Aging impairs type 2 immune responses to nematodes associated with reduced gut microbiota responsiveness.

Abstract

Gastrointestinal nematode infections elicit robust type 2 immune responses that facilitate rapid parasite expulsion. Our previous studies demonstrated that 18-month-old mice exhibit both impaired nematode clearance and reduced type 2-cytokine production, suggesting that aging diminishes the host's potential to mount effective immune defenses. To further investigate the underlying mechanisms, we compared young (3 months old) and aged mice (18 months old) infected with the nematode Heligmosomoides polygyrus (Hp), focusing on the interplay between type 2 immune responses and intestinal ecology. Hp infected young mice exhibited increased expression of Th2 cytokines (e.g., il-4) and short-chain fatty acid (SCFA) receptors GPR41/GPR43, while these responses were markedly diminished in aged mice. Correspondingly, cecal SCFA levels-particularly acetate and propionate-increased in Hp infected young mice but decreased in aged counterparts. Moreover, Hp infection induced a pronounced shift in the cecal microbiota composition of young mice, notably a reduced Bacillota/Bacteroidota ratio (F/B) ratio, a change much less evident in aged mice. These findings suggest that the age-related decline in type 2 immune responses to gastrointestinal nematode infection is linked to reduced gut microbiota responsiveness, which may compromise host resistance to the gastrointestinal parasites.