Dysregulation of immune system markers, gut microbiota and short-chain fatty acid production following prenatal alcohol exposure: A developmental perspective

Prenatal alcohol exposure (PAE) can severely impact fetal development, including alterations to the developing immune system. Immune perturbations, in tandem with gut dysbiosis, have been linked to brain and behavioral dysfunction, but this relationship is poorly understood in the context of PAE. This study takes an ontogenetic approach to evaluate PAE-induced alterations to brain and serum cytokine levels 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 (SCFA) levels were 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. This altered neuroimmune function was not seen in the PAE females. The effect of PAE on central cytokine levels was reduced at P22/38, the same age at which PAE-induced alterations in serum cytokine levels emerge in both sexes. PAE reduced bacterial diversity in both sexes at P8, but only in females at P38, where a PAE-induced unique community composition emerged. Both sexes had alterations to specific bacterial taxa (e.g., Firmicutes), some of which are important in producing the SCFA butyric acid, which was decreased in PAE animals at P22. These results demonstrate that PAE leads to sex- and age-specific alterations in immune function, gut microbiota and SCFA production, highlighting the need to consider both age and sex in future work.