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Aging and disease
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Prebiotics Regulation of Intestinal Microbiota Attenuates Cognitive Dysfunction Induced by Surgery Stimulation in APP/PS1 Mice
Dengyang Han1, Zhengqian Li1, Taotao Liu1, Ning Yang1, Yue Li1, Jindan He1, Min Qian1, Zhongshen Kuang1, Wen Zhang2, Cheng Ni1,*, Xiangyang Guo1,*
1 Department of Anesthesiology, Peking University Third Hospital, Beijing, China
2 National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China
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Emerging evidence indicates that the intestinal microbiota could interact with the central nervous system and modulate multiple pathophysiological changes, including the integrity of intestinal barrier and blood-brain barrier, as well as neuroinflammatory response. In the present study, we investigated the potential role of intestinal microbiota in the pathophysiological process of postoperative cognitive dysfunction. Six-month-old APP/PS1 mice were subjected to partial hepatectomy to establish surgery model and exhibited cognitive dysfunction. The expressions of inflammatory mediators increased and tight junction proteins (ZO-1 and Occludin) levels decreased in the intestine and hippocampus. The 16S ribosomal RNA gene sequencing showed altered β diversity and intestinal microbiota richness after surgery, including genus Rodentibacter, Bacteroides, Ruminococcaceae_UCG_014 and Faecalibaculum, as well as family Eggerthellaceae and Muribaculaceae. Furthermore, prebiotics (Xylooligosaccharides, XOS) intervention effectively attenuated surgery-induced cognitive dysfunction and intestinal microbiota alteration, reduced inflammatory responses, and improved the integrity of tight junction barrier in the intestine and hippocampus. In summary, the present study indicates that intestinal microbiota alteration, the related intestinal barrier and blood-brain barrier damage, and inflammatory responses participate the pathophysiological process of postoperative cognitive dysfunction. Prebiotics intervention could be a potential preventative approach.

Keywords intestinal microbiota      xylooligosaccharides      postoperative cognitive dysfunction      tight junction      inflammation.     
Corresponding Authors: Cheng Ni,Xiangyang Guo   
Just Accepted Date: 08 January 2020  
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Dengyang Han
Zhengqian Li
Taotao Liu
Ning Yang
Yue Li
Jindan He
Min Qian
Zhongshen Kuang
Wen Zhang
Cheng Ni
Xiangyang Guo
Cite this article:   
Dengyang Han,Zhengqian Li,Taotao Liu, et al. Prebiotics Regulation of Intestinal Microbiota Attenuates Cognitive Dysfunction Induced by Surgery Stimulation in APP/PS1 Mice[J]. Aging and disease, 10.14336/AD.2020.0106
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ALT (U/L)AST (U/L)ALP (U/L)TP (g/L)ALB (g/L)GLU (mmol/L)
Table 1  Liver function and glucose levels after experimental interventions.
Figure 1.  Surgery plus sevoflurane anesthesia, but not anesthesia alone, impaired spatial memory in APP/PS1 mice. (A) The mice in surgery (S) group, but not anesthesia group, had a longer escape latency on postoperative day two and three compared with control (Con) group. (B) There was no difference among three groups in swimming speeds during the training and probe tests. (C) The platform crossings of S group were significantly decreased on postoperative day three compared with Con group. (D) The trajectory of probe trial test of three groups on postoperative day three. Results were presented as mean ± SEM (n = 10). Two-way ANOVA with post-hoc Bonferroni test, *p<0.05, **p<0.01 compared with Con group, # p<0.05, # # p<0.05 compared with anesthesia group.
Figure 2.  XOS intervention attenuated spatial memory deficit of APP/PS1 mice induced by surgery. (A) The mice in S group had a longer escape latency on postoperative day two and three than Con group. (B) There was no difference among four groups in swimming speeds during the training and probe tests. (C) The platform crossings in S group were decreased on postoperative day three compared with Con or XOS+S groups. (D) The trajectory of probe trial test of 4 groups on postoperative day three. Results were presented as mean ± SEM (n = 10). Two-way ANOVA with post-hoc Bonferroni test, *p<0.05, **p<0.01 compared with Con group, # p<0.05 compared with S group.
