The findings, published in Communications Biology, suggest that specific gut bacteria are important in early life for healthy immune development.

Changes resulting from living in industrialized populations affect infant gut bacteria, reducing Bifidobacterium strains important for health. Factors including feeding mode and antibiotic use influence these bacteria and may impact childhood health, but the exact long-term effects aren’t yet well understood.

John Jarman at the University of Rochester School of Medicine and Dentistry in New York and his colleagues set out to examine the gut microbiota of US infants during their first 100 days to understand its impact on immune health.

Altered metabolism

The researchers collected stool samples from infants aged 1 to 3 months from most US states. They found an average of 12 types of bacteria in infants, which is fewer than adults have. About 24% of babies, especially those born through a C-section, lacked bacteria such as Bifidobacterium, which are important for healthy growth. In contrast, babies born vaginally or breastfed tended to have more of these good bacteria. C-section babies who were breastfed sometimes also had more potentially harmful bacteria such as Clostridium perfringens. 

Bifidobacterium, especially B. infantis, are the main bacteria that use specific sugars in breast milk, helping the baby’s immune system and gut to develop properly. Infants with higher levels of Bifidobacterium could digest these sugars better than those who lacked it. 

Infants lacking Bifidobacterium showed changes in important metabolic processes such as bile acid metabolism, vitamin production, and a shift toward producing more butyrate, which has been linked to certain harmful microbes. They also had less of some beneficial immune molecules and more genes linked to antibiotic resistance.

Lifelong impact

At two years old, more than half of the infants had taken antibiotics, and about 30% had conditions such as eczema or asthma. Babies with lower levels of Bifidobacterium were about three times more likely to develop these immune-related problems compared to those with more Bifidobacterium.

The presence of B. breve was linked to a much lower risk of allergic conditions, and specific bacterial genes—including genes from viruses that infect bacteria—were associated with higher risk. 

These results suggest that the makeup of the infant gut microbiota plays an important role in the development of allergies, the authors say. “Given the alarming rise in [non-communicable diseases] and their link to the infant gut microbiome, the gut microbiota offers an opportunity for early intervention with lifelong health impact.”

What is already known on this topic
Over the past decades, scientists have linked the gut microbiota to dozens of seemingly unrelated conditions — from depression to obesity. Asthma has some connections as well: babies born by cesarean section have an increased risk of developing asthma compared to those born by vaginal delivery and also have an altered gut microbiota composition. Scientists also know that children who grow up on a farm tend to be protected from asthma—a phenomenon that has been attributed to the exposure to a variety of environmental microbiota in animal sheds. But the mechanisms through which the gut microbiota could have an asthma-protective effects remain unclear.

What this research adds
Two independent research groups have assessed the role of gut microbes in protecting children from asthma. One team found that children born by cesarean section whose gut microbiota profile at one year of age remained similar to that at birth had an increased risk of developing asthma compared to babies born by vaginal delivery. The second team found that children with high levels of microbial metabolites such as butyrate in their stool have a reduced risk of asthma.

Conclusion
Findings from both studies suggest a key role for gut microbes in asthma protection, potentially through the production of metabolites such as butyrate.

Asthma affects millions of children already at a young age, but the risk factors for the condition are poorly understood. Now, two studies show that gut microbes could play an important role in protecting children from asthma—a finding that could lead to new strategies to prevent the condition by manipulating the microbiota.

Over the past decades, scientists have linked the gut microbiota to dozens of seemingly unrelated conditions — from depression to obesity. Asthma has some connections as well: babies born by cesarean section have an increased risk of developing asthma compared to those born by vaginal delivery and also have an altered gut microbiota composition.

Scientists also know that children who grow up on a farm tend to be protected from asthma—a phenomenon that has been attributed to the exposure to a variety of environmental microbiota in animal sheds. However, the mechanisms through which the gut microbiota could have an asthma-protective effects remain unclear.

Delivery matters

To assess the role of gut microbes in protecting children from asthma, researchers led by Søren Sørensen and Hans Bisgaard at the University of Copenhagen followed 700 children from birth and examined the effects of cesarean section delivery on gut microbial composition during the first year of life. The team then explored whether gut microbial perturbations due to delivery mode were associated with a risk of developing asthma in the first six years of life.

The researchers examined the children’s stool samples at one week, one month and one year to determine microbial diversity and maturity. They found that delivery by caesarean section was associated with substantial changes in the composition of the gut microbiota.

