Gut bacteria make neurotransmitters to shape the newborn immune system

Weill Cornell Medicine investigators discovered that unique bacteria colonize the gut shortly after birth and make the neurotransmitter serotonin to educate gut immune cells. This prevents allergic reactions to food and the bacteria themselves during early development.

The preclinical study, published in Science Immunology on Mar. 15, showed that bacteria abundant in the guts of newborns produce serotonin, which promotes the development of immune cells called T-regulatory cells or Tregs. These cells suppress inappropriate immune responses to help prevent autoimmune diseases and dangerous allergic reactions to harmless food items or beneficial gut microbes.

"The gut is now known as the second human brain as it makes over 90 percent of the neurotransmitters in the human body. While neurotransmitters such as serotonin are best known for their roles in brain health, receptors for neurotransmitters are located throughout the human body," explained the study's senior author, Dr. Melody Zeng, an assistant professor of immunology in the Gale and Ira Drukier Institute for Children's Research and the Department of Pediatrics at Weill Cornell Medicine.

Gut Bacteria in Babies Provide a Helping Hand

The researchers observed that the neonatal mouse gut had much higher levels of neurotransmitters, including serotonin, than the adult gut. "So far, almost all studies of gut neurotransmitters were conducted in adult animals or human subjects, where a specific gut cell type called enterochromaffin cells produce neurotransmitters," said Dr. Zeng. "However, we discovered that this isn't the case in the newborn gut where most of the serotonin is made by bacteria that are more abundant in the neonatal gut."

This was also confirmed in babies through a human infant stool biobank that the Zeng lab has established in collaboration with the Neonatal Intensive Care Unit in the NewYork-Presbyterian Alexandra Cohen Hospital for Women and Newborns. These samples were obtained with parental consent and deidentified.

The study results suggest that before the neonatal gut is mature enough to make its own neurotransmitters, unique gut bacteria may supply neurotransmitters that are needed for critical biological functions during early development.

"We found that gut bacteria in young mice not only directly produce serotonin but also decrease an enzyme called monoamine oxidase that normally breaks down serotonin, thus keeping gut serotonin levels high," said the study's lead author Dr. Katherine Sanidad, postdoctoral associate in pediatrics at Weill Cornell Medicine.

The high serotonin levels shift the balance of immune cells by increasing the number of Tregs, which helps prevent the immune system from overreacting and attacking gut bacteria or food antigens. "The neonatal gut needs these serotonin-producing bacteria to keep the immune system in check," Dr. Sanidad added.

Healthy Immune System Helps Later in Life

Dr. Zeng noted that this work underscores the importance of having the right types of beneficial bacteria soon after birth. Babies in developed countries have better access to antibiotics, less exposure to diverse microbes in their clean environments and potentially unhealthy diets that may significantly impact the abundance of serotonin-producing bacteria in their intestines.

As a result, these babies may have fewer Tregs and develop immune reactions to their own gut bacteria, or allergies to food. This may be one reason food allergies have become increasingly common in children, particularly in developed countries. "If educated properly, the immune system in babies would recognize that things like peanuts and eggs are okay, and it doesn't have to attack them," she said. This may also have an impact on developing autoimmune diseases -- when the immune system attacks the body's own healthy cells -- later in life.

The team next plans to look at bacteria in human infant stool samples to measure their production of serotonin, other neurotransmitters and molecules that may help train the immune system to prevent future immune-related diseases, such as allergies, infections and cancer.

"It's essential to understand how the immune system is trained during early life, but this is understudied in newborns and children. Further studies of these developmental periods may hopefully lead us to mitigation approaches to reduce the risk of inflammatory diseases like food allergies and inflammatory bowel disease later in life," Dr. Sanidad said.

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Blindness from some inherited eye diseases may be caused by gut bacteria

Sight loss in certain inherited eye diseases may be caused by gut bacteria, and is potentially treatable by antimicrobials, finds a new study in mice co-led by a UCL and Moorfields researcher.

The international study observed that in eyes with sight loss caused by a particular genetic mutation, known to cause eye diseases that lead to blindness, gut bacteria were found within the damaged areas of the eye.

The authors of the new paper, published in Cell and jointly led by researchers in China, say their findings suggest that the genetic mutation may relax the body's defences, thus allowing harmful bacteria to reach the eye and cause blindness.