Figure 3.  XOS intervention attenuated intestinal microbiota alteration induced by surgery. (A) Taxonomic cladogram obtained from linear discriminant analysis effect size (LEfSe). Biomarker taxa are highlighted by colored circles and shaded areas. The diameter of each circle reflects the abundance of that taxa in the community. (B) Taxa with a different abundance among four groups, and a total of 46 taxa were screened out with a linear discriminant analysis threshold score of 2.0. (C) The principal co-ordinates analysis (three-dimensional) of the intestinal microbiome composition on the genus level based on the weighted-unifrac distance among the four groups (n=6), Kruskal-Wallis test p<0.05 and log 10 LDA threshold=2.
Figure 4.  XOS intervention attenuated intestinal microbiota alteration induced by surgery Chart of the relative abundance of the differential levels of bacteria at the genus and family level. (A-C) Three genera (Rodentibacter, Bacteroides, Ruminococcaceae_UCG_014) were increased in S group compared with Con group, and XOS intervention attenuated the increase of these three genera after surgery. (D) One genus (Faecalibaculum) was decreased in S group compared with Con group, and XOS intervention attenuated the decrease of this genus after surgery. (E and F) Two genus (Muribaculum and Lactobacillus) were increased in XOS+S group compared with S group. (G) One family (Eggerthellaceae) was increased in S group compared with Con group, and XOS intervention attenuated the decrease of this genus after surgery. (H) One family (Muribaculaceae) was decreased in S group compared with Con group, and XOS intervention attenuated the decrease of this genus after surgery. Results were presented as mean ± SEM (n = 6). Two-way ANOVA with post hoc Bonferroni test, *p<0.05; **p<0.01; ***p<0.001.
Figure 5.  XOS intervention attenuated intestinal inflammation and barrier integrity damage induced by surgery. (A) IL-1β, IL-6 and IL-10 levels were increased in the intestine of mice in S group compared with Con group, and XOS intervention ameliorated the increase of IL-1β, IL-6 and IL-10 after surgery. (B and C) Western blot analysis showed that tight junction protein levels of ZO-1 and Occludin were downregulated in S group compared with Con group, and XOS increased the expression of ZO-1 and Occludin after surgery. There was no difference among four groups for Claudin-5 expression. Results were presented as mean ± SEM (n = 6). Two-way ANOVA with post hoc Bonferroni test, *p<0.05, **p<0.01.
Figure 6.  XOS intervention attenuated BBB disruption induced by surgery. (A and B) There was a decrease in the expression of tight junction proteins ZO-1 and Occludin in S group compared with Con group, and XOS intervention increased the expression of ZO-1 and Occludin after surgery. There was no difference among four groups for Claudin-5 expression in the hippocampus. (C) The transmission electron microscopy showed that the ultrastructure of the basal laminas of mice in Con group was continuous and integrated, while the mice in S group had BBB impairments on postoperative day two. XOS intervention ameliorated the disruption of the BBB ultrastructure after surgery. The arrow heads represent the basal laminas of BBB. Results were presented as mean ± SEM (n = 6). Two-way ANOVA with post hoc Bonferroni test, *p<0.05, **p<0.01.
Figure 7.  XOS intervention attenuated neuroinflammatory response induced by surgery. (A) IL-1β, IL-6 and IL-10 levels were increased in the hippocampus of mice in the S group compared with Con group, and XOS intervention attenuated the increase of IL-1β, IL-6 and IL-10 after surgery. The level of TNF-α was not changed among four groups. (B and C) The immunofluorescence showed an increase of Iba-1 positive cells in CA1 region and dentate gyrus in S group compared with Con group, and XOS intervention attenuated the increase of Iba-1 positive cells after surgery. (D) Western blot analysis showed that Iba-1 expression was increased in S group compared with Con group, and XOS intervention attenuated the increase of Iba-1 expression after surgery. (E) The expression of TREM2 was decreased in S group compared with Con group, and XOS intervention attenuated the decrease of TREM2 expression after surgery. Results were presented as mean ± SEM (n = 6). Two-way ANOVA with post hoc Bonferroni test, *p<0.05, **p<0.01, ***p<0.001.
Figure 8.  Schematic illustration of the proposed intestinal microbiota related mechanisms underlying cognitive dysfunction in APP/PS1 mice after surgery stimulation (partial hepatectomy). Surgery stimulation (partial hepatectomy) induces intestinal dysbiosis, intestinal inflammatory response and barrier damage, then hippocampal blood brain barrier damage and neuroinflammatory response, and results in cognitive dysfunction in in APP/PS1 mice. XOS stabilizes intestinal microbiota and inhibits the pathophysiological process after surgery and protects the cognitive function.
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