enriched oral formulation of five or six species of bacteria found in the human gut protected against food allergies and reversed established disease by reinforcing tolerance of food allergens.

The team’s results are published in Nature Medicine.

“This represents a sea change in our approach to therapeutics for food allergies,” said co-senior author Lynn Bry, MD, Ph.D., director of the Massachusetts Host-Microbiome Center at the Brigham.

“We’ve identified the microbes that are associated with protection and ones that are associated with food allergies in patients.

If we administer defined consortia representing the protective microbes as a therapeutic, not only can we prevent food allergies from happening, but we can reverse existing food allergies in preclinical models.

With these microbes, we are resetting the immune system.”

The research team conducted studies in both humans and preclinical models to understand the key bacterial species involved in food allergies.

The team repeatedly collected fecal samples every four to six months from 56 infants who developed food allergies, finding many differences when comparing their microbiota to 98 infants who did not develop food allergies.

Fecal microbiota samples from infants with or without food allergies were transplanted into mice who were sensitized to eggs.

Mice who received microbiota from healthy controls were more protected against egg allergy than those who received microbiota from the infants with food allergies.

Using computational approaches, researchers analyzed differences in the microbes of children with food allergies compared to those without in order to identify microbes associated with protection or food allergies in patients.

The team tested to see if orally administering protective microbes to mice could prevent the development of food allergies.

They developed two consortia of bacteria that were protective.

Two separate consortia of five or six species of bacteria derived from the human gut that belong to species within the Clostridiales or the Bacteroidetes could suppress food allergies in the mouse model, fully protecting the mice and keeping them resistant to egg allergy.

Giving other species of bacteria did not provide protection.

“It’s very complicated to look at all of the microbes in the gut and make sense of what they may be doing in food allergy, but by using computational approaches, we were able to narrow in on a specific group of microbes that are associated with a protective effect,” said co-first author Georg Gerber, MD, Ph.D., MPH, co-director of the Massachusetts Host-Microbiome Center and chief of the Division of Computational Pathology in the Department of Pathology at the Brigham.

“Being able to drill down from hundreds of microbial species to just five or six or so has implications for therapeutics and, from a basic science perspective, means that we can start to figure out how these specific bacteria are conferring protection.”

To understand how the bacteria species might be influencing food allergy susceptibility, the team also looked at immunological changes, both in the human infants and in mice.

They found that the Clostridiales and Bacteroidetes consortia targeted two important immunological pathways and stimulated specific regulatory T cells, a class of cells that modulate the immune system, changing their profile to promote tolerant responses instead of allergic responses.

These effects were found both in the pre-clinical models and also found to occur in human infants.

The new approach represents a marked contrast to oral immunotherapy, a strategy that aims to increase the threshold for triggering an allergic reaction by giving an individual small but increasing amounts of a food allergen.

Unlike this approach, the bacteriotherapy changes the immune system’s wiring in an allergen-independent fashion, with potential to broadly treat food allergies rather than desensitizing an individual to a specific allergen.

“When you can get down to a mechanistic understanding of what microbes, microbial products, and targets on the patient side are involved, not only are you doing great science, but it also opens up the opportunity for finding a better therapeutic and a better diagnostic approach to disease.

With food allergies, this has given us a credible therapeutic that we can now take forward for patient care,” said Bry.

Bry and Gerber, along with senior author Talal Chatila, MD, of Boston Children’s Hospital, are founders and have equity in ConsortiaTX, a company that is developing a live human biotherapeutic product (CTX-944).

(Co-senior author Rima Rachid, MD, of Boston Children’s Hospital, also has equity in the company.) ConsortiaTX is preparing for a Phase 1b trial in pediatric food allergy, followed by expansion into additional allergic diseases.

ConsortiaTX has obtained an exclusive global license to the intellectual property related to the microbial discoveries published in the Nature Medicine paper.

During the last several decades, a changing patterns in the epidemiology of food allergy [FA] have been observed, with an increased prevalence, severity of clinical manifestations, and risk of persistence until later ages [1].

Atopic family history, ethnicity, atopic dermatitis (AD), and related genetic polymorphisms have been associated with FA development [2].

Although genetic factors may predispose individuals to the development of FA among selected individuals, they cannot explain the changes in epidemiology over this short time frame, suggesting that environmental factors promote FA [3].

FA develops following loss of immune tolerance, which results in allergic sensitization and subsequent disease manifestation and progression.

The initial exposure to food allergens occurs predominantly via the gastrointestinal tract or skin.

