果寡糖恢复肠道功能并增加海马体短链脂肪酸水平，以缓解慢性脑灌注不足大鼠模型中线粒体自噬诱导的神经元凋亡

Abstract

Chronic cerebral hypoperfusion (CCH) contributes to vascular dementia (VaD) through intestinal dysfunction, reduced hippocampal short-chain fatty acids (SCFAs), neuroinflammation, mitochondrial dysfunction, and neuronal apoptosis. This study investigated whether fructooligosaccharides (FOS) alleviate CCH-induced cognitive and intestinal dysfunction and explored the potential involvement of SCFA-associated gut–brain signaling. CCH was induced in male Sprague–Dawley rats by bilateral common carotid artery occlusion (BCCAO). Rats were assigned to Sham, BCCAO, Sham + FOS, and BCCAO + FOS groups, and FOS were administered orally at 14 g/kg/day for four weeks. Cognitive function, intestinal barrier integrity, hippocampal SCFAs, neuroinflammation, apoptosis, and mitophagy were assessed. Primary neurons exposed to hypoxia were treated with SCFAs to evaluate apoptosis and mitophagy. FOS improved locomotor activity, anxiety-like behavior, spatial learning, and memory in BCCAO rats. FOS restored colonic goblet cells ( P  < 0.001) and ZO-1 expression ( P  < 0.01) and reduced intestinal TNF-α, IL-6, IL-17, and IL-33 levels ( P  < 0.05). In the hippocampus, FOS increased acetate and valerate levels ( P  < 0.05), decreased TNF-α and IL-33 expression, reduced cleaved caspase-3 ( P  < 0.01), preserved NeuN-positive neurons ( P  < 0.05), and alleviated mitochondrial injury. BCCAO-induced increases in P62, LC3B, Beclin-1, BNIP3, and NIX ( P  < 0.05) were attenuated by FOS, whereas PINK1/Parkin signaling remained unchanged. In primary neurons, SCFAs reduced CoCl₂-induced apoptosis and BNIP3/NIX activation and preserved MAP2/Tau-positive neuronal morphology. FOS alleviated intestinal barrier dysfunction, neuroinflammation, neuronal apoptosis, and cognitive impairment after CCH. These effects were accompanied by increased hippocampal SCFAs and changes in BNIP3/NIX-related mitophagy, supporting a potential role for SCFA-associated gut–brain signaling in FOS-mediated neuroprotection.