Circulating short-chain fatty acids (SCFAs) are primarily derived from bacterial fermentation of carbohydrates in the colon where they function as physiologic modulators of epithelial cell maturation. Butyrate has been shown to induce tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, and enkephalin neuropeptide gene transcription, suggesting a role in perinatal sympathoadrenal stress-adaptation. We sought to determine whether there were SCFA structural requirements for this effect. Nine biologically relevant SCFAs and butyrate derivatives were tested in an in vitro model (PC12, rat pheochromocytoma cells) for their ability to regulate neurotransmitter-related gene expression. Our results revealed that among all the studied SCFAs, only propionate and butyrate increased tyrosine hydroxylase and proenkephalin mRNA levels. The functional activity was selective to the carbon atom chain length and associated with the presence of an ethyl moiety in the carbon atom backbone chain. Modifications or absence of this domain affected the gene induction response, suggesting a receptor-mediated mechanism(s). Moreover, propionate, butyrate, and the drug 4-phenylbutyrate were each shown to regulate transmitter genes via at least three independent mechanisms: histone hyperacetylation, cAMP signaling, or peroxisome proliferator-activated receptor gamma-mediated pathways. Thus, the biologic impact of SCFAs on catecholaminergic and opioid systems depend on the activation of SCFA-specific, dose-specific, and gene-specific molecular mechanisms. We speculate that 1) circulating levels of SCFAs may influence sympathoadrenal transmitter biosynthesis and hence whole animal stress-adaptive responsiveness after birth, and 2) the adverse effects of antibiotics on delayed acquisition of postnatal gut flora may affect this apparent evolutionary advantage of gut colonization. Sympathoadrenal transmitter systems mature to adult capacity a week or more after birth in response to progressive cholinergic innervation, exposure to growth factors, and hormonal influences from both the hypothalamic-pituitary-adrenal cortical and thyroid hormonal systems (1-6). Although the importance of these conventional control mechanisms is well established, the evolutionary significance of other exogenous stimuli can be considered in a broader view of environmentally derived signal-transduction. For example, the delayed period of adrenal transmitter accumulation after birth coincides with the time taken to establish full enteral feedings, colonization of the intestine, and attendant production of SCFA (7). Moreover, in the rat (as well as in humans), this time frame is far longer than the capacity of the chromaffin cell to rapidly induce biosynthesis of either catecholamines or enkephalins, which can occur in a matter of hours (8)