An impaired skin barrier could lead to increased transcutaneous passage of antigens and subsequent sensitization.

An association between the early onset of AD and development of FA has been shown [4].

In the gastrointestinal tract, the two main factors influencing immune tolerance are dietary factors and microbiota composition and function [5].

Kim et al. demonstrated that under normal physiological conditions, macromolecules from the diet induce the bulk of regulatory T cells (Tregs) development, which is essential for suppressing a default immune response to dietary antigens [5].

Observational studies have suggested that the early introduction of peanut [6], egg [7], or cow’s milk [8] may prevent the development of allergy to these foods.

A randomized controlled trial (Learning Early about Peanut Allergy, LEAP) showed that the early consumption of peanut in high-risk infants with severe eczema, egg allergy, or both reduced the development of peanut allergy by 80% by 5 years of age [9].

The Persistence of Oral Tolerance to Peanut (LEAP-On) study showed that the absence of reactivity is maintained in these subjects [10].

The gut microbiota could be defined as the trillions of microbes that collectively inhabit the gut lumen [4,11], and increasing evidence shows that altered patterns of microbial exposure [dysbiosis] early in life can lead to FA development by negatively influencing immune system development [12].

Thus, the gut microbiota could be considered a potential target for preventive and therapeutic intervention against FA. Recent studies have reported the efficacy of intervention in the gut microbiota against FA.Here, we review the current understanding of the potential role of gut microbiota as potential target against FA.

Importance of Microbial Exposure for the Development of Immune Tolerance

Immune tolerance is the state of unresponsiveness of the immune system to substances or tissues that have the potential to induce an immune response. Tolerance is achieved through both central tolerance and peripheral tolerance mechanisms [13].

The exact mechanisms involved in the development of immune tolerance have not been not fully defined [14].

Current evidence suggests that the gut microbiota and its metabolites (mainly short chain fatty acids), together with to exposure to dietary factors in early life, critically influence the establishment of immune tolerance to food antigens [5] (Figure 1).

Germ-free mice are unable to achieve immune tolerance to food antigens [15]. During the early stage of post-natal life, development of the gut microbiota parallels maturation of the immune system [16].

During vaginal delivery, infants receive their first bacterial inoculum from the maternal vaginal tract, skin tissue, and often fecal matter, exposing the immature immune system of newborns to a significant bacterial load [17].

Maturation of a healthy gut microbiota in early life allows for a change in the Th2/Th1 balance, favoring a Th1 cell response [18], while dysbiosis alters host-microbiota homeostasis, favoring a shift in the Th1/Th2 cytokine balance toward a Th2 response [19].

Gut microbes induce the activation of Tregs which are depleted in germ-free mice [20].

Microbiota-induced Tregs express the nuclear hormone receptor RORγt and differentiate along a pathway that also leads to Th17 cells; while in the absence of RORγt in Tregs, there is an expansion of GATA-3-expressing Tregs, as well as conventional Th2 cells, and Th2-associated pathology is exacerbated [21].

Moreover, it has been demonstrated that under normal physiological conditions, macromolecules obtained via the diet induce Treg cell development in the small intestinal lamina propria, which is essential for suppressing the default strong immune response to dietary antigens [5]. The presence of both diet- and microbe-induced populations of Treg cells may be required to induce complete tolerance to food antigens [5].

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Figure 1
Immune tolerance network in the intestinal lumen: interaction between microbiome and the gut immune system in early-life. The immune tolerance network is mainly composed by the well-modulated activity of different components: gut microbiota (without gut microbiota, it is not possible to achieve oral tolerance); dietary factors (mainly dietary peptides, as amino acids are unable to drive immune tolerance); epithelial cells; dendritic cells; and regulatory T cells. Food antigens and intestinal microbiota constitute the majority of the antigen load in the intestine. CX3CR1+ cells (likely macrophages) extend dendrites between intestinal epithelial cells, sample antigens in the gut lumen, and transfer captured antigens via gap junctions to CD103+CCR7+dendritic cells (DCs). This subset of DCs migrates from the lamina propria to the draining lymph nodes, where the DCs express transforming growth factor-β (TGFβ), retinoic acid (RA), interleukin-10 (IL-10) and also express the enzyme indoleamine 2,3-dioxygenase (IDO), thereby inducing naïve CD4+ T cells to differentiate into regulatory T (Treg) cells. Macrophages also appear to secrete IL-10, leading to Treg cell proliferation. Treg cell express integrin α4β7, which results in homing to the gut where Treg cells may dampen the immune response. CD103+ DCs also sample antigens that pass through the epithelial barrier via M cell-mediated transcytosis or by extending a process through a transcellular pore in an M cell. Recent evidence suggests a role for regulatory B cells in activating Tregs after stimulation with microbial factors recognized by Toll-like receptors. B cell clones expressing antibodies specific for food allergen may undergo isotype switching in secondary lymphoid organs with the aid of follicular T helper (TFH) cells. Food tolerance is associated with IgA. For a broader prospective, the complex interaction between intestinal contents and immune and non-immune cells creates an environment that favors tolerance by the inducting IgA antibodies and Tregs, which produce IL-10, a molecule crucial for the induction of tolerance to food antigens.

