Coprococcus eutactus screened from healthy adolescent attenuates chronic restraint stress-induced depression-like changes in adolescent mice: Potential roles in the microbiome and neurotransmitter modulation.

ABSTRACT

The onset of depression commonly occurs in adolescence; therefore, depressive prevention and intervention are pivotal during this period. It is becoming evident that neurotransmitter imbalance and gut microbiota dysbiosis are prominent causes of depression. However, the underlying links and mechanisms remain poorly understood. In this study, with 16S ribosomal RNA gene sequencing, genus Coprococcus markedly differentiated between the healthy and unmedicated depressive adolescents. Based on this, transplantation of Coprococcus eutactus (C.e.) was found to dramatically ameliorate the chronic restraint stress (CRS) induced depression-like changes and prevent synaptic loss and glial-stimulated neuroinflammation in mice. The Ultra-high performance liquid chromatography tandem mass spectrometry analysis (UHPLC-MS/MS) further showed that neurotoxic neurotransmitters in kynurenine pathway (KP) such as 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) decreased in mouse brains, mechanistically deciphering the transfer of the tryptophan metabolic pathway to serotonin metabolic signaling in the brain after C.e. treatment, which was also verified in the colon. Molecularly, blockage of KP activities mediated by C.e. was ascribed to the restraint of the limit-step enzymes responsible for kynurenine, 3-HK, and quinolinic acid generation. In the colon, C.e. treatment significantly recovered goblet cells and mucus secretion in CRS mice which may ascribe to the rebalance of the disordered gut microbiota, especially Akkermansia, Roseburia, Rikenella, Blautia, and Alloprevotella. Taken together, the current study reveals for the first time the beneficial effects and potential mechanisms of C.e. in ameliorating CRS-induced depression, unraveling the direct links between C.e. treatment and neurotransmitter rebalance, which may provide efficacious therapeutic avenues for adolescent depressive intervention.