Mechanism of cognitiveimpairment induced by d-galactose and l-glutamate through gut-brain interaction in tree shrews.

Abstract

d-Galactose (d-gal) and l-glutamate (l-glu) impair learning and memory. The mechanism of interaction between the gutmicrobiome and brain remains unclear. In this study, a model of cognitive impairment was induced in tree shrews by intraperitoneal (ip) injection of d-gal (600mg/kg/day), intragastric (ig) administration with l-glu (2000mg/kg/day), and the combination of d-gal (ip, 600mg/kg/day) and l-glu (ig, 2000mg/kg/day). The cognitive function of tree shrews was tested by the Morris water maze method. The expression of Aβ1-42 proteins, the intestinal barrier function proteins occludin and P-glycoprotein (P-gp), and the inflammatory factors NF-κB, TLR2, and IL-18 was determined by immunohistochemistry. The gutmicrobiome was analyzed by 16SrRNA high-throughput sequencing. After administering d-gal and l-glu, the escape latency increased (p<.01), and the times of crossing the platform decreased (p<.01). These changes were greater in the combinedadministration of d-gal and l-glu (p<.01). The expression of Aβ1-42 was higher in the perinuclear region of the cerebral cortex (p<.01) and intestinal cell (p<.05). There was a positive correlation between the cerebral cortex and intestinal tissue. Moreover, the expression of NF-κB, TLR2, IL-18, and P-gp was higher in the intestine (p<.05), while the expression of occludin and the diversity of gut microbes were lower, which altered the biological barrier of intestinal mucosal cells. This study indicated that d-gal and l-glu could induce cognitiveimpairment, increase the expression of Aβ1-42 in the cerebral cortex and intestinal tissue, decrease the gut microbial diversity, and alter theexpression of inflammatory factors in the mucosal intestines. The dysbacteriosis may produce inflammatory cytokines to modulate neurotransmission, causing the pathogenesis of cognitiveimpairment. This study provides a theoretical basis to explore the mechanism of learning and memory impairment through the interaction of microbes in the gut and the brain.