It has been speculated that microbiota can activate MyD88 signaling in the lamina propria and follicular dendritic cells (DCs) [22].

Mucosal plasma cells, upon induction by DCs, produce secretory IgA (sIgA). The sIgA system is considered important in the pathogenesis of FA.

Delayed development of IgA-producing cells or insufficient sIgA-dependent function at the intestinal surface barrier appears to contribute substantially to FA [21].

This agrees with previous study of minor dysregulations of both innate and adaptive immunity (particularly low levels of IgA) in children with multiple FAs [23].

Furthermore, the gut microbiota stimulates DCs in the Peyer’s patches to secrete transforming growth factor (TGF)-β, C-X-C motif chemokine ligand 13, and B-cell activating protein, which leads to IgA production and class switching [24].

Accordingly, it has been recently demonstrated that dietary elements, including fibers and vitamin A, are essential for the tolerogenic function of CD103+ DCs and maintenance of mucosal homeostasis, including IgA production and epithelial barrier function [25].

Moreover, in experimental studies, some mice are protected from the development of FA (non-responders) compared with animals showing marked systemic FA symptoms after immunizations [26,27].

This differential immune response is associated with a distinct microbiota composition in mice with a non-responding phenotype [28]. Recent findings have also suggested that neonatal gut microbiome dysbiosis promotes CD4+ T cell dysfunction associated with allergy [29] and supports age-sensitive interactions with microbiota [30].

Early-life may be a key “window of opportunity” for intervention given the age-dependent association of the gut microbiome and FA outcomes [31].

The microbiota also promotes B cell receptor editing within the lamina propria upon colonization [32].

Regulatory B (Breg) cells are characterized by their immunosuppressive capacity, which is often mediated by interleukin (IL)-10 secretion, but also IL-35 and TGF-β production [33].

An additional immunoregulatory role is the up-regulation of IgG4 antibodies during differentiation to plasma cells.

Several studies have demonstrated a potential role for Breg in the induction and maintenance of the tolerance mechanism [34,35,36].

Several types of Bregs with distinct phenotypic characteristics and mechanisms of suppression have been described [34,35,36]; therefore, additional studies are necessary to understand the effective role of Bregs in oral tolerance.

In addition, there is a body of data reporting the activation of non-immune pathways in food oral tolerance. Data suggest that a healthy gut microbiota may protect against allergic sensitization by affecting enterocyte function and regulating its barrier-protective properties. Similarly, innate lymphoid cells (ILCs) that are abundant in mucosal and barrier sites are involved in these defence mechanisms [37].

While several subsets of ILCs have been identified, particular attention has been given to ILC3 and its interactions with the microbiota.

Among other factors, these cells produce IL-22, a cytokine of central importance in maintaining tissue immunity and physiology via its pleiotropic action in promoting antimicrobial peptide production, enhancing epithelial regeneration, increasing mucus production, and regulating intestinal permeability [38].

How the microbiota affects the turnover of ILC3 remains unclear, but recent evidence supports that defined commensals preferentially impact this subset.

Particularly, Clostridia-induced IL-22 has been demonstrated to be an innate mechanism by which the microbiota can regulate the permeability of the epithelial barrier and contribute to protection against food allergen sensitization [15].

In contrast, gut microbiota dysbiosis induces alterations in intestinal epithelial function resulting in aberrant Th2 responses toward allergic, rather than tolerogenic, responses [39].

More information: Microbiota therapy acts via a regulatory T cell MyD88/RORγt pathway to suppress food allergy, Nature Medicine (2019). DOI: 10.1038/s41591-019-0461-z ,

Journal information: Nature Medicine
Provided by Brigham and Women’s Hospital


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