Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice
Authors: Zhou Manfei , Fan Yichun , Xu Liuting , Yu Zheng , Wang Sizhe , Xu Huaisha , Zhang Jiuping , Zhang Linwei , Liu Wenwei , Wu Linlin , Yu Jing , Yao Honghong , Wang Jun , Gao Rong 
Published: June 2023

Abstract
Background
Adolescent depression is becoming one of the major public health concerns, because of its increased prevalence and risk of significant functional impairment and suicidality. Clinical depression commonly emerges in adolescence; therefore, the prevention and intervention of depression at this stage is crucial. Recent evidence supports the importance of the gut microbiota (GM) in the modulation of multiple functions associated with depression through the gut-brain axis (GBA). However, the underlying mechanisms remain poorly understood. Therefore, in the current study, we aimed to screen the microbiota out from healthy and depressive adolescents, delineate the association of the targeted microbiota and the adolescent depression, address the salutary effects of the targeted microbiota on anti-depressive behaviors in mice involving the metabolism of the tryptophan (Trp)-derived neurotransmitters along the GBA.

Results
Here, we found the gut microbiota from healthy adolescent volunteers, first diagnosis patients of adolescent depression, and sertraline interveners after first diagnosis displayed significant difference, the relative abundance of Faecalibacterium, Roseburia, Collinsella, Blautia, Phascolarctobacterium, Lachnospiraceae-unclassified decreased in adolescent depressive patients, while restored after sertraline treatment. Of note, the Roseburia abundance exhibited a high efficiency in predicting adolescent depression. Intriguingly, transplantation of the fecal microbiota from healthy adolescent volunteers to the chronic restraint stress (CRS)-induced adolescent depressed mice significantly ameliorated mouse depressive behaviors, in which the Roseburia exerted critical roles, since its effective colonization in the mouse colon resulted in remarkably increased 5-HT level and reciprocally decreased kynurenine (Kyn) toxic metabolites quinolinic acid (Quin) and 3-hydroxykynurenine (3-HK) levels in both the mouse brain and colon. The specific roles of the Roseburia were further validated by the target bacteria transplantation mouse model, Roseburia intestinalis (Ri.) was gavaged to mice and importantly, it dramatically ameliorated CRS-induced mouse depressive behaviors, increased 5-HT levels in the brain and colon via promoting tryptophan hydroxylase-2 (TPH2) or -1 (TPH1) expression. Reciprocally, Ri. markedly restrained the limit-step enzyme responsible for kynurenine (indoleamine2,3-dioxygenase 1, IDO1) and quinolinic acid (3-hydroxyanthranilic acid 3,4-dioxygenase, 3HAO) generation, thereby decreased Kyn and Quin levels. Additionally, Ri. administration exerted a pivotal role in the protection of CRS-induced synaptic loss, microglial activation, and astrocyte maintenance.

Conclusions
This study is the first to delineate the beneficial effects of Ri. on adolescent depression by balancing Trp-derived neurotransmitter metabolism and improving synaptogenesis and glial maintenance, which may yield novel insights into the microbial markers and therapeutic strategies of GBA in adolescent depression.