Fecal microbiota from chronically stressed donors transfers behavioral and prefrontal cortex gene expression...

Over the past decades, alterations in gut microbiota composition have emerged as a key contributor to the neurobiology of stress-related psychiatric conditions, including Major Depressive Disorder (MDD). Clinical and preclinical evidence consistently demonstrates correlational associations indicating that the gut microbiota not only responds to stress but also modulates the host stress response, thereby influencing behavioral domains relevant to depressive symptomatology. However, relatively few studies have investigated the causal relationship between stress-induced microbiota alterations and stress-associated behavioral impairments. Here, we examined the role of the enteric microbiota in stress-related behaviors using fecal microbiota transplantation (FMT) from animals exposed to a Chronic Unpredictable Stress (CUS) protocol to reproduce stress-associated behavioral phenotypes in recipient mice. Donor animals subjected to a 28-day CUS protocol exhibited behavioral alterations across despair-like, anhedonia-like, and anxiety-like domains, as assessed by the Novelty Suppressed Feeding, Sucrose Spray, Tail Suspension, and Elevated Plus Maze tests. FMT from stressed donors successfully transferred similar behavioral alterations to recipient animals. Dysregulated expression of synapsin 1 (Syn1) and oligodendrocyte transcription factor 1 (Olig1) was observed in the prefrontal cortex of both donor and recipient animals. In the hippocampus, CUS-exposed donors showed reduced Olig1 and a trend toward reduced Sox2 expression, whereas no significant hippocampal changes were detected in FMT recipients, suggesting that prefrontal, but not hippocampal, molecular alterations are preferentially transferable via the gut microbiota. Sequencing of the V4 region of the 16S rRNA gene revealed increased relative abundance of Lachnospiraceae and Parabacteroides and reduced Lactobacillales in both stressed donors and FMT recipients. In contrast, recipients of control microbiota exhibited higher levels of genera commonly associated with gut homeostasis, including Bacteroides, Ligilactobacillus and Lactobacillus. Together, our findings demonstrate that stress-induced microbiota alterations can mediate the transmission of stress-associated behavioral and molecular alterations, particularly in the prefrontal cortex, supporting the relevance of the gut-brain axis in stress-related disorders, while the underlying signaling mechanisms remain to be elucidated.