Prebiotic raffinose attenuates surgery-induced delirium-like behaviors through gut microbiota-mediated serotonergic signaling in frail senescence-accelerated mice: an experimental study using SAMP10 mice.

BACKGROUND: Postoperative delirium (POD) is a severe neuropsychiatric complication characterized by acute cognitive dysfunction and neuroinflammation, particularly prevalent in frail elderly patients. While the gut-brain axis is recognized as a regulator of neuroinflammation, specific preventive strategies remain limited. We investigated whether preoperative administration of raffinose, a prebiotic trisaccharide, prevents POD-like behaviors through gut microbiota-mediated neuroimmune modulation in frail senescence-accelerated mice. METHODS: Twenty-six-week-old senescence-accelerated mice (SAMP10) were randomly assigned to control (N), surgery (O), or raffinose-treated surgery (R) groups (n = 5-6 per group, depending on the endpoint). Raffinose (5% w/v) was administered via drinking water for 4 weeks prior to laparotomy under general anesthesia. Delirium-like behaviors were assessed using the open field, Y-maze, and buried food tests at 6 h post-surgery. Serum biomarkers were quantified via ELISA. Gut microbiota composition was analyzed using 16S rRNA sequencing. RESULTS: Surgery was associated with a numerical reduction in Y-maze spontaneous alternation that showed a large effect size but did not reach conventional statistical significance (O: 4.32 ± 3.46% vs. N: 10.71 ± 5.41%; p = 0.097, Cohen's d = 1.41, 95% CI -0.04 to 2.79), whereas a robust and statistically significant motivational deficit was observed in the Buried Food Test (O: 240.8 ± 116.7 s vs. N: 35.2 ± 25.6 s; p = 0.001, d = 2.52). Raffinose pretreatment was associated with higher Y-maze spontaneous alternation compared with the surgery group (R: 12.4 ± 4.20%; p = 0.034 vs. O, d = 2.10) and with restoration of motivational behavior in the BFT (R: 18.7 ± 4.74 s; p = 0.0006 vs. O, d = 2.77). Systemically, raffinose reduced circulating IL-6 by 56% and preserved gut microbial α- and β-diversity, with significant enrichment of Lactobacillus. Lactobacillus abundance was strongly correlated with preserved serum serotonin (r = 0.72, p = 0.003). CONCLUSIONS: Prebiotic raffinose attenuates surgery-induced systemic inflammation and preserves cognitive-attentional and motivational performance in frail mice, providing convergent behavioral, biochemical, and microbiome evidence consistent with a gut-microbiota-serotonergic mechanism, which requires direct causal validation in future studies. These findings provide a preclinical rationale for prehabilitation nutritional strategies targeting the gut-brain axis, while acknowledging that individual behavioral readouts differ in the strength of the surgery-induced control-vs-surgery contrast.