The secret to our big brains might be in our gut

Brain tissue is among the most energetically costly in the body, and as a result, larger-brained mammals require more energy to support brain growth and maintenance. Exactly which biological changes allowed human ancestors to meet the very high needs for energy as they evolved larger brains has remained unclear. A new Northwestern University study points to the role of gut microbes, tiny living organisms in our digestive system that help break down food and produce energy.

In a controlled lab experiment, researchers implanted microbes from two large-brain primate species (human and squirrel monkey), and one small-brain primate species (macaque), into mice. Their findings showed the mice with microbes from large-brain primate species produced and used more energy, while those with microbes from the small-brain species stored more energy as fat. The data is the first to show gut microbes from different animal species shape variations in biology between animal species and supports the hypothesis that gut microbes might influence evolution by changing how an animal's body works. The study offers a new perspective on human evolution, particularly the evolution of our large brains. The findings will be published in the journal Microbial Genomics on Dec. 2. Prior studies have compared the influence of genes and the environment on primates with bigger and smallerbrains. However, there are very few studies comparing how different primates use energy. Even less information is available on how metabolism develops in different primate species. "We know the community of microbes living in the large intestine can produce compounds that affect aspects of human biology -- for example, causing changes to metabolism that can lead to insulin resistance and weight gain," said the study's first author Katherine Amato, associate professor of anthropology at Northwestern. "Variation in the gut microbiota is an unexplored mechanism in which primate metabolism could facilitate different brain-energetic requirements," Amato said. After introducing the gut microbes into microbe-free mice, the researchers measured changes in mouse physiology over time, glucose, liver function and other traits. They also measured differences in the types of microbes and the compounds they were producing in each group of mice. The researchers expected to find microbes from different primates would lead to differences in the biology of the mice inoculated with them. They also expected mice with human microbes to have the greatest difference in biology from mice with "While we did see that human-inoculated mice had some differences, the strongest pattern was the difference between large-brained primates (humans and squirrel monkeys) and smaller-brained primates (macaques)," Amato said. The mice given microbes from the humans and squirrel monkeys had similar biology, even though these two larger-brained primate species are not close evolutionary relatives of one another. This suggests something othermicrobes from the other two than shared ancestry -- likely their shared trait of large brains is driving the biological similarities seen in the mice inoculated with their microbes. "These findings suggest that when humans and squirrel monkeys both separately evolved larger brains, their microbial communities changed in similar ways to help provide the necessary energy," Amato said. In future studies, the researchers hope to run the experiment with microbes from additional primate species varying in brain size. They would also like to collect more information on the types of compounds the microbes are producing and gather additional data on the biological traits of the hosts such as immune function and behavior.species.including weight gain, fat percentage, fasting

New therapy targets gut bacteria to prevent and reverse food allergies

New therapy targets gut bacteria to prevent and reverse food allergies

A new study 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.

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.

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Materials provided by Brigham and Women's Hospital. Note: Content may be edited for style and length.