Sometimes the end of an intestinal infection is just the beginning of more misery. Of those who contract traveler’s diarrhea, for example, an unlucky few go on to develop irritable bowel syndrome (IBS), a chronic inflammation of the intestinal tract.
Study finds altered gut microbiota in infants with food allergy; oral therapy to replenish bacteria prevented food allergy and suppressed established disease in mice.
Boston, MA — 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, PhD, 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, PhD, 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.
This work was supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (grants 1R56AI117983 and 1R01AI126915), the National Institute of Diabetes and Digestive and Kidney Diseases (grant P30DK056338) the Clinical and Translational Science Center/Harvard Catalyst, the Bunning Food Allergy Fund, the Jasmine and Paul Mashikian Fund, the Massachusetts Life Sciences Center, and a Partners Healthcare Innovations Development Grant.
Brigham Health, a global leader in creating a healthier world, consists of Brigham and Women’s Hospital, Brigham and Women’s Faulkner Hospital, the Brigham and Women’s Physicians Organization and many related facilities and programs. With more than 1,000 inpatient beds, approximately 60,000 inpatient stays and 1.7 million outpatient encounters annually, Brigham Health’s 1,200 physicians provide expert care in virtually every medical and surgical specialty to patients locally, regionally and around the world. An international leader in basic, clinical and translational research, Brigham Health has nearly 5,000 scientists, including physician-investigators, renowned biomedical researchers and faculty supported by over $700 million in funding. The Brigham’s medical preeminence dates back to 1832, and now, with 19,000 employees, that rich history is the foundation for its commitment to research, innovation, and community. Boston-based Brigham and Women’s Hospital is a teaching affiliate of Harvard Medical School and dedicated to educating and training the next generation of health care professionals. For more information, resources, and to follow us on social media, please visit brighamandwomens.org.
Research led by Consortia TX Founders underscores the potential for microbial therapeutics for food allergies
BOSTON–(BUSINESS WIRE)–Consortia TX (the “Company”), a leading early-stage biotherapeutic company developing novel microbial therapies, today announced the publication of comprehensive research into the potential for microbial therapies to prevent and treat human disease and allergies, in the peer-reviewed medical journal, Nature Medicine. The article describes major advances in the science behind the Company’s effort to develop a therapy to treat and prevent food allergies. The article links changes in the microbiome to food allergies in children and overviews the development of consortia of therapeutic microbes that completely suppressed this disorder in a preclinical animal model with detailed analysis of the related host mechanisms underlining the therapeutic effect. Titled “Microbiota Therapy Acts Via a Regulatory T Cell MyD88/RORγt Pathway to Suppress Food Allergy,” the article details extensive research carried out by Talal Chatila M.D., MSc., Lynn Bry M.D., Ph.D., Rima Rachid M.D. and Georg Gerber M.D., Ph.D., the scientific team behind the Company. Consortia TX is now building on the findings in this article to develop its proprietary microbial therapeutic, CTX-944.
“We are thrilled to publish breakthrough research and data focused on the causal links between the microbiome and food allergy, which demonstrated that a live biotherapeutic product has the potential to suppress responses to allergens at the cellular level,” said lead author Talal Chatila, MD, MSc., Co-Founder of Consortia TX, who, with first co-authors Azza Abdel-Gadir, Ph.D., and Emmanuel Stephen-Victor PhD and their colleagues at the Boston Children’s Hospital, undertook the genetic, immunological and microbial therapeutic studies on germ-free and allergy-prone mice and on immune cells of food allergic human subjects.
Food allergies continue to grow in incidence and severity driving a need for better therapeutic approaches given the substantial economic and psychological impacts they have on patients, families and the overall healthcare system. Based on this extensive research, the scientific founders of Consortia TX believe that our microbiome, comprised of an assortment of microorganisms that live ‘in and on us,’ have the ability to fundamentally change cell types to suppress reactions, ultimately training the immune system away from an inflammatory state.
In a clinical study at Boston Children’s Hospital led by Dr. Rima Rachid, an advisor to Consortia TX and co-senior author on the paper, the team carried out serial sampling of the gut bacteria of infants and young children with food allergy and compared results to those of healthy control subjects.
“Our studies confirmed the presence of changes in the gut bacteria of food allergic subjects which, when tested in mouse models, were found critical for the development of disease,” said Dr. Rachid. “The research thus established a link between the disruption of a healthy gut microbiome and the development of food allergy.”
In parallel, co-senior author Dr. Lynn Bry led a team at Brigham and Women’s Hospital that completed the microbiologic portions of the study. “We identified culturable human-origin bacteria that modulate the immune system to become tolerant to food allergens,” said Dr. Bry.
Co-first author Dr. Georg Gerber at Brigham and Women’s Hospital designed computational algorithms to define the temporal dynamics of the microbiota and its relationship to food allergy. “By examining microbiomes at many time-points rather than just one snapshot, our team was able to narrow down the commensal bacteria that may prevent food allergy from hundreds to a short list that we then developed into therapeutic consortia,” said Dr. Gerber.
About Consortia TX, Inc.
Consortia TX, Inc. is a biotherapeutic company developing therapies based on microbes and microbial products to prevent and treat human diseases. The Company’s lead asset, CTX-944, is a live biotherapeutic product for the reversal of food allergy. Consortia TX is built on extensive research conducted by research teams at the Boston-based laboratories of Children’s Hospital and Brigham and Women’s Hospital, both of which are affiliated with Harvard Medical School. Consortia TX has an exclusive global license to intellectual property from the two hospitals related to two microbial therapies detailed in the Nature Medicine paper. The Company was founded in 2017 by Lynn Bry (M.D., Ph.D.), Georg Gerber (M.D., Ph.D.), and Talal Chatila (M.D., M.Sc.) who have equity in Consortia TX and/or receive compensation for their roles, in addition to certain members of the research team. To learn more, please visit www.consortiatx.com.
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Gasthalter & Co.
The role of dysbiosis in food allergy (FA) remains unclear. We found that dysbiotic fecal microbiota in FA infants evolved compositionally over time and failed to protect against FA in mice. Infants and mice with FA had decreased IgA and increased IgE binding to fecal bacteria, indicative of a broader breakdown of oral tolerance than hitherto appreciated. Therapy with Clostridiales species impacted by dysbiosis, either as a consortium or as monotherapy with Subdoligranulum variabile, suppressed FA in mice as did a separate immunomodulatory Bacteroidales consortium. Bacteriotherapy induced expression by regulatory T (Treg) cells of the transcription factor ROR-γt in a MyD88-dependent manner, which was deficient in FA infants and mice and ineffectively induced by their microbiota. Deletion of Myd88 or Rorc in Treg cells abrogated protection by bacteriotherapy. Thus, commensals activate a MyD88/ROR-γt pathway in nascent Treg cells to protect against FA, while dysbiosis impairs this regulatory response to promote disease.