Research ‘Paves the Way’ for Early Interventions to Prevent Childhood Inflammatory Diseases
A study of newborn infants has identified a compound produced by gut bacteria that appears to predispose certain infants to allergies and asthma later in life.
“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 study senior author Susan Lynch, PhD, a professor of medicine at UC San Francisco. “This finding paves the way for early-life gut microbiome interventions to prevent these diseases from developing.”
Lynch’s lab has previously shown that one-month-old infants with unhealthy gut microbial ecosystems – more like a weedy lot than a well-functioning garden – are at increased risk of developing asthma later in childhood. They have also shown that a specific fatty molecule, or lipid, called 12,13-diHOME, found at high concentrations in the feces of these babies, reduced the number and activity of a key group of immune cells called regulatory T cells (Tregs) that normally suppress allergic inflammation.
In their newest study, published July 22, 2019, in Nature Microbiology, research led by MD/PHD candidate Sophia Levan set out to test whether this bacterial molecule might directly drive the risk of asthma and allergy in young infants. First, they showed that injecting 12,13-diHOME into the gut of mice reduced Treg cell numbers in the animals’ lungs, and that this molecule alters Treg and other immune cell function at a molecular level.
To understand where this pro-inflammatory lipid was coming from, the researchers studied the microbial genes present in stool samples from 41 one-month-old infants collected as part of the racially and ethnically diverse WHEALS (Wayne County Health, Environment, Allergy and Asthma Longitudinal Study) cohort in Detroit. They found that the number of copies of three bacterial genes for 12,13 DiHOME or the concentration of the lipid itself in the babies’ stool samples predicted which infants went on to develop allergy by age 2 or asthma by age 4. They then replicated this finding in the stool samples of an independent cohort of 50 one-month-olds based in San Francisco.
“While these findings need to be replicated in an even larger study group, 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,” Levan said.
The researchers emphasize that 12,13-diHOME is likely just one of many microbial-derived products that contribute to early-life immune dysfunction and susceptibility to 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.”
The researchers plan to pursue this finding to develop screening protocols to identify newborns at high risk for asthma and allergy based on the presence of this and other microbial molecules in their stool, as well as interventions that could reduce infants’ risk, either through therapies that reduce levels of these compounds or by promoting early life gut microbiomes that prevent production of such compounds.
Authors: Additional authors on the study were Kelsey A. Stamnes, Din L. Lin, Ariane R. Panzer, Elle Fukui, Katherine McCauley, Kei E. Fujimura, Michelle McKean, Homer A. Boushey, and Michael D. Cabana of UCSF; Dennis R. Ownby of Augusta University in Georgia; and Edward M. Zoratti and Christine C. Johnson of Henry Ford Health System in Detroit.
Funding: This research was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (AI089473).
Disclosures: Lynch is co-founder of Siolta Therapeutics Inc., and serves as both a consultant and a member of its Board of Directors. The Regents of the University of California, UCSF have filed a provisional patent application (number 62/637,175) on behalf of Lynch and Levan relating to the research.
The University of California, San Francisco (UCSF), is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes UCSF Health, which comprises three top-ranked hospitals as well as affiliations throughout the Bay Area.