Studies in newborn infants and in mice have linked the microbiome, and more specifically a compound produced by gut bacterial enzymes, with childhood allergies and asthma. The research in mice found that high levels of a bacterial lipid called 12,13-diHOME, were linked with an increase in lung inflammation and reduced numbers of regulatory T (Treg) cells that would normally act to suppress allergic inflammation. Tests on fecal samples from month-old human infants found increased levels of bacterial genes that produce the lipid, 12,13-diHOME, in samples from individuals that went on to develop allergies or asthma in childhood.

“We have discovered a specific bacterial lipid in the neonatal gut that promotes immune dysfunction associated with allergic asthma and can be used to assess which babies are at risk of developing the disease in childhood,” said research lead Susan Lynch, PhD, a professor of medicine at the University of California, San Francisco (UCSF). “This finding paves the way for early-life gut microbiome interventions to prevent these diseases from developing.”

Lynch and colleagues at UCSF, Augusta University, and the Henry Ford Health System, report their findings in Nature Microbiology, in a paper titled, “Elevated fecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance.”

“The development of severe asthma during childhood is often preceded by eczema and/or atopy—a heightened immune response to multiple food allergens and aeroallergens,” the authors wrote. Although genetic factors may impact on predisposition, the fact that allergies, eczema, and asthma are on the increase, particularly in developing nations particularly, suggests that lifestyle and environment may also play a role in the development of such conditions.

Studies in North America have implicated a link between the infant microbiome and the development of childhood atopy and asthma. “Neonates at risk of childhood atopy and asthma exhibit perturbation of the gut microbiome, metabolic dysfunction, and increased concentrations of 12,13-diHOME in their feces,” the researchers pointed out. “However, the mechanism, source, and contribution of this lipid to allergic inflammation remain unknown.”

Through their reported studies the UCSF researchers first showed that mice given intraperitoneal injections of 12,13-diHOME and then subjected to a known allergen developed worse lung inflammation than control animals, and exhibited reduced levels of Treg cells in their lungs. The researchers then used shotgun metagenomic sequencing to examine microbial genes in stools samples from 41 one-month-old infants in the racially and ethnically diverse Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) in Detroit. They found elevated levels of 12,13-diHOME in samples from infants who went on to develop allergies and/or asthma, even after adjusting for potential confounding factors.

12,13-diHOME is generated by epoxide hydrolase (EH) enzymes as the end product of linoleic acid (LA) metabolism. The researchers analyzed the sequencing results to look for any of the roughly 73,000 bacterial, 5,000 fungal, or 50 or so human EH genes in the sequence reads. They identified three genes, in Enterocuccus faecalis, and in Bifidobacterium bifidum that could carry out the catalytic reaction generating 12,13-diHOME. Test in mice showed that animals given oral doses of linoleic acid and supplemented with bacteria that overexpress the three EH genes generated much higher levels of 12,13-diHOME than did the control animals when subjected to a lung allergen, and also exhibited reduced numbers of Treg cells in their lungs. “Together, these results indicate that oral supplementation with 12,13-diHOME-producing bacteria and LA is sufficient to recapitulate the decrease in mouse lung Treg cells, a cardinal immune feature of airway allergic inflammation,” the researchers wrote.

Interestingly, fecal 3EH gene copy number was significantly higher in one-month-old human infants who subsequently developed childhood atopy and/or asthma. To validate this finding the researchers turned to an independent cohort of one-month-old neonates in the Trial of Infant Probiotic Supplementation (TIPS) study, in San Francisco, and again found that increased fecal 3EH copy number was linked with the development of eczema at two years of age, and/or asthma at four years of age. “Despite the differences in geography and study design between the WHEALS and TIPS cohorts, neonates who went on to develop eczema and/or asthma during childhood exhibited a significant increase in the fecal abundance of 3EH genes,” the investigators pointed out.

“Our data indicate that an increased copy number of specific bacterial EH genes and elevated concentration of their product—12,13-diHOME—in the gut microbiome during early life are related to clinical outcomes of atopy, eczema, and asthma during childhood,” they wrote. “This study exemplifies just one component of a complex microbiome–immune interaction in high-risk neonates that promotes allergic inflammation and offers a mechanism by which metabolic products of neonatal gut bacteria may increase susceptibility to allergies and asthma during childhood.”

The researchers acknowledge that their findings will need validation in much larger numbers of infants, and that 12,13-diHOME will likely be just one of a number or microbial-derived products that impact on the development of immune dysfunction associated with childhood allergy and asthma. “This is likely just one component of a complex microbiome-immune interaction in young infants that promotes allergy and asthma development in childhood,” Lynch said. “But it is a first step towards a more mechanistic understanding of the suite of microbial products that increase susceptibility to allergies and asthma during childhood.”

Lead UCSF study author Sophia Levan, added “… the fact that these two cohorts collected in demographically different populations in very different cities showed the same results gives us confidence that the association between this bacterial lipid and childhood asthma and allergy risk may generalize to a broader population.”

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