Babies born by cesarean section whose gut microbiota profile at one year of age remained similar to that at birth had an increased risk of developing asthma and allergies compared to babies born by vaginal delivery. Babies who had gut microbiota perturbations that occurred at birth but resolved by one year of age weren’t more at risk of asthma than those born by vaginal delivery.

“Every generation of mothers hands over its microbiome to the next, as the baby is coated with beneficial germs while being squeezed through the birth canal – but this doesn’t happen for babies born through C-section,” says study co-author Martin Blaser. “It takes a while for babies born through C-section to develop a normal microbiome. And during that time, while the immune system is also developing, they become more at risk for later developing certain diseases like asthma,” he says.

The study shows that delivery by caesarean section interferes with a baby’s ability to obtain beneficial germs from the mother’s microbiota, and it provides a mechanism for the association between cesarean section birth and increased risk of asthma, Blaser says.

The findings, published in Science Translational Medicine, could lead to new prevention strategies, including targeted efforts to fix disturbances in a child’s microbiota. “This study has implications for understanding the microbiota’s role in asthma development after delivery by caesarean section and could in the future potentially lead to novel prevention strategies and targeted, efficient microbiota manipulation in children who had early perturbations of the microbiome” Sørensen says.

Farm life

In a second study, researchers led by Markus Ege at Ludwig Maximilian University followed children growing up in European rural areas.

Previous research from the same group showed an asthma-protective effect by a diverse environmental microbiota, which was particularly pronounced in farm children. To assess whether the effect could be attributed to the maturation process of the early gut microbiota, the researchers analyzed fecal samples from more than 800 children aged 2 and 12 months growing up on traditional farms in Austria, Germany, Finland and Switzerland.

The team found that children with high levels of microbial metabolites such as butyrate in their stool have a reduced risk of asthma. Butyrate is a short chain fatty acid which is known to protect mice from asthma. Bacteria such as Roseburia and Coprococcus, which produce short chain fatty acids, may contribute to asthma protection in people. Indeed, at 12 months, children who were never affected by wheeze or asthma showed increases in bacterial species such as Ruminococcus, Roseburia, and Coprococcus compared to other children.

“We found that a comparatively large part of the protective farm effect on childhood asthma was mediated by the maturation of the gut microbiome in the first year of life,” says study co-author Martin Depner. “This suggests that farm children are in contact with environmental factors possibly environmental microbiota that interact with the gut microbiome and lead to this protective effect,” he says.

The researchers also showed that babies born by vaginal delivery and those who were breastfed had a protective microbiota in the first two months of life.

The findings, published in Nature Medicine, show that the asthma-protective effect is dependent on the maturation of the entire gut microbiota, and they emphasize the need for prevention strategies in the first year of life, when the microbiota is amenable to modification, Ege says.

What is already known on this topic
In parts of Europe and North America, the incidence of childhood asthma has been decreasing in recent years. Previous studies have associated the use of antibiotics in childhood with a higher risk of developing asthma.

What this research adds
To test whether a decrease in the incidence of asthma is linked to fewer antibiotics, researchers used data on annual rates of antibiotic prescriptions and asthma diagnoses in British Columbia, Canada. Between 2000 and 2014, there was a 26% drop of new asthma diagnoses. The drop in asthma incidence was correlated with reduced antibiotics use—from more than 1,200 prescriptions to about 500 prescriptions for 1,000 children.

Conclusion
The findings show a strong association between the prescription of antibiotics and the incidence of asthma. They also suggest that the decrease in the incidence of childhood asthma observed in recent years is an unexpected benefit of reduced antibiotic use during infancy.

The incidence of childhood asthma has been decreasing in recent years in parts of Europe and North America. A new observational study may explain why. The findings, published in The Lancet Respiratory Medicine, suggest that the recent decrease in the incidence of childhood asthma is an unintended consequence of reduced antibiotic use in early life.

Asthma is the most common chronic disease of childhood in developed countries, but the causes of its high incidence remain unclear. Previous studies have associated the use of antibiotics in childhood with a higher risk of developing asthma.

To test whether a decrease in the incidence of asthma is linked to fewer antibiotics, a team of researchers led by Stuart Turvey and David M Patrick at the University of British Columbia in Vancouver, Canada, used data on annual rates of antibiotic prescriptions and asthma diagnoses in British Columbia.

