Alteration of colonic circadian rhythm by gut microbiota dysbiosis and SCFA reduction links chronic stress-induced depressive-like behavior.

BACKGROUNDChronic stress partially leads to depression through the gut-brain axis, yet the underlying multi-level mechanisms remain unclear. This study aims to delineate the pathway from chronic restraint stress (CRS) to depressive-like behaviors, focusing on interactions among gut microbiota, their metabolites, and host transcriptional responses in the colon and hippocampus.

METHODSA CRS mice model was established and validated by behavioral tests. We performed 16S rRNA sequencing of gut microbiota, RNA-sequencing of colon and hippocampal tissues, and integrated these with assessments of intestinal histology, systemic and neuroinflammation, synaptic integrity, and levels of circulating neurotransmitters and microbial metabolites. Data were synthesized using bioinformatics and correlation network analyses.

RESULTSCRS induced significant depressive-like behaviors, hippocampal neuroinflammation, and synaptic damage. Additionally, it resulted in intestinal barrier damage, dysbiosis of the gut microbiota (e.g., an increase in Akkermansia/Dubosiella and a decrease in Ileibacterium), and a general decrease in fecal short-chain fatty acids (SCFAs). Transcriptomic analysis revealed tissue-specific disorders, with the circadian clock pathways in the colon (e.g. Nr1d1 and Nr1d2) being notably altered, while changes in the hippocampus were primarily concentrated on synaptic signaling. Correlation network analysis revealed significant correlations among microbiota alterations, reduced SCFAs, circadian clock gene dysregulation in the colon, systemic inflammation, and hippocampal pathological phenotypes.

CONCLUSIONThis study supports an integrated association framework linking gut microbiota imbalance, reduced SCFAs, colonic circadian alteration, and depressive-like behavior, and highlights a novel 'gut microbiota-SCFAs-colonic clock' axis associated with stress-related phenotypes. Disruption of this axis is correlated with systemic inflammation and alterations in the hippocampal synaptic gene network, providing a new target for the intervention of stress-related mental disorders.