The gut contains trillions of bacteria, many of which are key to healthy digestion. However, they can also be potentially harmful.

The researchers were investigating the impact of the Crumbs homolog 1 (CBR1) gene, which is known to be expressed in the retina (the thin layer of cells at the back of the eye) and is crucial to building the blood-retina barrier to regulate what flows in and out of the eye.

The CRB1 gene is associated with inherited eye disease, most commonly forms of Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP); the gene is the cause of 10% of LCA cases and 7% of RP cases worldwide.

Using mouse models, the research team discovered the CRB1 gene is key to controlling the integrity of the lower gastrointestinal tract, the first ever such observation. There, it combats pathogens and harmful bacteria by regulating what passes between the contents of the gut and the rest of the body.

The team found that when the gene has a particular mutation, dampening its expression (reducing its effect), these barriers in both the retina and the gut can be breached, enabling bacteria in the gut to move through the body and into the eye, leading to lesions in the retina that cause sight loss.

Crucially, treating these bacteria with antimicrobials, such as antibiotics, was able to prevent sight loss in the mice even though it did not rebuild the affected cell barriers in the eye.

Inherited eye diseases are the UK's leading cause of blindness in working-age people. Onset of disease may vary from very early childhood to adulthood, but deterioration is irreversible and has lifelong implications. To date, the development of treatments has largely focused on gene therapies.

The findings of this study suggest that simply using antimicrobials might help prevent deterioration in CRB1-associated inherited eye diseases. Future work will investigate whether this applies in humans.

Co-lead author Professor Richard Lee (UCL Institute of Ophthalmology and Moorfields Eye Hospital NHS Foundation Trust) said: "We found an unexpected link between the gut and the eye, which might be the cause of blindness in some patients.

"Our findings could have huge implications for transforming treatment for CRB1-associated eye diseases. We hope to continue this research in clinical studies to confirm if this mechanism is indeed the cause of blindness in people, and whether treatments targeting bacteria could prevent blindness.

"Additionally, as we have revealed an entirely novel mechanism linking retinal degeneration to the gut, our findings may have implications for a broader spectrum of eye conditions, which we hope to continue to explore with further studies."

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Common origin behind major childhood allergies

Several major childhood allergies may all stem from the community of bacteria living in our gut, according to a new study led by researchers at the University of British Columbia and BC Children's Hospital.

The research, published in Nature Communications, identifies gut microbiome features and early life influences that are associated with children developing any of four common allergies -- eczema, asthma, food allergy and/or hay fever. The findings could lead to methods of predicting whether a child will develop allergies, and ways to prevent them from developing at all.

"We're seeing more and more children and families seeking help at the emergency department due to allergies," said Dr. Stuart Turvey, professor in the department of pediatrics at UBC and an investigator at BC Children's Hospital Research Institute, and co-senior author on the study. "Hundreds of millions of children worldwide suffer from allergies, including one in three children in Canada, and it's important to understand why this is happening and how it can be prevented."

The study is one of the first to examine four distinct school-aged pediatric allergies at once. While these allergic diseases each have unique symptoms, the Turvey lab was curious whether they might have a common origin linked to the infant gut microbiota composition.

"These are technically different diagnoses, each with their own list of symptoms, so most researchers tend to study them individually," says Dr. Charisse Petersen, co-senior author on the paper and postdoctoral fellow in the Turvey lab. "But when you look at what is going wrong at a cellular level, they actually have a lot in common."

For the study, researchers examined clinical assessments from 1,115 children who were tracked from birth to age five. Roughly half of the children (523) had no evidence of allergies at any time, while more than half (592) were diagnosed with one or more allergic disorders by an expert physician. The researchers evaluated the children's microbiomes from stool samples collected at clinical visits at three months and one year of age.

The stool samples revealed a bacterial signature that was associated with the children developing any of the four allergies by five years of age. The bacterial signature is a hallmark of dysbiosis, or an imbalanced gut microbiota, that likely resulted in a compromised intestinal lining and an elevated inflammatory response within the gut.