Less antibiotics, fewer asthma diagnoses

The researchers found that, between 2000 and 2014, there was a 26% drop of new asthma diagnoses—from 27.3 to 20.2 per 1,000 children. The drop in asthma incidence was correlated with a 61% decrease in antibiotic use in children under the age of one during the same period— from 1,253 prescriptions to 489.1 per 1,000 infants.

The team calculated that a 10% increase in the prescription of antibiotics increases the incidence of childhood asthma by 24%.

The researchers also found a correlation between increasing asthma incidence and the number of antibiotics exposures. Five-year-olds who had never taken antibiotics were less likely to be diagnosed with asthma than those who had taken antibiotics.

Altered microbiota

To assess how the composition of the gut microbiota relates to antibiotic exposure and asthma incidence, the researchers analyzed data from fecal samples of 917 children in the Canadian Healthy Infant Longitudinal Development (CHILD) study, which includes children recruited in four Canadian cities from 2008 to 2012.

The results show that the gut microbiota of children who had taken antibiotics had lower levels of six key bacterial families compared to that of infants who had not taken antibiotics. Among the depleted bacteria, Faecalibacterium prausnitzii is known to be an anti-inflammatory microbe that is reduced in the stool of people with asthma.

The findings suggest that gut bacteria could play a role in asthma development, the researchers say. However, the team cautions that the study only shows correlations: more work is needed to test causal relationships between exposure to antibiotics during early childhood and the development of asthma.

“Our findings suggest that the reduction in the incidence of pediatric asthma observed in recent years might be an unexpected benefit of prudent antibiotic use during infancy, acting via preservation of the gut microbial community,” the researchers say.

What is already known on this topic
Prenatal life is considered a critical window for the development of asthma and other long-term inflammatory conditions. Both the gut bacterial composition of newborns and specific microbes in infants’ airways have been associated with increased disease risk later in life, and taking high doses of vitamin D during pregnancy seems to protect newborns against asthma.

What this research adds
By analyzing microbiota samples from nearly 700 pregnant women and their children, researchers found that taking daily doses of vitamin D and omega-3 fatty acids during pregnancy affects the newborns’ airway microbiota, but not their gut microbiota.

Conclusion
The findings suggest that taking vitamin D and omega-3 fatty acids during pregnancy can change the infant airway microbiota, but these microbes appear to be a minor mediator of the protective effect of the two dietary interventions on risk of asthma.

Prenatal life is considered a critical window for the development of asthma and other long-term inflammatory conditions. Both the gut bacterial composition of newborns and specific microbes in infants’ airways have been associated with increased disease risk later in life, and taking high doses of vitamin D during pregnancy seems to protect newborns against asthma. A new study found that taking vitamin D and omega-3 fatty acids during pregnancy can change the newborns’ airway microbiota.

The findings, published in Nature Communications, suggest that the beneficial effects of dietary interventions during pregnancy are mediated by different factors, including the infant airway microbiota, changes in fetal development, and immune maturation.

“In recent years, the human microbiome has received increased attention as a potential contributor to disease development, especially the earliest microbial compositions,” the researchers say. To examine the effect of omega-3 and vitamin D supplements during pregnancy on the risk of asthma in newborns, Hans Bisgaard at the University of Copenhagen and his colleagues analyzed microbiota samples from 695 pregnant women and their children.

Dietary supplement

The participants were recruited from the Copenhagen Prospective Studies on Asthma in Childhood 2010, a large study of infants born to asthmatic mothers in Denmark. The researchers randomly administered some of the women a daily dose of two omega-3 fatty acids in the form of fish oil from week 24 of pregnancy to one week postpartum. The control group received a daily dose of olive oil. Similarly, the team randomly assigned some of the women to a group that received daily vitamin D3 tablets. In this case, the control group received a placebo tablet each day.

The team collected microbiota samples from the vagina of women at 24 and 36 weeks of pregnancy. The researchers also acquired infant microbiota samples at one week, one month, and three months of age, and infant fecal samples one week, one month, and one year after birth.

Microbiota composition

The average bacterial composition of maternal vaginal samples appeared similar and was dominated by Lactobacillus and Gardnerella bacteria. Fecal samples from one-week and one-month-old infants were instead dominated by Bifidobacterium, Enterobacteriaceae, and Bacteroides. One year later, the level of Enterobacteriaceae, Staphylococcus, Streptococcus and Bifidobacterium decreased in favor of Bacteroides and other microbes, including Faecalibacterium and Prevotella.

