Maternal high fat diet exposure results in maternal microbiome dependent increase in inflammatory cytokines and decrease in neurons in offspring brain.

Abstract

Abstract Introduction: We hypothesized that maternal high fat diet (mHFD) exposure will result in a microbiota dependent increase in inflammation and inhibition of axonal development in offspring brain. Methods: Conventional and germ-free murine dams were exposed to 60% high fat diet (HFD) or regular diet (RD) prior to mating. Offspring brains were collected at 2-weeks of life and analyzed for inflammatory (TNF-α, IL-6, IL-17A, IL1β and TGF-β) and regulatory markers of neuronal development (Nurr1) by quantitative RT-PCR. RNA seq was performed on whole brain in conventional mice. We quantified differences in regional neurons by histology (Nissl and H&E). Behavioral studies on mHFD and RD offspring are ongoing. Results: mHFD offspring had a significant increase in the inflammatory cytokines IL-17A and IL-6 when compared to controls. Nurr1 was increased 50-fold in mHFD offspring. In germ-free mHFD offspring, there was no difference. Quantification of neurons by Nissl staining demonstrated a decrease in neuron cell count in the cortex (20% decrease), and in hippocampal regions (22% in CA2 and 32% in CA3). Preliminary RNAseq analysis showed upregulation of specific genes involved in immunoregulation, neuron development and migration, and apoptosis in mHFD offspring. Conclusion: mHFD exposure resulted in increased inflammatory cytokines and reduced neurogenesis in the offspring brain. This change was ameliorated in germ free mice, demonstrating a microbiome dependent diet effect. RNAseq findings demonstrate changes in specific immunoregulatory pathways which warrant further exploration. We speculate that maternal diet interacts with the maternal microbiome to increase immune activation in the fetal brain which affects neurogenesis. Supported by grants from NIH (R01 1K12HD068369) and Children’s Medical Center Research Grant