Maternal diet-induced excess adiposity programs multisystem vulnerability that is unmasked by postnatal infection challenge

Abstract Excess adiposity before and during pregnancy has been linked to cardiometabolic inflammatory disease in offspring, yet programmed vulnerabilities may remain latent until challenge. Using a mouse model of maternal high-fat diet (mHF)-induced excess adiposity, we investigated whether maternal excess adiposity programs immune, intestinal, and metabolic vulnerabilities that emerge after postnatal Streptococcus pneumoniae challenge. Wildtype C57BL/6J female mice were fed either standard chow or a high-fat diet before conception and throughout pregnancy and lactation. Offspring were assessed during neonatal life and again in adulthood before and after intranasal Streptococcus pneumoniae challenge. Neonates born to high-fat-diet-fed mothers showed elevated expression of inflammatory mediators (Ptafr, Tlr2, Tlr4) and decreased surfactant proteins (Sftpa, Sftpb, Sftpc) in the lung, indicating dysregulated host defence at birth. Before infection, adult mHF offspring had reduced circulating leukocytes and altered glucose handling. Although mHF did not alter acute pneumococcal burden, recovery was associated with increased intestinal permeability, altered intestinal morphology, shifts in cecal microbial community structure, and changes in glucose-insulin homeostasis. Several outcomes were sex dependent, indicating that maternal excess adiposity programs organ-specific and sex-specific responses to postnatal challenge. These findings suggest that maternal adiposity establishes vulnerabilities in immune, intestinal, and metabolic systems that become evident after inflammatory stress.