In airway samples from one-week-old infants, the three major genera were Staphylococcus, Streptococcus, and Moraxella. One month and three months after birth, the researchers observed an increase in the abundance of Streptococcus, Moraxella, and Haemophilus, and a decrease in Staphylococcus.

Diet-driven changes

Supplements of vitamin D and omega-3 during pregnancy didn’t affect neither the infants’ gut microbiota nor their airway microbiota at one week and three months of age. But the dietary interventions did change the airway microbiota of one-month-old babies, leading to a substantial decrease in Firmicutes and a corresponding increase in Proteobacteria.

However, the team found that the changes in the one-month-old infants’ airway microbiota could account for only a small part of the total asthma prevention effect of omega-3 and vitamin D supplements. This suggest that the microbial changes observed as a result of dietary interventions had a minor effect on later risk of asthma, the researchers say. The clinical effects of omega-3 and vitamin D supplements, they add, “are probably working through many different mechanistic pathways.”

What is already known on this topic
Unfavorable or insufficient microbial stimulation in early life, when the child’s immune system is maturing, has been linked to the development of asthma. Previous studies have looked for airway microbial signatures related to asthma, but they didn’t capture the complexity of the entire respiratory-tract microbiota.

What this research adds
By studying the airway microbiota of 700 children, researchers found that kids who develop asthma by age six tend to have an increased microbial diversity and higher proportion of Veillonella and Prevotella bacteria than kids who don’t develop asthma. Higher abundance of Veillonella and Prevotella are also associated with increased levels of specific pro-inflammatory molecules in the airways.

Conclusion
If confirmed, the results suggest a mechanism underlying the predisposition to asthma in early infancy.

The diversity and composition of the airway microbiota in early life could predispose to the development of asthma later in childhood, according to a new study.

The findings, published in Nature Communications, support the idea that specific bacteria may make kids more susceptible to asthma.

Several studies have shown that unfavorable or insufficient microbial stimulation in early life, when the child’s immune system is maturing, are associated with the development of chronic inflammatory diseases such as asthma. Many of those studies have looked for airway microbial signatures related to asthma, but they didn’t capture the complexity of the entire respiratory-tract microbiota.

Jonathan Thorsen at the University of Copenhagen and his colleagues set out to study the early-life airway microbiota of 700 children born to asthmatic mothers, and analyze the relationship between microbiota composition and asthma development.

Differential abundance

The researchers collected airway aspirates from children at age one week, one month, and three months. Then, the children were monitored for asthma development through follow-up visits during the first six years of life.

At one week of age, the children’s airway microbiota was dominated by Staphylococcus, Streptococcus, Moraxella, Haemophilus, and Corynebacterium. But after three months, the levels of Staphylococcus bacteria started to decrease, whereas those of Streptococcus, Moraxella, and Haemophilus increased.

At age one month, kids who developed asthma by age six tended to have an increased microbial diversity and higher proportion of Veillonella and Prevotella bacteria in the airways compared to kids who didn’t develop asthma.

In addition to Veillonella and Prevotella, other bacteria that could predict asthma by six years of age included Gemella, Streptococcus, and Lactobacillus.

Immune response

When the researchers looked at immune molecules from the airway lining, they found that higher abundance of Veillonella and Prevotella was associated with increased levels of specific pro-inflammatory molecules that are predictors for asthma.

However, because of the observational nature of the study, it’s unclear whether the presence of certain bacteria is a cause or a consequence of asthma. It also remains elusive how the airway microbiota contributes to asthma development and whether any bacteria-related effect could depend on the host’s genetic predisposition.

If future studies determine that specific bacteria can trigger asthma, manipulating the composition of the developing airway microbiota could help to prevent asthma in early life, the researchers say.

What is already known on this topic
Studies have linked the infant microbiota and the development of childhood asthma. But the mechanisms through which bacteria cause allergic inflammation remain unknown.

What this research adds
Researchers have found that mice with high levels of a bacterial compound called 12,13-diHOME had increased lung inflammation and fewer immune cells that act to suppress allergic inflammation. In people, increased levels of bacterial genes that produce 12,13-diHOME were observed in infants that went on to develop childhood allergies or asthma.

