Maternal OM-85 administration alleviates offspring allergic airway inflammation by downregulating IL-33/ILC2 axis.

BACKGROUND

Type 2 innate lymphoid cells (ILC2s) are essential for maintaining immune regulation and promoting tissue homeostasis in allergic asthma. How the development of gut microbiota on neonatal ILC2s influences allergic airway inflammation remains unclear. Here we focus on offspring ILC2 development in the context of alterations in maternal gut microbiota.

METHODS

C57BL/6 maternal mice were gavaged with OM-85 during pregnancy and/or lactation, ILC2-driven allergic airway inflammation in the OVA-sensitized adult offspring was observed. ILC2 development in offspring early life were investigated using recombinant (r)IL-33, rIL-25 and Bromodeoxyuridine in the vivo experiments. Further ILC2 promoting factors- IL-33 and IL-25 production in offspring early life were analysed. Finally, we examined the changes in gut microbiota and its metabolites in both dams and pups, and explored the effects of short-chain fatty acids (SCFAs) on IL-33 expression and secretion.

RESULTS

Maternal OM-85 administration restrained ILC2-driven allergic airway inflammation in the OVA-sensitized adult offspring. During ILC2 development in offspring early life, maternal OM-85 administration suppressed IL-33 and IL-25 production to inhibit ILC2 expansion and ILC2 responsiveness to alarmins, and infantile ILC2s could persist into adulthood. Maternal OM-85 administration increased SCFAs in breast milk and SCFA-producing gut probiotics (predominant Bacteroides and Blautia) in offspring, especially during pregnancy and lactation. SCFAs down-regulated IL-33 expression and reduced IL-33 secretion by inhibited gasdermin D (GSDMD) formation.

CONCLUSION

Maternal OM-85 administration restrains ILC2-driven allergic airway inflammation in adult offspring by increasing offspring intestinal SCFAs to modulate ILC2 development at an early stage, demonstrating that the transgenerational effects of maternal OM-85 exposure on offspring innate immunity.