"Typically, our bodies tolerate the millions of bacteria living in our guts because they do so many good things for our health. Some of the ways we tolerate them are by keeping a strong barrier between them and our immune cells and by limiting inflammatory signals that would call those immune cells into action," says Courtney Hoskinson, a PhD candidate at UBC and first author on the paper. "We found a common breakdown in these mechanisms in babies prior to the development of allergies."

Many factors can shape the infant gut microbiota, including diet, how we are born, where we live, and our exposure to antibiotics. For example, antibiotics may wipe out sensitive bacteria, while breastfeeding tends to replenish and provide necessary food for bacteria in the infant gut. The researchers examined how these types of influences affected the balance of gut microbiota and the development of allergies.

"There are a lot of potential insights from this robust analysis," says Dr. Turvey. "From these data we can see that factors such as antibiotic usage in the first year of life are more likely to result in later allergic disorders, while breastfeeding for the first six months is protective. This was universal to all the allergic disorders we studied."

Now the researchers hope to leverage the findings to inform treatments that correct an imbalanced gut microbiota and could potentially prevent allergies from developing.

"Developing therapies that change these interactions during infancy may therefore prevent the development of all sorts of allergic diseases in childhood, which often last a lifetime," says Dr. Turvey.

The research is part of the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study that recruited families through BC Children's Hospital and BC Women's Hospital + Health Centre and other pediatric hospitals across Canada. Since launching in 2008, the team of Canadian researchers has tracked the health, growth and environments of kids from birth and made important discoveries about how asthma and allergies develop.

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How some gut microbes awaken 'zombie' viruses in their neighbors

Some gut bacteria have a spooky superpower: they can reanimate dormant viruses lurking within other microbes.

This viral awakening unleashes full-blown infections that destroy the virus-carrying cells, Howard Hughes Medical Institute Investigator Emily Balskus's lab first published as a preprint on bioRxiv and later in the journal Nature on February 23, 2022. A cryptic molecule called colibactin can summon the killer viruses from their slumber, they found.

Microbes often generate noxious compounds to attack one another within the cramped quarters of the gut. But among these chemical weapons, colibactin appears unusual, says Balskus, a chemical biologist at Harvard University. "It doesn't directly kill the target organisms, which is what we normally think of bacterial toxins doing within microbial communities." Instead, colibactin tweaks microbial cells just so, activating latent -- and lethal -- viruses tucked away in some bacteria's genomes.

Humans have long sought out the potent compounds that microbes produce. "We know a lot about their chemical properties, we purify them in the lab, and we use them as medicine, including antibiotics," says Breck Duerkop, who studies bacterial viruses at the University of Colorado School of Medicine.

But why bacteria make these compounds and what effects they have on neighboring organisms are open-ended questions, says Duerkop, who was not involved in this research. He calls Balskus's teams new work "one step in the right direction."

Chemical dark matter

Scientists have known for years that colibactin can wreak havoc on human cells. Research by Balskus and many others has shown that the compound damages DNA, which can lead to colorectal cancer. But establishing a connection between this compound and disease proved particularly formidable.

In 2006, a French team reported that mammalian cells that encountered the gut bacteria E. coli suffered fatal damage to their DNA. The researchers linked this damage to a cluster of E. coli genes encoding machinery for building a complex molecule. Dubbed colibactin, the molecule was extraordinarily difficult to study. After many tries, researchers simply couldn't isolate it from the E. coli making it.

Colibactin is one of many ephemeral compounds that scientists suspect microbes make. Like invisible particles of dark matter in space, this "chemical dark matter" requires creative means to study. As part of her exploration of the gut's microbial chemistry, Balskus uses indirect approaches to examine these elusive molecules.

Over the past 10 years, her team has probed colibactin by studying the microbial machinery that manufactures it. She and her colleagues have pieced together colibactin's structure and determined that it damages DNA by forming errant connections within the double helix.

Building off this work, scientists elsewhere uncovered a definitive link to cancer: the molecule's distinctive fingerprints appear in genes known to drive colorectal tumor growth.

A role for viruses

Balskus's most recent colibactin study got its start with another disease: COVID-19. Like many other labs, hers had to rearrange things to reduce physical contact among researchers. As part of the reshuffling, postdoc Justin Silpe and graduate student Joel Wong ended up working near one another for the first time. Their conversations led them and Balskus to wonder how colibactin affected other microbes in a crowded gut.