Conclusions
The findings in people and mice suggest that 12,13-diHOME is linked to childhood asthma and allergy risk in the broader population.

A microbial compound could increase the risk of asthma in children, a study finds. The research, published in Nature Microbiology, identified one of the potential mechanisms that link infant microbiota to the development of childhood allergies.

Several studies have shown that newborns at risk of childhood asthma have imbalances in their gut microbiota and increased levels of a bacterial compound called 12,13-diHOME in their feces.

To assess the role of this compound in childhood asthma risk, Sophia Levan at the University of California, San Francisco, and her colleagues injected mice with 12,13-diHOME and then exposed the animals to a known allergen.

Microbial compound

Mice injected with 12,13-diHOME developed worse lung inflammation than rodents that had not been given the compound. Compared to these animals, the injected mice also had lower lung levels of regulatory T cells, which act to suppress allergic inflammation.

Next, the researchers analyzed the microbes in fecal samples from 41 one-month-old infants who were part of the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) in Detroit.

The team found higher levels of 12,13-diHOME in samples from infants that went on to develop childhood allergies or asthma, compared to infants who did not.

Immune regulation

When the researchers treated human cells with 12,13-diHOME, they observed fewer regulatory T cells and reduced production of anti-inflammatory molecules.

Sequencing the infants’ fecal samples indicated that specific bacterial genes are more abundant in the gut microbiota of those who went on to develop allergies or asthma. Three of these bacterial genes produce 12,13-diHOME. The researchers replicated this finding in another group of 50 infants based in San Francisco.

Expressing some of the genes that produce 12,13-diHOME into the gut of mice resulted in a reduction of regulatory T cell numbers in the rodents’ lungs. This suggests that the bacterial compound plays an important role in the susceptibility to childhood allergy and asthma. However, it’s likely that other microbial-derived products also contribute to childhood allergy and asthma risk, the scientists say.

What is already known on this topic
The number of people who suffer from food allergy has risen sharply over the last decade. One hypothesis is that certain lifestyle factors, such as an increase in births by Caesarean section and a decline in breastfeeding, disrupt the normal microbial composition in the gut, depriving infants of beneficial bacteria that prepare the immune system to recognize food as harmless.

What this research adds
By analyzing 56 food-allergic infants and 98 healthy kids, researchers found that the bacteria in the feces of food-allergic babies were different from those of healthy individuals. Mice given fecal bacteria from food-allergic children developed allergic reactions. But when the animals were given specific bacteria that are known to protect against food allergies, they didn’t develop food allergies, whereas mice given other common bacteria did.

Conclusions
The study suggests that the loss of protective gut bacteria is a critical factor in food allergy and that manipulating the microbiota could treat such allergies.

Beneficial gut microbes may prevent and even reverse food allergies, study finds. The research, published in Nature Medicine, suggests that the loss of protective gut bacteria is a critical factor in food allergy and that manipulating the microbiota could treat such allergies.

The number of people who suffer from food allergy has risen sharply over the last decade. In the United States, nearly 8% of children are affected. One hypothesis is that certain lifestyle factors, such as an increase in births by Caesarean section and a decline in breastfeeding, disrupt the normal microbial composition in the gut, depriving infants of beneficial bacteria that prepare the immune system to recognize food as harmless.

To test this hypothesis, a team led by Azza Abdel-Gadir and Emmanuel Stephen-Victor, both at Boston’s Children Hospital, and Georg Gerber at Brigham and Women’s Hospital looked at gut bacteria in babies with and without food allergies.

Bacterial imbalance

The researchers collected stool samples from 56 food-allergic infants and 98 healthy kids, then analyzed their microbial composition. The bacteria in the feces of food-allergic babies were different from those of healthy individuals. In particular, food-allergic kids had less bacteria belonging to the Clostridiales family.

Next, the team transferred fecal bacteria from infants with or without food allergies into mice who were sensitized to eggs. Rodents that received gut microbes from healthy kids were more protected against egg allergy than those that received microbiota from the infants with food allergies.

“Good” bacteria

The researchers developed mixes of different species of bacteria belonging to the Clostridiales and Bacteroidetes families, which are known to protect against food allergies. Mice that were given the beneficial bacteria didn’t develop allergies to eggs, whereas mice given other common bacteria did.

To explore how these bacteria influence food allergy susceptibility, the team looked at immunological changes in both people and mice. Clostridiales and Bacteroidetes stimulated specific regulatory T cells, a type of immune cells that promote tolerant responses instead of allergic responses.

