Targeted Microbial Therapies for Food Allergy: Comparison
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Food allergies have been rising in prevalence in recent decades and are also the most common cause of anaphylaxis in children. Food allergies impose significant burdens on patients and families due to the need for specialized diets and constant monitoring for allergens in food, increased healthcare usage, and anxiety related to developing an anaphylactic reaction.

  • microbiome
  • food allergy
  • live microbial therapeutics
  • bacteriotherapy

1. Food Allergy

Food allergies have been rising in prevalence in recent decades and are also the most common cause of anaphylaxis in children [1,2][1][2]. Anaphylaxis is a serious allergic reaction that can be life-threatening and involves various organ systems, including the respiratory tract, gastrointestinal tract, and skin; it is primarily treated with epinephrine administration [3]. Food allergies impose significant burdens on patients and families due to the need for specialized diets and constant monitoring for allergens in food, increased healthcare usage, and anxiety related to developing an anaphylactic reaction [4,5,6][4][5][6]. The main treatments for food allergies include allergen avoidance, treatment of allergic reactions with epinephrine and other medications, and oral immunotherapy [7,8][7][8]. Oral immunotherapy involves oral administration of a food allergen, either in fixed doses or in gradual doses until a maintenance dose is reached [9]. The goal of oral immunotherapy is to desensitize a patient against a food allergen; that is, to increase the threshold dose needed for a patient to develop an allergic reaction to food. There is only one FDA-approved treatment for food allergies, and it is the peanut oral immunotherapy called Palforzia [10]. However, oral immunotherapy is not a cure for food allergies, and discontinuation of immunotherapy usually results in a loss of tolerance to the allergen. In addition to oral immunotherapy, other immunotherapies for food allergies exist, including sublingual and epicutaneous immunotherapy. Oral immunotherapy is the most effective of these, but comes with high rates of adverse events, including allergic reactions and the development of eosinophilic esophagitis [8]. Adjunct therapies to oral immunotherapy to help decrease adverse reactions include the use of monoclonal antibodies, such as omalizumab (anti-IgE) and dupilumab (anti-IL-4Rα) [11,12,13][11][12][13]. Given the few treatment options for food allergies, there is a substantial interest in and need for the new strategies to prevent and treat food allergies.
Food allergies are thought to arise due to a combination of genetic and environmental factors [14,15][14][15]. Genetic association studies have identified some risk alleles for food allergies, particularly in the genes MALT1, FLG, and HLA; these findings implicate genes involved in immune and barrier function in the development of food allergies [16]. Environmental exposures have also been associated with allergy development [17,18,19,20][17][18][19][20]. For example, it has been observed that different dietary exposures can lead to different rates of food allergy acquisition, as seen in discordant peanut allergy rates among genetically similar populations in Israel and the UK who, notably, had different peanut consumption rates [21,22][21][22]. Furthermore, exposure to the farm environment and pets is associated with a decreased risk of allergy development, while exposure to antibiotics and the Western diet increases future allergy risk [18,23,24,25,26][18][23][24][25][26].

2. Targeted Microbial Therapies

2.1. Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) involves the transfer of microbial communities, for example from select healthy donors to recipients with gut dysbiosis. Indeed, FMT has been shown to be effective for treating Clostridioides difficile colitis and represents a promising novel therapeutic strategy for many disorders associated with perturbations of the gut microbiome [121,122,123][27][28][29]. Early experiments by Rodriguez et al. demonstrated that FMT from healthy human infants could protect against cow’s milk allergy in a gnotobiotic mouse model [124][30]. On the other hand, Rivas et al. later showed that increased susceptibility towards food allergies could be imparted onto germ-free mice via microbial transplantation [125][31]. These complementary results emphasize the critical role of the microbiome in food allergies and need for careful selection of FMT donors. Recent preclinical studies have continued to provide promising evidence that healthy human microbiota can protect against food allergy development in mouse models [30,31,126,127][32][33][34][35]. Feehley et al. demonstrated that transplantation of gut microbiota from healthy infants afforded protection against cow’s milk allergy to germ-free recipient mice sensitized to cow’s milk allergen [31][33]. Further studies by Abdel-Gadir et al. similarly showed that healthy donor FMT led to mitigation of food allergy response in mice with increased genetic susceptibility (Il4raF709), whereas this protective effect was not observed following FMT using infant donors with food allergies [30][32]. Clinical trials of FMT for food allergies are being conducted to build upon these promising results. One such study is a phase I open-label trial which recently completed enrollment as of September 2021. It aims to evaluate the safety and efficacy of oral encapsulated FMT for patients with peanut allergy (NCT02960074). Patients in this restudyearch will either undergo FMT alone or FMT with an antibiotic pre-treatment, and they will subsequently undergo a double-blind placebo-controlled food challenge with peanut protein. Although FMT presents a rich avenue for investigating novel therapeutics against food allergies, the potential adverse effects of FMT must be rigorously considered. Severe side effects of FMT have been documented in the literature, such as drug-resistant microbial associated sepsis and unanticipated systemic immune responses [128,129][36][37]. Continued studies will, therefore, be imperative to better characterize the risks associated with FMT for food allergies, as well as to optimize donor and host characteristics for effective therapy.

