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

Poster Number: 252
Publication Number: 252.13

Tuan Tran, University of Texas Southwestern Medical School, Grand Prairie, TX, United States; Xinying Niu, Ut southwestern medical center, Grapevine, TX, United States; Dongmei Lu, University of Texas Southwestern Medical School, Dallas, TX, United States; Julie Mirpuri, UTSW, Dallas, TX, United States

Background: Fat consumption in the United States has increased over time with the average American diet consisting of over 40% fat, contributing to the steady rise in obesity over the last decade. Maternal high fat diet (mHFD) is known to alter both the maternal and offspring microbiome and intestinal immunity. Further, recent data support a role for the maternal microbiome in modifying neurodevelopment in neonatal murine offspring. The effect of mHFD on neurodevelopment of offspring remains understudied.

Objective: To determine if mHFD exposure will result in a microbiota dependent increase in inflammation and inhibition of axonal development in offspring brain.

Design/Methods: Conventional and germ-free dams were exposed to 60% high fat diet (HFD) or control diet (CD) for 4 weeks prior to mating. Offspring brains were collected at 2-weeks of life and examined for inflammatory (TNF-α, IL-6, IL-17A, IL1β and TGF-β) and regulatory markers of neuronal development (Nurr1) by quantitative RT-PCR. Hematoxylin and eosin staining was used to quantify the total number of cells in brain tissue, and Nissl staining of brain tissue was completed to quantify neurons in mHFD and control offspring. Behavioral studies on mHFD and RD offspring are ongoing.

Results: When compared with the CD offspring, mHFD offspring had a significant increase in the inflammatory cytokines IL-17A (2-fold increase, p< 0.05) and IL-6 (3-fold increase, p< 0.05) compared to controls. Nurr1 was increased 50-fold in mHFD offspring (p< 0.01). In germ-free mHFD offspring, there was no difference in IL-17A, IL-6 or Nurr1 expression when compared to germ-free regular diet offspring. Quantification of neurons by Nissl staining found a decrease in neuron cell count by 20% in the cortex, and a decrease by 22% in CA2 and by 32% in CA3 Hippocampal regions. Preliminary RNAseq analysis showed upregulation of specific genes involved in immunoregulation, neuron development and migration, and apoptosis in mHFD offspring.

Conclusion(s): mHFD exposure resulted in increased inflammatory cytokines and reduced neurulation 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.