The scientists hope that the findings will eventually lead to new treatments that prevent food allergies in newborns at risk or even reverse the condition in people who already suffer from food allergies.

Rates of food allergy in infants and children are spiking in many areas of the world, with milk, eggs, soy, wheat, and peanuts being some of the most common offenders. It’s not certain why this increase in prevalence has occurred—but it makes the scientific study of food allergy prevention and treatment ever more important. And the latest research indicates that the gut microbiome of infants and children could play a part in how food allergy ends up developing.

Food allergy is characterized by an adverse health effect upon exposure to a specific food, or ‘antigen’. In the most common form of the condition, so-called ‘IgE-mediated allergy’, a very specific immune response occurs: the antigen activates immune cells called Th2 cells, which spur the production of antibodies belonging to a class called immunoglobulin E (IgE) and set them loose in the bloodstream. This triggers symptoms, ranging from a skin rash to a severe, whole-body anaphylactic reaction.

Cow’s milk allergy is of particular interest because in the first months of life, babies have to drink milk of one kind or another, with cow’s milk being a common alternative to breast milk. It’s been observed that children with cow’s milk allergy have pronounced differences in their gut microbiota compared with healthy children; and one study showed differences in gut microbiota composition of infants at 3-6 months whose milk allergy ended up resolving by the age of eight.

A humanized mouse study from the laboratory of Cathryn Nagler of University of Chicago (USA) took this work a step further, exploring whether the gut microbiota could have a causal role in allergic reactions to foods. First, the researchers took fecal samples from a small group of infants who were healthy and a small group who had confirmed IgE-mediated cow’s milk allergy, and confirmed the existence of significantly different bacterial communities.

Then came the mouse experiment: germ-free mice were ‘sensitized’ (made allergic) to a cow’s milk component before being colonized with the gut microbes of the healthy infants and those with cow’s milk allergy.

When the mice were exposed to the antigen, researchers saw an anaphylaxis reaction and a more pronounced immune response in the ones colonized with microbiota from allergic infants; and the mice that had received a healthy infant’s microbiota were protected from the anaphylactic response.

The researchers then took a closer look, correlating various bacterial species with genes that were upregulated in the mice who experienced or didn’t experience anaphylaxis; they identified a bacterial species that appeared to be protective against allergic responses: Anaerostipes caccae. Sure enough, if germ-free mice were colonized only with this species they did not experience anaphylaxis when they encountered the cow’s milk antigen.

A more recent mouse study provided further evidence for the potential ‘calming’ effect of the early life gut microbiota on immune responses related to food allergy. Researchers were exploring a known phenomenon: young germ-free mice that after weaning start to eat normal foods, typically experience an allergy-linked immune response. Korean and Australian researchers found that this response happens along with a spike in T follicular helper (TFH) cells—which are typically generated in early life but are dampened when a gut microbiota is present. This work supports the existence of a food-allergy-protective microbiota in infancy, at a time when the immune system is rapidly developing.

All of this evidence contributes to the idea that the gut microbiota could play an active role in food allergy and how it emerges in early life. But what about kids who already deal with food allergy—is there any hope to mitigate it?

Some microbiome-focused treatments are already under investigation: for instance, one trial found that peanut oral immunotherapy plus a specific probiotic (Lactobacillus rhamnosus CGMCC 1.3724) was effective for inducing immune changes and unresponsiveness to a peanut protein in children with established peanut allergy.

Further research from different angles and in different models should help uncover the role of the gut microbiota in the immune responses involved in food allergy—with the hope that microbiota manipulation could soon help more children enjoy a peanut butter sandwich without consequence.

Kristina Campbell

• Different allergic responses based on the donors
• A protective bacterial species

• What is already known on this topic
  Food allergies are on the rise, especially among children. Intestinal bacterial alterations seem to be among the causes, but this aspect needs to be explored further.

• What this research adds
  In order to better understand the role of commensal bacteria in food allergies, some germ-free mouse models were colonized with faeces from healthy subjects or individuals allergic to cow’s milk.

• Conclusions
  Commensal bacteria, different between the two groups, influence the antigenic response to cow’s milk. Targeted microbiota interventions could be a valid therapeutic strategy.

The intestinal microbiome of healthy children plays a protective role against food allergies, a study published in Nature Medicine concludes.

