Bacteroides Species Differentially Modulate Depression- Like Behavior via Gut-Brain Metabolic Signaling1

Gut microbiome disturbances have been widely implicated in major depressive disorder (MDD), although the identity of causal microbial species and the underlying mechanisms are yet to be fully elucidated. Here we show that Bacteroides species enriched in the gut microbiome from MDD patients differentially contribute to the susceptibility to depressive behaviors. Transplantation of fecal microbiota from MDD patients into antibiotic-treated mice induced anxiety and despair-like behavior and impaired hippocampal neurogenesis. Colonization of Bacteroides fragilis, Bacteroides uniformis, and, to a lesser extent, Bacteroides caccae, but not Bacteroides ovatus, recapitulated the negative effects of MDD microbiota on behavior and neurogenesis. The varying impact of Bacteroides species was explained by differential alternations of tryptophan pathway metabolites and neurotransmitter levels along the gut-brain axis. Notably, an intensified depletion of cerebral serotonin concurred with the enhanced susceptibility to depression. Together, these findings identify select Bacteroidetes species that contribute to depression susceptibility by metabolic regulation along the gut-brain axis.