Fatty acid metabolism changes in association with neurobehavioral deficits in animal models of fetal alcohol spectrum disorders

Fetal alcohol spectrum disorders (FASD) show various behavioral problems due to prenatal alcohol exposure (PAE). Our previous study found significant changes in gene expressions linked to fatty acid metabolism in the brain of the PAE mouse model. Given the importance of fatty acids in normal brain functions and the contributions to neurodegenerative diseases, we hypothesized that the fatty acids changed by PAE contribute to neurobehavioral deficits in FASD. This study found an increase of palmitic acid and arachidonic acid in phospholipid compositions in the cerebral cortex of PAE at postnatal day 30. The increase of palmitic acid was consistent with the increase of the producing enzyme, fatty acid synthase ( Fasn ). The decrease of 26:6 fatty acid was also found in phospholipid. It is consistent with the increase of the Elongation of very long chain fatty acids protein 4 (ELOVL4) which uses 26:6 as a substrate for making very long chain fatty acids. However, there was no increase in the elongated products. Rather, we found an accumulation of the lipid droplets (LDs) in the PAE brain, suggesting changes in fatty acid metabolism that lead to the accumulation of excessive fatty acids. Although metabolic measurements, including plasma triglyceride level, were not affected by PAE, the abundance of fatty acid-related gut microbiota was altered. Interestingly, multi-omics association analysis revealed a potential contribution of the altered gut microbiota, primarily Ruminococcaceae that produces short chain fatty acid, to LD formation in the PAE brain and the behavioral problems, suggesting that the gut microbiome could serve as a tool to facilitate uncovering the brain pathophysiology of FASD and a potential target to mitigate neurobehavioral problems.