More and more people, especially children, report suffering from food allergies. The intestinal bacterial alteration determined by the lifestyles typical of the twenty-first century, including the incorrect use of antibiotics, the increasing use of cesarean section and artificial feeding and dietary changes, seems to be among the causes.

Previous research has already shown that the intestinal microbiota of children with cow’s milk allergy is altered compared to that of healthy children. Some bacterial species are also known to have protective functions against allergies.

Starting from these premises, the researchers coordinated by Taylor Feehley at the University of Chicago investigated the role of the intestinal microbiome in food allergies by colonizing germ-free mouse models with faeces obtained from healthy children (n = 4) and children allergic to cow’s milk (n = 4). To reduce the effect of the diet, which notoriously affects the composition of the intestinal microbiota, all the children were fed with formula.

The aim of the study was to evaluate the role of commensal bacteria in the allergic response to vaccine beta-lactoglobulin (BLG), by monitoring the differences in microbiome composition, blood immune parameters and gene expression between the two groups.

Different allergic responses based on the donors

After colonizing the mouse models with the faeces from the two groups and having them sensitized with BLG the researchers observed that:

• the models colonized with faeces of allergic donors recorded a significantly higher serum concentration of IgG anti-IBG and mMCTP-1 (mouse mast cell protease-1) compared to the other group
• all models receiving material from healthy donors have shown complete protection from the allergic response
• body temperature was different between the two groups, while bacterial diversity and evenness were similar

To exclude any interference of formula, the experiment was repeated by colonizing the models with faeces of other breastfed, allergic and non-allergic babies. The results proved to be in line with the previous ones.

Once the possible antigenic response was determined, the bacterial composition was analyzed and 58 OTUs were identified, differentially expressed between the two groups but in line with the configurations of the donors.

Three of the five OTUs associated with anti-allergic activity have been shown to belong to the Lachnospiraceae family, particularly to the Anaerostipes caccae species.

A protective bacterial species

In addition to presenting a favorable ratio of protective / non-protective bacteria, healthy subjects and related recipient mouse models also presented a specific gene expression. For example:

• Fbp1, a gene implicated in gluconeogenesis in the intestinal epithelium, presented greater expression in models colonized with faeces of healthy donors
• Tgfbr3 and Ror2, encoding the TFG-beta growth factor receptor, recorded less activity in models receiving from allergic subjects, as opposed to Acot12 and Me1, genes involved in pyruvate metabolism

Finally, through mono-colonization, the researchers showed that the single species Anaerostipes caccae, given its protective activity, presented in itself a gene expression comparable to that of the microbiota of healthy donors.

In conclusion, despite the many factors involved in the development of allergies, commensal bacteria play an important protective role, as is the case with Anaerostipes caccae.

Appropriately manipulating the intestinal microbiome could therefore prove to be a valid strategy to treat food allergies.

Translated from italian by editorial staff

• What is already known on this topic
  The increasing prevalence of food allergies and intolerances is likely due to environmental factors. Alterations in the gut microbiota could promote adverse reactions to food, but the specific mechanisms remain unclear.

• What this research adds
  This review summarizes and discusses the evidence that supports a link between changes in the gut microbiota and the appearance of adverse food reactions.

• Conclusions
  Understanding the mechanisms underlying these processes could help to develop therapeutic and prevention strategies.

The recent increase in the prevalence of food allergies and intolerances is likely due not only to genetic predispositions but also to environmental factors. Studies have linked adverse food reactions to alterations in the gut microbiota, but the exact mechanisms are unknown.

A review by Alberto Caminero and his colleagues, published in Nature Reviews Gastroenterology & Hepatology, summarizes the clinical and experimental evidence to support a link between changes in the gut microbiota and the appearance of adverse reactions to specific dietary components, especially gluten. The authors focus on the mechanisms through which diet-microbe and host-microbe interactions can trigger specific adverse food reactions. The review also discusses treatment strategies that could be developed to prevent or treat food allergies.

Adverse food reactions: introduction

About 20% of the world’s population experiences adverse food reactions, with different manifestations depending on the causes and pathophysiological processes involved. Adverse food reactions can be divided into food allergies and food intolerances, according to their underlying pathophysiology.

