Maternal Exposure to Antibiotics Increases the Severity of Asthma in Offspring Mice

RATIONALE: The prevalence of allergic asthma has been increasing steadily in recent decades, a time frame too short to be due to genetics alone, suggesting that environmental changes may be responsible. As many environmental exposures also alter microbial colonization, we sought to determine if early life changes in microbial colonization would influence asthma development in a murine model of asthma.

METHODS: On day 15 of gestation, the water of dams was supplemented with sucralose, or an antibiotic cocktail until birth, when regular drinking water was supplied. At 6 – 7 weeks of age, offspring of control, and antibiotics (ABX)-exposed mothers were given PBS, or sensitized with HDM i.p. (experimental days 0, 7) and i.t. (experimental days 14, 21). 72 hours after the last HDM treatment, mice were sacrificed and airway hyperresponsiveness (AHR) was measured. Flow cytometric analysis of lung cell populations was performed, and allergen-stimulated cytokine production was assessed in lung cell cultures.

RESULTS: Compared to offspring of control mothers, offspring of ABX-exposed mothers demonstrated significantly elevated AHR. More severe AHR was associated not with altered Th2, Th17 or ILC2 recruitment, but excessive ILC3 recruitment, and production of IL-17A and IL-22.

CONCLUSIONS: Consistent with epidemiological data, we find that early life microbial dysregulation is associated with altered asthma development. Morevoer, we identify a potential link between microbial dysbiosis, long term alterations in ILC3 recruitment and activity, and elevated production of IL-17A/IL-22. Dissecting the mechanisms whereby ILC3 recruitment is altered may suggest ways of mitigating the risk of early life microbial dysregulation on asthma development.