Binbin Shao,1 Yanfei Nong,1 Yongshuang Lin,2 Yan Meng,1 Yi Zhou,1 Meiying Huang,3 Feifan Huang,3 Jie Wang3 

1Graduate School, Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, People’s Republic of China; 2The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning, 530000, People’s Republic of China; 3Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, People’s Republic of China

Correspondence: Jie Wang, Email yyfywj@126.com

Objective: To investigate the mechanism by which resveratrol (Res) ameliorates cognitive impairment (CI) in chronic kidney disease (CKD) rats through modulation of gut microbiota and suppression of inflammation.
Methods: A CKD model was established in rats via two intravenous injections of doxorubicin (4 mg/kg, 2 weeks apart). After 8 weeks, renal function and histopathological assessments were performed to confirm the establishment of the CKD model.Rats were divided into control, CKD, and CKD+Res groups. The CKD+Res group received intragastric Res for 6 weeks. Cognitive function was assessed using the Morris water maze. Serum Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Lipopolysaccharide (LPS) levels were measured via ELISA. Histopathology evaluated kidney, colon, and hippocampal damage. Gut microbiota composition was analyzed by 16S rRNA sequencing, and hippocampal Toll-Like Receptor 4 (TLR4)/ the Nuclear Factor-κB (NFκB) pathway proteins were quantified via Western blot.
Results: CKD groups exhibited elevated 24-hour urinary albumin, serum urea nitrogen, and creatinine (P < 0.01), with glomerular atrophy. During water maze navigation (days 3– 4), CKD groups showed prolonged escape latency and increased swimming distance versus controls (P < 0.05), which Res intervention alleviated (P < 0.05). In the spatial probe test, CKD rats had fewer platform crossings and shorter target quadrant occupancy (P < 0.01; P < 0.05), both improved by Res (P < 0.05). Hippocampal neuronal damage and elevated serum IL-6, TNF-α, and LPS levels (P < 0.01) were observed in CKD rats, while Res reduced IL-6 and LPS (P < 0.05). Western blot revealed upregulated TLR4/NFκB pathway activation in the CKD group (P < 0.01), suppressed by Res (P < 0.05). Gut microbiota analysis showed increased Gram-negative bacteria in CKD rats and higher Gram-positive bacteria abundance in the Res group. LPS biosynthesis was enhanced in CKD rats (P < 0.05) but attenuated by Res.

Keywords: resveratrol, chronic kidney disease, CKD, cognitive impairment, gut microbiota, TLR4/NFκB pathway