<b>Characterization of Gut Microbiome and Cognition in Adolescents with and without Subthreshold Depression: A Shotgun Metagenomics Sequencing Study</b>

To investigate the association between gut microbiome and cognitive function in adolescents with subthreshold Depression (SD). Thirty-eight adolescents with SD and 139 clinically-well (CW) adolescents were recruited. Gut microbiome and cognitive function were assessed by metagenomic sequencing and the MATRICS Consensus Cognitive Battery (MCCB), respectively. Compared with the CW adolescents, the SD group showed higher relative abundance of <i>Spirochaetes, Synergistetes, Spirochaetia, Synergistia,</i><i> </i><i>Spirochaetales, Rhizobiales,</i><i> </i><i>Synergistales, Thermoanaerobacterales, Rhodospirillales, </i><i>Synergistaceae</i> and <i>Oxalobacteraceae</i> at four levels. The Spatial Span scores were higher in the SD group compared to the CW groups. Moreover, EggNOG analyses showed a significant negative correlation of the intracellular trafficking secretion and vesicular transport with the Spatial Span scores. The KEGG pathway of the neurodegenerative diseases and translation was depleted in the microbiome of adolescents with SD. The higher abundance of <i>Spirochaetes, Spirochaetia</i> and <i>Spirochaetales</i> were the best predictors of SD in adolescents. Our findings suggest that gut microbiome dysbiosis, depressive symptoms, and cognitive influences co-occur in adolescents with SD, which may play a crucial role in the pathogenesis of SD and cognitive function in adolescent. Gut microbiome may serve as a potential biomarker for the identification and treatment of adolescents with SD.