Figure 3. External metabolic cues regulate histone acetylation via the tricarboxylic acid (TCA) cycle. This hypothetical model illustrates how gut microbial regulated serum metabolites, which are readily used by mitochondria to generate ATP, may influence host cell gene transcription. (A) SCFAs are produced in the colon and disseminated directly into the blood stream or trafficked to the liver and released as glucose or β-hydroxybutyrate, depending on the host’s metabolic status. These metabolites are then used by cells within the CNS to generate ATP via the TCA cycle. (B) ATP-citrate lyase (ACL) uses mitochondrial derived citrate to generate acetyl-CoA in the cytoplasm and nucleus. In the nucleus, histone acetyl-transferases (HATs) transfer the acetyl group from acetyl-CoA onto histone lysine residues to facilitate cell proliferation and the expression of genes important for learning and memory. Histone deacetylases (HDACs) remove acetyl groups from histones to suppress gene transcription. HDACs can be inhibited bya histone deacetylase inhibitors (HDACi), including gut microbial regulated serum metabolites, e.g., β-hydroxybutyrate, butyrate, and propionate. This is illustration is not to scale.