2.2. Bacteriotherapy

A popular avenue for modulating the gut microbiome is through the introduction of specific bacterial strains thought to have direct beneficial properties and/or to promote healthy microbiome composition and function, in lieu of complete microbiome transplantation. Unlike probiotics, which are regulated as foods, these live microbial products are considered active pharmaceutical ingredients and would be subject to regulation by the FDA [130][38]. Determining which bacterial species would be good candidates for bacteriotherapy for food allergies requires determining the beneficial functionality of the species. Methods include assessing for differential abundance of bacterial species between affected and control groups, in combination with transcriptomics or metabolomics, to identify the microbiota with likely beneficial gene expression or metabolite production seen in healthy controls but not in affected subjects [131,132][39][40]. For example, Feehley et al. paired transcriptomics with differential microbiome composition in infants with and without cow’s milk allergy to identify a bacterial species that protected against food allergies [31][33]. They first determined which bacteria were enriched in healthy infants compared to those with cow’s milk allergy, then determined if the genes upregulated in the microbiota of mice colonized with healthy infant stool were also upregulated in mice colonized with the bacteria that was identified (Anaerostipes caccae) as enriched in healthy infants. Additional factors to consider in picking bacteriotherapy candidates include engraftment of the species in the gut microbiome, which may require antibiotic use prior to administration of bacteriotherapy, as well as prebiotics to encourage growth and retention of these species. In the field of food allergies, various observational studies noted differences in gut microbiota in subjects who have developed food allergies compared to those who did not [30,32,34,36,133,134,135][32][41][42][43][44][45][46]. Not only were there compositional differences in the microbiota, but gene content and metabolomic signatures were also different, suggesting differential functionality of the microbiota between subjects with food allergies and without [31,32,106,133][33][41][44][47]. Various groups have tried to identify specific candidate microbial species with therapeutic potential against food allergies. Atarashi et al. found that a subset of regulatory T-cell-inducing Clostridium species (belonging to clusters IV, XIVa, and XVIII) conferred resistance to colitis and systemic immunoglobulin E response, and demonstrated a protective effect against ovalbumin-induced allergic diarrhea in mice following the oral administration of these Clostridium species [136,137][48][49]. Stefka et al. also showed that colonization of germ-free mice with Clostridium species from clusters IV and XIVa led to a protective effect against sensitization to peanut allergens [36][43]. Abdel-Gadir et al. found that multiple Clostridial taxa were affected in dysbiosis associated with food allergies, and they used bacteriotherapy with a consortium of six Clostridial species to successfully suppress food allergies in sensitized mice [30][32]. They also found they were able to suppress food allergies with phylogenetically distinct microbiota, specifically a consortium of five Bacteroidales species. Furthermore, they were also able to suppress food allergies using a single Clostridial bacterium (Subdoligranulum variabile). Similar to Abdel-Gadir’s group, Feehley et al. were able to identify, using transcriptomics, a single Clostridial species (Anaerostipes caccae) that afforded protection against cow’s milk allergy to germ-free recipient mice [31][33]. Bao et al. expanded on these findings, correlating differential bacterial abundance and metabolites in healthy as compared to allergic twins to identify an additional two Clostridial species (Ruminococcus bromii and Phascolarctobacterium faecium) that could be candidates for bacteriotherapy in food allergies [32][41].

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