Abstract
BACKGROUND: Maternal high fat diet (mHFD) exposure expands IL-17 producing group 3 innate lymphoid cells (IL17(+ve) ILC3) in the small intestine of neonatal murine offspring and increases their susceptibility to intestinal inflammation. How mHFD modulates innate immunity in the fetal offspring remains unclear. METHODS: Dams were exposed to 60% high fat diet or maintained on regular diet (RD) prior to and during mating. Amniotic fluid (AF) was collected during mid-pregnancy and metabolites examined by global non-targeted mass spectrometry in conventional wild-type (WT) and germ-free pregnant dams. Offspring were delivered by C-section or vaginally and fecal contents examined for major bacterial phyla and small intestinal lamina propria cells (LP) by flow cytometry. Susceptibility to intestinal inflammation was determined using a lipopolysaccharide and platelet-activating factor model (LPS/PAF) in WT, germ-free and MyD88 deficient offspring. Neonatal germ-free pups were exposed to HFD or RD AF by gavage and LP examined by flow cytometry. RESULTS: We identified differentially produced metabolites in mHFD AF when compared to RD AF in conventionally raised mice, with no difference seen in germ-free mice. C-section delivery maintained the mHFD phenotype of expansion of IL17(+ve) ILC3 and increased susceptibility to inflammation in neonatal offspring. In addition, mHFD offspring had expansion of IL17(+ve) ILC3 at birth and 2 weeks of life, which was not seen in germ-free and MyD88 KO mice exposed to mHFD. Germ-free and MyD88 KO mice were protected from mHFD induced LPS/PAF injury and IL17(+ve) ILC3 expansion, demonstrating that the maternal microbiome and MyD88 are prenatally necessary for the expansion of IL17(+ve) ILC3 in mHFD offspring. Furthermore, introduction of mHFD AF to neonatal germ-free pups by gavage was sufficient to expand IL17(+ve) ILC3 in the small intestine. CONCLUSION: Our findings indicate that mHFD interacts with the maternal microbiome to modify AF metabolites and signal via MyD88 to expand IL17(+ve) ILC3 in murine neonatal offspring.