Clostridium butyricum Modulates the Microbiome to Protect Intestinal Barrier Function in Mice with Antibiotic-Induced Dysbiosis.

Clostridium butyricum MIYAIRI 588 (CBM 588) is a probiotic bacterium that has previously been used to prevent antibiotic-associated diarrhea. However, the underlying mechanism by which CBM 588 protects the gut epithelial barrier remains unclear. Here, we show that CBM 588 increased the abundance of Bifidobacterium, Lactobacillus, and Lactococcus species in the gut microbiome and also enhanced the intestinal barrier function of mice with antibiotic-induced dysbiosis. Additionally, CBM 588 significantly promoted the expansion of IL-17A-producing γδT cells and IL-17A-producing CD4 cells in the colonic lamina propria (cLP), which was closely associated with changes in the intestinal microbial composition. Additionally, CBM 588 plays an important role in controlling antibiotic-induced gut inflammation through upregulation of anti-inflammatory lipid metabolites such as palmitoleic acid, 15d-prostaglandin J2, and protectin D1. This study reveals a previously unrecognized mechanism of CBM 588 and provides new insights into gut epithelial barrier protection with probiotics under conditions of antibiotic-induced dysbiosis.

Prostaglandin E2 receptor EP3 subtype in the paraventricular hypothalamic nucleus mediates corticotropin-releasing factor-induced elevation of plasma noradrenaline levels in rats.

Corticotropin-releasing factor (CRF) plays an important role in sympathetic regulation. Centrally administered CRF elevates plasma catecholamine levels, resulting in CRF-dependent hypertension and tachycardia. We previously reported that brain thromboxane A2 mediates CRF-induced elevation of plasma adrenaline levels, whereas prostanoids other than thromboxane A2 mediate elevations in plasma noradrenaline levels. However, the mechanism by which CRF induces elevations in plasma noradrenaline levels remains unknown. Previous studies have revealed that brain prostaglandin (PG) E2, but not other PGs, causes sympathetic activation. In this study, we examined the roles of brain PGE2 and its receptors in CRF-induced elevation of plasma noradrenaline levels in rats. Our results showed that intracerebroventricular pretreatment with an antagonist of the PGE2 receptor EP3 subtype, but not other subtypes, suppressed CRF-induced elevations in plasma noradrenaline levels. We also examined the role of PGE2 and EP3 receptors in the paraventricular hypothalamic nucleus (PVN), the major integrative center for sympathetic regulation, in CRF-induced elevation of plasma noradrenaline levels. Centrally administered CRF increased PGE2 levels in PVN microdialysates, and microinjection of an EP3 receptor agonist into the PVN elevated plasma noradrenaline levels. Bilateral blockade of EP3 receptors in the PVN suppressed the elevation of plasma noradrenaline levels evoked by intracerebroventricular administration and PVN-microinjection of CRF. Our results suggest that CRF stimulates PGE2 release into the PVN that activates EP3 receptors in the PVN, resulting in the elevation of plasma noradrenaline levels.

GABAB receptors in the hypothalamic paraventricular nucleus mediate ß-adrenoceptor-induced elevations of plasma noradrenaline in rats.

In the brain, various neurotransmitters such as noradrenaline and GABA regulate peripheral sympathetic functions. Previously, it has been reported that both ß-adrenoceptor activation and GABAB receptor activation in the brain are involved in the elevation of plasma noradrenaline levels. However, it is unknown whether these pathways interact with each other. In the present study, we examined the relationship between the central actions of ß-adrenoceptor activation and GABAB receptor activation with regard to plasma noradrenaline responses using urethane-anesthetized rats. Intracerebroventricular pretreatment with the GABAA receptor antagonist bicuculline did not affect the ß-adrenoceptor agonist isoproterenol-induced elevation of plasma noradrenaline levels. In contrast, pretreatment with the GABAB receptor antagonist CGP 35348 suppressed the isoproterenol-induced elevation of noradrenaline levels. Intracerebroventricular pretreatment with the ß-adrenoceptor antagonist propranolol did not alter the GABAB receptor agonist baclofen-induced elevation of plasma noradrenaline levels. We next examined the central effects of ß-adrenoceptor activation on GABA release in the paraventricular hypothalamic nucleus (PVN), the major integrative center for sympathetic regulation in the brain. Intracerebroventricular administration of isoproterenol increased GABA content in PVN dialysates. In addition, baclofen microinjected unilaterally into the PVN resulted in elevated plasma levels of noradrenaline, but not adrenaline. Finally, unilateral blockade of GABAB receptors in the PVN suppressed the isoproterenol-induced elevation of plasma noradrenaline level. Our results suggest that activation of ß-adrenoceptors in the brain, likely in the PVN, induces GABA release in the PVN, which in turn activates GABAB receptors in the PVN, leading to elevated plasma noradrenaline.