Early on, they found that exposing colibactin-producing bacteria to non-producers had little effect, suggesting that, on its own, the molecule isn't particularly deadly. Silpe and Wong weren't sure if colibactin, a large, unstable molecule, could even enter bacterial cells to damage their DNA. They then wondered if a third party -- bacteria-infecting viruses -- might be involved. Hardly more than bits of genetic information, these viruses can slip into bacteria's DNA and lie quietly in wait. Then, once triggered, they cause an infection that blows up the cell like a landmine.

When the researchers grew colibactin producers alongside bacteria carrying such latent viruses, they saw the number of viral particles spike, and the growth of many virus-containing bacteria drop. That suggested the molecule sparked a surge in active, cell-killing infections. Colibactin does indeed enter bacteria and damage DNA, the team showed. That damage sounds a cellular wake-up bell that rouses the viruses.

Many microbes appeared equipped to protect themselves against colibactin. Balskus's lab identified a resistance gene encoding a protein that neutralizes the compound in a wide variety of bacteria.

Though colibactin clearly has a dangerous side, it may serve as more than just a lethal weapon, Balskus says. For example, both DNA damage and awakened viruses can also induce genetic changes, rather than death, in neighboring bacteria, potentially benefiting colibactin producers.

Balskus's team's discoveries suggest that cancer may be collateral damage caused by whatever else colibactin-producing bacteria are doing. "We always suspected that bacteria made this toxin to target other bacteria in some way," she says. "It didn't make sense from an evolutionary perspective that they acquired it to target human cells."

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Gut bacteria influence brain development

Extremely premature infants are at a high risk for brain damage. Researchers have now found possible targets for the early treatment of such damage outside the brain: Bacteria in the gut of premature infants may play a key role. The research team found that the overgrowth of the gastrointestinal tract with the bacterium Klebsiella is associated with an increased presence of certain immune cells and the development of neurological damage in premature babies.

Complex interplay: the gut-immune-brain axis

The early development of the gut, the brain and the immune system are closely interrelated. Researchers refer to this as the gut-immune-brain axis. Bacteria in the gut cooperate with the immune system, which in turn monitors gut microbes and develops appropriate responses to them. In addition, the gut is in contact with the brain via the vagus nerve as well as via the immune system. "We investigated the role this axis plays in the brain development of extreme preterm infants," says the first author of the study, David Seki. "The microorganisms of the gut microbiome -- which is a vital collection of hundreds of species of bacteria, fungi, viruses and other microbes -- are in equilibrium in healthy people. However, especially in premature babies, whose immune system and microbiome have not been able to develop fully, shifts are quite likely to occur. These shifts may result in negative effects on the brain," explains the microbiologist and immunologist.

Patterns in the microbiome provide clues to brain damage

"In fact, we have been able to identify certain patterns in the microbiome and immune response that are clearly linked to the progression and severity of brain injury," adds David Berry, microbiologist and head of the research group at the Centre for Microbiology and Environmental Systems Science (CMESS) at the University of Vienna as well as Operational Director of the Joint Microbiome Facility of the Medical University of Vienna and University of Vienna. "Crucially, such patterns often show up prior to changes in the brain. This suggests a critical time window during which brain damage of extremely premature infants may be prevented from worsening or even avoided."

Comprehensive study of the development of extremely premature infants

Starting points for the development of appropriate therapies are provided by the biomarkers that the interdisciplinary team was able to identify. "Our data show that excessive growth of the bacterium Klebsiella and the associated elevated ??-T-cell levels can apparently exacerbate brain damage," explains Lukas Wisgrill, Neonatologist from the Division of Neonatology, Pediatric Intensive Care Medicine and Neuropediatrics at the Department of Pediatric and Adolescent Medicine at the Medical University of Vienna. "We were able to track down these patterns because, for a very specific group of newborns, for the first time we explored in detail how the gut microbiome, the immune system and the brain develop and how they interact in this process," he adds. The study monitored a total of 60 premature infants, born before 28 weeks gestation and weighing less than 1 kilogram, for several weeks or even months. Using state-of-the-art methods -- the team examined the microbiome using 16S rRNA gene sequencing, among other methods -- the researchers analysed blood and stool samples, brain wave recordings (e.g. aEEG) and MRI images of the infants' brains.

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