Morinda Officinalis Oligosaccharides Alleviate Post‐Stroke Depression‐Like Behaviors Alongside Increased Gut Microbial Diversity and Butyrate Levels and Reduced Hippocampal Pla2g4a Expression

BACKGROUND AND PURPOSE: Post-stroke depression (PSD) represents a common and debilitating complication after cerebral ischemia, yet mechanism-based therapies remain an urgent unmet need. The microbiota-gut-brain axis has been implicated in PSD pathophysiology, but the precise molecular pathways are largely elusive. Morinda officinalis oligosaccharides (MOO), a clinically approved antidepressant in China, exhibit poor oral absorption, raising the possibility of a gut-dependent mechanism. EXPERIMENTAL APPROACH: Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion (MCAO) followed by 21 days of chronic restraint stress (CRS) to establish a PSD model. MOO (50 mg/kg/day) was administered via gavage from Day 7 to 27. Depression-like behaviors, 16S rRNA-based gut microbiota profiling, short-chain fatty acid (SCFA) quantification, intestinal and blood-brain barrier integrity assessments, and hippocampal proteomics were performed. The transferability of MOO-associated fecal effects was assessed using a donor-controlled fecal microbiota transplantation (FMT) design. The butyrate-Pla2g4a relationship was further examined by sodium butyrate supplementation and AAV-mediated hippocampal Pla2g4a overexpression. KEY RESULTS: MOO administration altered gut microbial composition, increased the abundance of probiotics and decreased the abundance of harmful bacteria, and was accompanied by increased fecal butyrate levels. The donor-controlled FMT experiment provided preliminary evidence that fecally transferable factors from MOO-treated PSD donors may contribute to behavioral improvements in PSD recipients. MOO and sodium butyrate treatment were associated with improved indices of intestinal and blood-brain barrier integrity. Hippocampal proteomics identified Pla2g4a, a phospholipase linked to neuroinflammation, as a candidate molecule related to the observed effects. Both MOO and sodium butyrate treatment were associated with reduced hippocampal Pla2g4a expression, and Pla2g4a expression was inversely correlated with butyrate levels. Hippocampal Pla2g4a overexpression attenuated the behavioral improvements associated with sodium butyrate treatment, supporting the functional involvement of Pla2g4a in the response to sodium butyrate. CONCLUSIONS AND IMPLICATIONS: MOO treatment was associated with improved depression-like behaviors in PSD mice, accompanied by gut microbial alterations, increased fecal butyrate, improved barrier integrity, and reduced hippocampal Pla2g4a expression. FMT findings provided preliminary evidence that fecally transferable factors from MOO-treated donors may contribute to behavioral improvements, while Pla2g4a overexpression attenuated the behavioral effects of sodium butyrate. These findings highlight a potential association among MOO, gut-derived butyrate, barrier integrity, and hippocampal Pla2g4a in PSD.