Distinct Adrenal Medulla Activity in Germ-Free Versus Conventional Male Rats Under Acute and Chronic Stress.

It has now been well established that gut microbiota significantly influences emotional and neuroendocrine responses to stress. Specifically, multiple pieces of evidence from various preclinical models indicate that gut microbiota regulates the response of the hypothalamic-pituitary-adrenocortical (HPA) axis to acute and chronic stress. In contrast, the influence of gut microbiota on the adrenomedullary tissue, which is responsible for the production and release of catecholamines-the first hormones released in response to stress-has received little attention. Therefore, our study aimed to explore whether adrenal corticosterone and catecholamine biosynthesis were differently regulated in germ-free (GF) and conventional, specific pathogen-free (SPF) male rats when exposed to unpredictable chronic mild stress, acute metabolic stress, or both. Results showed that both GF and SPF chronically stressed rats had significantly (p < 0.05) heavier adrenal glands (+30% for GF, +21% for SPF) compared to unstressed animals. Gene expression levels of corticosterone biosynthesis enzymes and plasma and adrenal corticosterone concentrations did not differ significantly between control rats and those exposed to chronic, acute, or both stress factors, whether in GF or SPF rats. The same result was observed for the genes encoding tyrosine hydroxylase and dopamine β-hydroxylase, two enzymes involved in catecholamine biosynthesis. By contrast, GF rats exhibited a 2.3-fold increase (p = 0.0271) in Pnmt gene expression (which encodes phenylethanolamine N-methyltransferase, the enzyme responsible for converting norepinephrine to epinephrine) and a 2.6-fold increase (p = 0.0786) in epinephrine concentration in the adrenal glands under combined stress conditions. This response was not observed in SPF rats. In these animals, chronic stress was found to reshape the composition and metabolic functions of the gut microbiota. Interestingly, this was accompanied by a 40% decrease in norepinephrine (p = 0.0364) and epinephrine (p = 0.0840) concentrations in their adrenal glands. This study highlights the gut microbiota as a regulator of adrenomedullary activity, enhancing our understanding of the interaction between peripheral and central stress circuitry.