The Intestinal Microbiota Determines Mouse Behavior and Brain BDNF Levels

Abstract

Aim: Corticotropin-releasing hormone (CRH) is a major mediator of stress response in the brain-gut axis. We previously reported that peptidergic modification of CRH receptors changes visceral sensorimotor function in patients with irritable bowel syndrome (IBS). However, evidence how CRH agonist changes human brain function was lacking. We hypothesized that exogenous CRH accelerates regional brain activity during visceral stimulation in human. Methods: Sixteen healthy males aged 22.8 +/2.5 were randomly allocated into the CRH injection group and saline injection (placebo) group. A barostat bag was inserted into the colorectum and was randomly inflated with sham (0 mmHg), mild (20mmHg), or intense (40 mmHg) distention for 90s. CRH (2μg/dl) or placebo was then injected and same distention protocol was repeated. Radioactive H2[O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in regional cerebral blood flow were analyzed using statistical parametric mapping. Plasma adrenocorticotropic hormone (ACTH) and cortisol were measured at each stimulation. Results: Colorectal distention with 20 mmHg with CRH activated the right insula and parahippocampal gyrus significantly greater than that with placebo (p < 0.001). Colorectal distention with 40 mmHg with CRH activated the right dorsolateral prefrontal cortex, right orbitofrontal cortex, right insula, extended amygala, and pons significantly greater than that with placebo (p < 0.001). Twoway ANOVA of plasma ACTH showed significant CRH effect (p = 0.012), distention effect (p = 0.026) and CRH × distention interaction (p = 0.035). Post-hoc test of plasma ACTH revealed significantly higher level at 40mmHg with CRH than that with placebo (p = 0.011). Plasma cortisol showed similar pattern to plasma ACTH.Conclusion:During visceral stimulation in men, administration of CRH likely accelerates the activity of the brain regions which regulate interoception, hypothalamic regulation, stress coping, stress response, and negative emotion. These results also suggest that exogenous CRH may amplify ACTH and cortisol secretion due to colorectal distention.