title: Short-chain fatty acids alter the neurolipidome, neuronal cell function, and neurobehaviour: what are the consequences for overall brain health?
Creators: name: Fillier, Tiffany
Publisher: name: Memorial University of Newfoundland
Year: 2025

description: There is emerging recognition in the scientific community that the gut microbiota can communicate with the brain to modulate chemistry, function, and ultimately behaviour. However, this communication is poorly understood. A proposed mechanism of this communication includes short-chain fatty acids (SCFAs), which are enteric microbial metabolites containing two to four carbons. These fatty acids are produced via the diet's bacterial fermentation of indigestible carbohydrates. Elevated levels of SCFAs in systemic circulation have been linked to dysbiosis of the gut, which is an imbalance in the gut microbiota. This can be caused by stress, aging, medications, diet, etc. These SCFAs travel through the blood to the brain. The brain is the human body’s most energetically demanding organ and the central control modulating behaviour as well as host mental or brain health outcomes. The brain is also the fattiest organ, comprising approximately 60% lipids. Brain lipids are important indices in assessing brain function, neurological behaviours, and ultimately brain health status. Thus, I hypothesized that the administration of SCFAs at levels reported in the systemic circulation of human patients would modulate brain lipid metabolism and neuronal cell function resulting in adverse effects on brain health and behavioural outcomes. To investigate this hypothesis, I utilized in vitro and in vivo studies along with mass spectrometry, fluorescence-based cell analysis, and mammalian behavioural experiments to (1) analyze neuronal cell viability and brain lipid metabolism after administration or exposure to elevated doses of SCFAs, (2) determine spatial lipid metabolism in different brain anatomical regions, and (3) analyze changes in behavioural phenotypes associated with the observed SCFA induced altered brain lipidome. I observed significant alterations in overall brain lipidome in both the Long-Evans rat brain and SH-SY5Y cell line after SCFA treatment, including major lipid classes, phospholipids and neutral lipids. Treatment also elicited a reduction in cell viability, adenosine triphosphate production, and an increased apoptotic response in neuronal cells. Furthermore, I observed SCFA exposure spatially altered the lipidome in the cortex, corpus callosum, thalamus, hypothalamus, and amygdala of Long-Evans rats. Behavioural analysis of Long-Evans rats after SCFA treatment revealed the altered lipidome was associated with deficits in memory and learning, locomotor activity, and anxiety behaviours. Overall, these findings demonstrate that SCFAs appear to adversely alter the brain lipidome, neuronal cell function, mitochondrial morphology, and viability and that these occur concomitantly with deficits in cognitive related behaviours. Although SCFAs have been widely reported in the scientific literature to be very beneficial in improving overall host health, the results from this work suggest that this health-promotive benefit may not accrue to overall brain health.