Maternal high fat diet interacts with the maternal microbiome to expand IL-17 producing type 3 innate lymphoid cells in offspring.

Abstract

Abstract Introduction: Previously, we demonstrated that maternal high fat diet (mHFD) exposure results in a unique pattern of microbial colonization in offspring and subsequent expansion of IL-17 producing type 3 innate lymphoid cells (ILC3). We hypothesized that in utero mechanisms involving the maternal microbiome were responsible for the phenotype in offspring. Methods: To assess if the maternal microbiome was responsible for altering the mHFD offspring phenotype, we delivered mHFD and regular diet (RD)-exposed pups at birth by C-section (CS) and exposed mHFD mothers to broad-spectrum antibiotics (ABX) throughout pregnancy. We cross-fostered the offspring to RD mothers at birth. Microbial colonization in 2-week-old offspring was determined by 16s-based rRNA analysis, intestinal cytokines were quantified by qRT-PCR and lamina propria cells (LP) were profiled by flow cytometry. To determine if innate immunity is altered prenatally by maternal diet, we delivered mHFD and RD offspring by CS and examined the small intestine (SI) at birth for cytokine expression, TLR signaling and LP profiling. Global MyD88 KO mice on mHFD or RD were also examined for the same endpoints. Results: mHFD offspring at 2-weeks showed an expansion of Firmicutes and IL-17 producing ILC3, independent of the mode of delivery. ABX in mHFD mothers ameliorated the mHFD offspring phenotype, with microbial colonization and ILC3 similar to controls. mHFD offspring had altered TLR signaling at birth in SI. ILC3 were expanded at birth in mHFD offspring (14.2% vs 9.5%). MyD88−/− offspring exposed to mHFD did not have an expansion of ILC3. Conclusion: mHFD prenatally alters the offspring microbiome and ILC3 and this effect is dependent on the maternal microbiome and TLR signaling.