AUTHOR=Shi Jiangwei , Yin Qingsheng , Zhang Lin , Wu Yu , Yi Pengrong , Guo Mengqing , Li Huhu , Yuan Liuyi , Wang Zixuan , Zhuang Pengwei , Zhang Yanjun 

TITLE=Zi Shen Wan Fang Attenuates Neuroinflammation and Cognitive Function Via Remodeling the Gut Microbiota in Diabetes-Induced Cognitive Impairment Mice

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.898360

DOI=10.3389/fphar.2022.898360

ISSN=1663-9812

ABSTRACT=Background: Cognitive dysfunction is a critical complication of diabetes mellitus, and there are still no clinically approved drugs. Increasing evidence suggests that maintaining intestinal microbiome homeostasis may be a therapeutic target for diabetic cognitive impairment (DCI). Zi Shen Wan Fang (ZSWF) is an optimized prescription composed of Anemarrhenae Rhizoma, Phellodendri Chinensis Cortex and Cistanches Herba. The purpose of this study is to investigate the effect of ZSWF on DCI and explore its mechanism from the perspective of maintaining intestinal microbial homeostasis, in order to find an effective prescription for treating DCI. 
Methods: The diabetes model was established by high-fat diet combined with intraperitoneal injections of streptozotocin (STZ, 120 mg/kg), and the DCI model was screened by Morris Water Maze (MWM) after 8 weeks of continuous hyperglycemic stimulation. The DCI mice were randomly divided into the model group (DCI), the low-, high-ZSWF-dose groups (9.63 g/kg, 18.72 g/kg), the mixed antibiotic group (ABs) and the ZSWF combined with mixed antibiotic group (ZSWF+ABs). ZSWF was administrated orally once a day for 8 weeks. Then, cognitive function was assessed using MWM, neuroinflammation and systemic inflammatoy were analyzed by ELISA kits, intestinal barrier integrity was assessed by hematoxylin-eosin (HE) staining, Western blot and high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Further, the alteration to intestinal flora was monitored by 16S rDNA sequencing.
Results: ZSWF restored cognitive function in DCI mice and reduced levels of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. Moreover, ZSWF protected the integrity of intestinal barrier by increasing intestinal Zo-1 and Occudin protein expression and decreasing urinary lactilose to mannitol ratio. ZSWF also reshaped the imbalanced gut microbiota in DCI mice by reversing the abundance changes of a wide range of intestinal bacteria at plyla and genus levels. Inversely, removing gut microbiota with antibiotics partially eliminated the effects of ZSWF on improving cognitive function and reducing inflammation, confirming the essential role of gut microbiota in the improvement of DCI by ZSWF. 
Conclusions: ZSWF can reverse cognitive impairment in DCI mice by remolding the structure of destructed gut microbiota community, which is a potential chinese medicine prescription for DCI treatment.