EAACI 2024: Role of The Gut Microbiome in Food Allergy Potential For Prevention and Treatment

Speaker: Rima A. Rachid

In the 21st century, it's understood that humans are supraorganisms, comprising both human cells and microorganisms in roughly equal measure. While human cells contribute around 20,000 genes, microorganisms contribute up to 46 million. These microorganisms interact with human cells, producing metabolites that can impact health positively or negatively. Research increasingly indicates the significant role of gut microbiota in food allergies. Initial studies comparing the microbiota in healthy individuals and those with food allergies showed differences, supported by murine models and ongoing clinical trials. A pivotal 2019 study in Nature Medicine explored this relationship further, finding persistent dysbiosis in food-allergic individuals up to 20-30 months of age. Certain bacterial taxa were more prevalent in healthy controls than in allergic patients. Further research focused on specific bacteria, particularly 6 Clostridiales species and 5 Bacteroidales species. In mouse models, these bacteria protected anaphylaxis, as evidenced by body temperature stabilization and decreased levels of relevant biomarkers. This protection mechanism involves the upregulation of RoRTY+ Treg cells. While these specific bacteria aren't yet clinically available, fecal microbiota transplantation shows promise. Transplanting stools from healthy infants into allergic mouse models demonstrated reduced anaphylaxis symptoms compared to those receiving stools from allergic infants or no stools. Early microbial composition plays a crucial role, particularly in the low abundance of bifidobacteria and lactobacillus, followed by a bloom of Clostridiales and Bacteroidales species upon solid food introduction. This triggers pathways that regulate immune responses, crucially impacting allergy development. By ages three to four, the microbiome typically resembles that of adults, supporting a healthy intestinal barrier. However, disruptions in this process, leading to increased permeability, may contribute to allergy development.

Regarding treating and preventing food allergies, no strong evidence supports the effectiveness of commercially available probiotics or prebiotics. A study in Australia evaluated the probiotic Lactobacillus rhamnosus ATCC 5310 combined with peanut oral immunotherapy. After 8 weeks, there was no difference in efficacy, defined as no reaction to a cumulative dose of 4,900 mg of peanut protein. However, younger patients experienced fewer side effects, particularly abdominal symptoms and hypersensitivity. Currently, the ADORED study is ongoing. This randomized, placebo-controlled trial assesses the safety and efficacy of the bacterial consortium STMC-103H in preventing allergic diseases in infants. It began with safety trials in older patients and is now testing efficacy in neonates under 14 days old. The study will continue for a year, evaluating eczema and specific IgE levels for milk, egg, peanut, and aeroallergens, though it will not include food challenges.

In Chicago, an ongoing study evaluates a prebiotic administered for one year and oral immunotherapy continued for four years. Another method to manipulate the microbiome is fecal microbiota transplantation (FMT), also known as stool transplant. First documented in 4th century China as "yellow soup," FMT involves placing stool from a healthy donor into a patient's gut to treat specific diseases. It has become the standard treatment for recurrent Clostridium difficile infection (CDI), with a cure rate of 96%, although some patients may need multiple treatments. The FDA has approved two FMT products for preventing recurrent CDI: a spore-like product and one administered by enema. FMT has a strong safety profile, with over 100,000 procedures performed in the US and serious adverse events being rare, typically occurring in severely immunocompromised patients. Donors undergo rigorous screening, with only 1-5% becoming eligible donors after extensive health questionnaires and blood and stool testing, repeated 60 days post-donation. Initially administered via colonoscopy, FMT is now also delivered through NMR, NG tube, NJ tube, and duodenal tube, and since 2014, encapsulated forms have shown similar cure rates to colonoscopy.

The key strength of FMT (fecal microbiota transplantation) compared to a close consortium of bacteria is its ability to transfer beneficial microbes and their intricate supporting ecosystem. Researchers conducted the first study evaluating FMT's role in adult patients with peanut allergies, with a primary objective of assessing safety. They administered universal donor oral encapsulated FMT to subjects aged 18-40, and secondary objectives included increasing the threshold of peanut reactivity during food challenges. The study involved 10 adults aged 18-34 with peanut allergies. They underwent a food challenge followed by FMT, with 36 capsules administered over three hours. Follow-up food challenges were conducted at one month and four months post-FMT. The trial showed no serious adverse events or allergic reactions to FMT, with only minor symptoms in 4 patients resolved within 48 hours. In terms of efficacy, three patients showed increased peanut tolerance. One patient with a high peanut IgE level reacted at 100 mg initially, then tolerated 300 mg at one and 4 months post-FMT. Another patient increased tolerance from 10 to 600 mg, and a third tolerated up to 600 mg from an initial 100 mg reaction. The study also included a cohort pre-treated with antibiotics (oral vancomycin, neomycin, and metronidazole), showing a higher efficacy signal. Among 5 patients, 3 demonstrated increased peanut tolerance, with significant improvements at 4 months post-FMT. Overall, the study found FMT safe, with a 30% efficacy signal without antibiotics and a 60% efficacy signal with antibiotics, persisting for at least 4 months.

In human studies, patients who responded to bacterial therapy showed a significant increase in RoRTY+ Treg cells, which are important for tolerance, and a decrease in effector cells, compared to non-responders. When the stool samples from responders at baseline were introduced to a highly allergic mouse model, significant anaphylaxis occurred, indicating the presence of an intrinsic microbiome. However, stool samples from responders collected 4 months post-FMT provided complete protection against anaphylaxis, a result confirmed by repeating the experiment 3 times. In these responsive mice, there was a reduction in Ovalbumin (OVA) IgE, murine mast cell protease 1, mast cell frequency in the intestine, IL-4 positive CD4 positive T cells, and T follicular helper 13 cells, along with an increase in RoRTY+ Treg cells.

During the session, a phase two, double-blind, randomized, placebo-controlled trial in teenagers with peanut allergies was discussed. This trial involves using a treatment called MTT, a type of fecal transplant that undergoes two additional purification cycles. MTT is highly concentrated in microorganisms and contains less than 1% fecal material. It is encapsulated and stored in the fridge at 4 °C for six months. This is a significant improvement over previous methods, as with FMT, the material had to be stored at minus 80°C and consumed within 90 minutes of thawing. The advantage of MTT is that it can be administered at home, as it only requires five capsules, compared to the 30 capsules needed for FMT due to its high concentration. It makes it particularly attractive for long-term administration. Promising results have been observed in the treatment of conditions such as autism, inflammatory bowel disease, cancer, and GVHD. Even a chocolate formulation is available where the MTT is mixed with chocolate for consumption. A phase two trial is underway in autism, with plans for two more trials, one of which will utilize the sachet formulation. The trial design includes screening visits, with 24 patients randomized to receive either MTT or placebo. Patients will undergo a food challenge, and if they react to 100 mg of peanut protein or less, they will be randomized to receive antibiotics followed by MTT or placebo. The treatment will last 28 days, with five capsules administered under medical supervision after antibiotics, followed by five capsules at home the next day, and then two capsules daily for 26 days. Patients will undergo a food challenge at week four and again at four months post-MTT. Currently, five patients are enrolled, with three more scheduled for screening in June.

European Academy of Allergy and Clinical Immunology (EAACI), 2024 31st May-3rd June, Valencia