Dysregulation of Immune Function, Gut Microbiota Composition and Short-Chain Fatty Acid Production Following Prenatal Alcohol Exposure: A Developmental Perspective

Abstract

Prenatal alcohol exposure (PAE) severely impacts fetal development, including alterations to the developing immune system. Immune perturbations, in tandem with gut dysbiosis, have been linked to brain and behavioural dysfunction, but this relationship is poorly understood in the context of PAE. This study takes an ontogenetic approach to evaluate PAE- induced alterations to central/peripheral immune function and both the composition and metabolic output of the gut microbiota. Using a well-established rat model of PAE, cytokine levels in the serum, prefrontal cortex, amygdala and hypothalamus as well as gut microbiota composition and short-chain fatty acid output was assessed at three postnatal (P) timepoints: P8 (infancy), P22 (weaning), and P38 (adolescence). Male PAE rats had increased cytokine levels in the amygdala and hypothalamus (but not prefrontal cortex) at P8. However, this pattern of neuroinflammation was not seen in the PAE females. While the effect of PAE on central cytokine levels was reduced at P22/38, these are the ages at which PAE-induced alterations in serum cytokine levels emerge, an effect which occurred in both sexes. PAE-induced alterations to the gut microbiota occurred namely in females, with reduced bacterial diversity and unique community composition at P38. Both sexes saw alterations to specific bacterial taxa, some of which are important in producing the SCFA butyric acid, which was decreased in PAE animals at P22. These results show that PAE leads to sex and age specific alterations in immune function, gut microbiota composition and SCFA production, highlighting the critical need for both these factors to be considered in future work.