Effects of Oligosaccharides From Morinda officinalis on Gut Microbiota and Metabolome of APP/PS1 Transgenic Mice - PubMed (original) (raw)

doi: 10.3389/fneur.2018.00412. eCollection 2018.

Chen Diling 3, Yang Jian 3, Liu Ting 2, Hu Guoyan 2, Liang Hualun 4, Tang Xiaocui 3, Lai Guoxiao 3 5, Shuai Ou 3, Zheng Chaoqun 3, Zhao Jun 6, Xie Yizhen 3

Affiliations

Effects of Oligosaccharides From Morinda officinalis on Gut Microbiota and Metabolome of APP/PS1 Transgenic Mice

Yang Xin et al. Front Neurol. 2018.

Abstract

Alzheimer's disease (AD), a progressive neurodegenerative disorder, lacks preclinical diagnostic biomarkers and therapeutic drugs. Thus, earlier intervention in AD is a top priority. Studies have shown that the gut microbiota influences central nervous system disorders and that prebiotics can improve the cognition of hosts with AD, but these effects are not well understood. Preliminary research has shown that oligosaccharides from Morinda officinalis (OMO) are a useful prebiotic and cause substantial memory improvements in animal models of AD; however, the mechanism is still unclear. Therefore, this study was conducted to investigate whether OMO are clinically effective in alleviating AD by improving gut microbiota. OMO were administered to APP/PS1 transgenic mice, and potential clinical biomarkers of AD were identified with metabolomics and bioinformatics. Behavioral experiments demonstrated that OMO significantly ameliorated the memory of the AD animal model. Histological changes indicated that OMO ameliorated brain tissue swelling and neuronal apoptosis and downregulated the expression of the intracellular AD marker Aβ1-42. 16S rRNA sequencing analyses indicated that OMO maintained the diversity and stability of the microbial community. The data also indicated that OMO are an efficacious prebiotic in an animal model of AD, regulating the composition and metabolism of the gut microbiota. A serum metabolomics assay was performed using UHPLC-LTQ Orbitrap mass spectrometry to delineate the metabolic changes and potential early biomarkers in APP/PS1 transgenic mice. Multivariate statistical analysis showed that 14 metabolites were significantly upregulated, and 8 metabolites were downregulated in the model animals compared to the normal controls. Thus, key metabolites represent early indicators of the development of AD. Overall, we report a drug and signaling pathway with therapeutic potential, including proteins associated with cognitive deficits in normal mice or gene mutations that cause AD.

Keywords: APP/PS1 transgenic mice; Alzheimer's disease; gut microbiota; metabolites; metabolomics; oligosaccharides of Morinda officinalis.

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Figures

Figure 1

Figure 1

Effect of OMO on APP/PS1 transgenic mice. Body weight changes were measured weekly (A). Escape latencies in the H maze (B) and probe test results (C), and histopathological changes in brain tissues (D) are shown. N represents the C57 group, M denotes the APP/PS1 transgenic group, BD indicates the group treated with 50 mg/kg OMO, and BH designates the group treated with 100 mg/kg OMO; the treatments were administered for 6 months (n = 10). Values are presented as the means ± SDs of six independent experiments. #p < 0.05 compared with the control group; **p < 0.01 compared with the M group.

Figure 2

Figure 2

Effects of OMO on the gut microbiota of the APP/PS1 transgenic mice, as determined from fecal samples. The rarefaction curve (A), the results of the NMDS analysis (B), PLS-DA results (C), classification and abundance of fecal contents at the phylum level (D), and the results of 16S rRNA sequencing of the gut microbiota using an Illumina MiSeq sequencing system are shown. N denotes the C57 group, M represents the APP/PS1 transgenic group, BD denotes the 50 mg/kg OMO-treated group, and BH indicates the 100 mg/kg OMO-treated group.

Figure 3

Figure 3

Effects of OMO on the microbiota in fecal samples from the APP/PS1 transgenic mice. A Venn diagram of OTUs (A), a sample species classification tree (B), and the heatmap of 16S rRNA gene sequencing analysis of fecal contents at the genus level (C) are shown. N denotes the control group, M denotes the APP/PS1 transgenic group, and BD designates the 50 mg/kg OMO-treated group.

Figure 4

Figure 4

Effects of OMO on the microbiota in fecal samples from the APP/PS1 transgenic mice. The graph in (A) shows the classification and abundance of fecal contents at the phylum level, (B) shows the classification and abundance of fecal contents at the family level, and (C) shows the results of the KEGG pathway enrichment analysis of the gut microbiota with respect to the metabolic systems. Values are presented as the means of six independent experiments. N denotes the control group, M represents the APP/PS1 transgenic group, and BD designates the 50 mg/kg OMO-treated group.

Figure 5

Figure 5

Analysis of the metabolic profiles based on the UPLC/MS spectra of serum samples. Serum BPI chromatograms of APP/PS1 and wild-type mice collected in positive ion mode (A) and negative ion mode (B). N denotes the control group, M represents the APP/PS1 transgenic group, BD denotes the 50 mg/kg OMO-treated group, and BH designates the 100 mg/kg OMO-treated group.

Figure 6

Figure 6

Score plots of metabolite levels in a serum sample. OPLS-DA score plots of the serum metabolic profile (A): (a) N vs. BD, (b) N vs. BH, and (c) N vs. M. Permutation score plots of serum metabolic profiles (B): (a) N vs. BD, (b) N vs. BH, and (c) N vs. M. Loading score plot of the serum metabolic profile (C): (a) N vs. BD, (b) N vs. BH, and (c) N vs. M. N denotes the control group, M represents the APP/PS1 transgenic group, BD denotes the 50 mg/kg OMO-treated group, and BH represents the 100 mg/kg OMO-treated group.

Figure 7

Figure 7

Comparison of the relative intensities of the potential biomarkers (A). KEGG pathway annotations of differentially expressed genes in serum samples (B). Heatmap showing the levels of 24 different metabolites (C). The degree of change is marked with different colors: red represents upregulation, and green indicates downregulation. Each row represents an individual sample, and each column represents a metabolite. N denotes the C57 mice, M represents the APP/PS1 transgenic mice, BD indicates the group treated with 50 mg/kg OMO, and BH denotes the group treated with 100 mg/kg OMO. Values are presented as the means ± SDs of six independent experiments. #p < 0.05 compared with the control group; *p < 0.05 and **p < 0.01 compared with the M group.

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