In case of food allergies, the exposure to the allergen produces an abnormally vigorous immune response, normally mediated by immunoglobulin E. In case of food intolerances, the immune system is not involved, but the organism lacks an enzyme required to digest the food component – for example, the enzyme β-galactosidase in lactose intolerance – which leads to gas production and bloating.

Microbial environmental factors

Several studies have reported a link between adverse food reactions and practices, such as early eating behaviors, antibiotics, or Caesarean section, that can alter the gut microbiota composition. In the case of coeliac disease, one of the most common food allergies, an increasingly accepted hypothesis is that a combination of factors, from genetic predisposition to viral and bacterial infections to an alteration of the gut microbiota, could play a role.

Clinical and preclinical studies have shown that:

• In mice, the severity of gluten immunopathology depends on the gut microbiota background
• In vitro and in mice, the gut microbiota is involved in gluten metabolism and gluten-peptide immunogenic modification
• People with coeliac disease show an intestinal dysbiosis, which seems to be characterized by Proteobacteria expansion
• People with coeliac disease who do not respond to a gluten-free diet have altered duodenal microbiota
• Coeliac disease as well as other food allergies and intolerances have been associated with practices, including Caesarean section and antibiotic intake, that affect the gut microbiota

Diet and microbiota

Our dietary habits are key in determining the gut microbiota diversity, as they affect microbial community structure and metabolite production.

The gut microbiota is considered a metabolic organ that uses dietary food components that are not metabolized by the host. Gut microbes can also metabolize food protein antigens, altering their immunogenicity. Changes in the gut microbiota make-up or its metabolic capabilities could promote immune system-mediated food sensitivities in genetically predisposed people.

For example, lactobacilli, which are able to metabolize non-digested gluten peptides,

have been reported to be less abundant in people with coeliac disease compared to healthy subjects. Further studies are needed to test if this reduced lactobacilli abundance is a cause or an effect of the disease.

Gut microbes are implicated not only in gluten degradation, but also in its deamidation and, in turn, in its immunogenicity. This aspect could apply to other food allergies, including those to peanut or egg proteins.

Metabolites with immunomodulatory function

Under healthy conditions, the gut microbiota plays a pivotal role in maintaining a “tolerant” gut environment, which prevents an inflammatory response against foreign antigens by promoting epithelial integrity and the function of regulatory T cells (Treg).

Bacterial metabolites resulting from the metabolism of dietary substrates mediate many of these effects.

Short-chain fatty acids

Among the bacterial metabolic products, some of the most relevant for food allergies are short-chain fatty acids (SCFAs). Alterations of these metabolites have been reported in people with food allergies. Studies have found that:

• The SCFA butyrate regulates both the proportion and the function of FOXP3+Treg (pTreg) cells, which contribute to maintain tolerance to food antigens or allergens
• In mice, a high-fiber diet increased the release of SCFAs, improving oral tolerance to food allergens by activating a specific enzymatic activity in CD103+ dendritic cells
• The SCFA acetate promotes epithelial integrity during enteropathogenic infections in mouse models

Other microbial determinants

Gut bacteria prevent the development of adverse food reactions. For example, Bacteroides fragilis was shown to promote the production of IL-10 and the differentiation of pTreg cells. What’s more, studies in mice reported that germ-free animals developed more severe allergies and more severe immunopathology.

Probiotic treatments with either mouse- or human-derived strains of live bacteria reduced or even prevented food allergies, as in the case of Bifidobacterium breve M-16V and Bifidobacterium longum BB536 supplementation.

However, probiotic bacteria aren’t yet recommended in the clinic, and further evidence of their efficacy is needed.

Allergies and other non-bacterial factors

Additional factors that contribute to the development of food allergies are mainly inflammatory events, such as:

• Dysfunction of the gut epithelial barrier and innate immunity
• Altered immune response mediated by T helper 1 and 2 cells and IL-15
• Reovirus-mediated inflammatory responses

Conclusions

• The mechanisms involved in the development of food allergies and intolerances remain unclear, although several studies have shown that gut bacteria, among other factors, play an important role in adverse food reactions.
• The gut microbiota can degrade and transform food antigens and allergens, altering their immunogenicity.
• In addition to bacterial dysbiosis, which is found in some people with food allergies, the integrity of the gut epithelial barrier as well as the activity of Treg immune cells are key factors for the development of adverse food reactions.

Further studies to unravel specific diet-microbes interactions and their underlying mechanisms are needed to develop new prevention and treatment approaches to food allergies.