Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 May 26:13:875101.
doi: 10.3389/fmicb.2022.875101. eCollection 2022.

Integrated Microbiome and Host Transcriptome Profiles Link Parkinson's Disease to Blautia Genus: Evidence From Feces, Blood, and Brain

Xingzhi Guo  1   2   3 , Peng Tang  1   2 , Chen Hou  1   2 , Li Chong  1   2 , Xin Zhang  1   2 , Peng Liu  1   2 , Li Chen  1   2 , Yue Liu  1   2 , Lina Zhang  1   2 , Rui Li  1   2   3
Affiliations

Integrated Microbiome and Host Transcriptome Profiles Link Parkinson's Disease to Blautia Genus: Evidence From Feces, Blood, and Brain

Xingzhi Guo et al. Front Microbiol. .

Abstract

A link between the gut microbiome and Parkinson's disease (PD) has been intensively studied, and more than 100 differential genera were identified across the studies. However, the predominant genera contributing to PD remain poorly understood. Inspired by recent advances showing microbiota distribution in the blood and brain, we, here, comprehensively investigated currently available fecal microbiome data (1,914 samples) to identify significantly altered genera, which were further validated by comparison to the results from microbiome analysis of blood (85 samples) and brain (268 samples). Our data showed that the composition of fecal microbiota was different from that of blood and brain. We found that Blautia was the unique genus consistently depleted across feces, blood, and brain samples of PD patients (P < 0.05), despite using rigorous criteria to remove contaminants. Moreover, enrichment analyses revealed that host genes correlated with Blautia genus abundance were mainly involved in mitochondrial function and energy metabolism, and mapped to neurodegenerative diseases (NDDs) and metabolic diseases. A random forest classifier constructed with fecal microbiota data demonstrated that Blautia genus was an important feature contributing to discriminating PD patients from controls [receiver operating characteristic (ROC)-area under curve (AUC) = 0.704, precision-recall curve (PRC)-AUC = 0.787]. Through the integration of microbiome and transcriptome, our study depicted microbial profiles in the feces, blood, and brain of PD patients, and identified Blautia genus as a potential genus linked to PD. Further studies are greatly encouraged to determine the role of Blautia genus in the pathogenesis of PD.

Keywords: 16S; Blautia; Parkinson’s disease; feces; microbiome.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The geographical distribution of included studies and integrative meta-analysis pipeline. There were ten, one, and five studies included in microbiota analysis for feces (16S rRNA), blood (16S rRNA), brain (RNA-Seq) individually, and nine brain microarray studies were enrolled in transcriptome analysis (A). Raw sequence data were downloaded from SRA and ENA database, and brain transcriptome data (microarray) were downloaded from GEO. 16S rRNA sequences were processed with DADA2/QIIME2 pipeline to obtain taxonomy data, and also were processed PICRUSt2 for functional prediction (B). The five RNA-Seq studies used in microbiota analysis (Kraken2) were also used in brain transcriptome analysis (GREIN web platform) (B). Different genera and genes (RNS-Seq) were first calculated with DESeq2 in each study, and then pooled together using fixed effect model meta-analysis. Enrichment analyses (GO, KEGG, and GSEA) were performed using genes significantly associated with commonly changed genera (B).
FIGURE 2
FIGURE 2
The fecal microbiota composition in PD patients and controls. All microbiota composition data here were first filtered with the pan-contaminants list before further analysis. There were 18 genera with an average relative abundance more than 0.5% across all fecal samples (A). (B) Showed the microbiota composition among feces, blood, and brain samples of patients with PD and controls at the genus level after removing the contaminants (not pan-contaminants). The major fecal Phylum were Firmicutes and Bacteroidetes, while the main Phylum in blood and brain were Proteobacteria and Actinobacteria (B). There was obvious Firmicutes proportion in PD brain, which were almost depleted after filtering the brain genera data using pan-contaminants list (Supplementary Figure 2). The α-diversity, including Observed, Shannon, Simpson and Chao1 indices, was significantly increased in the feces of PD patients compared to controls (C). There was an obvious difference in β-diversity between PD patients and controls with Bray–Curtis distance (adonis: R = 0.009, P = 0.001) (D). ****: P value less than 0.0001, ***: P value less than 0.005.
FIGURE 3
FIGURE 3
Heatmap showing the different genera among feces, blood, and brain between patients with PD and controls. All microbiota data here were first filtered with the pan-contaminants list. Most of genera in feces and blood were not shown in the brain. Blautia was the only genus decreased among feces, blood, and brain samples (labeled in red). Bacteroides genus was also found to be decreased in both feces and brain samples, but not in blood samples. The blank rectangle area in the heatmap without any annotation means genera not found in corresponding sample type. **: P value less than 0.01, *: P value less than 0.05, ns: no significance.
FIGURE 4
FIGURE 4
The biotype distribution of genes significantly associated with Blautia genus. A Spearman correlation analysis was performed between Blautia genus with all host genes identified from RNA-Seq using the GREIN (http://www.ilincs.org/apps/grein/?gse=). The relative abundance of microbiota composition data and log2 transformed genes counts were used to calculate r values with limma (V.3.46.0) package. The absolute r values ranged from 0.12 to 479 with P less than 0.05. An absolute r value greater than 0.3 and P value less than 0.05 was considered as significant correlation. The biotype of all genes was classified with the biomaRt (V.2.46.3) package and was described in Manhattan plot (A). The top nine genes (including lncRNA) with an absolute r value greater than 0.45 were labeled with corresponding gene symbol (A). An UpSet plot showed the KEGG results of Blautia genus correlated genes (|r| > 0.3 and p < 0.05) (B).
FIGURE 5
FIGURE 5
Descriptions of DEGs (RNA-Seq) significantly associated with Blautia genus. A Venn graph showing the intersected DEGs between RNA-Seq and microarray data, and genes significantly correlated with Blautia genus (|r| > 0.3 and p < 0.05). A total of 1,357 DEGs associated with Blautia genus were only detectable in RNA-Seq data, but not in microarray data (A). On the other hand, 36 DEGs associated with Blautia genus were found in both RNA-Seq and microarray data (A). Over 98% genes identified in microarray data were also detectable in RNA-Seq data (Supplementary Figure 7A). A volcano plot showed the distribution of Blautia genus associated genes identified from RNA-Seq data (B). Red dots indicated increased expression, while green dots indicated decreased expression in PD. Black dot signified no statistical significance (B). Those DEGs with absolute effect size greater than 0.5 were labeled with corresponding gene symbol. The CNet plot showed the KEGG results of DEGs significantly associated with Blautia genus (C). The top five enriched KEGG terms mapped by the DEGs were DCM, PD (labeled with red), HD, NAFLD, and oxidative phosphorylation (C).
FIGURE 6
FIGURE 6
GSEA based GO enrichment analysis of DEGs (RNA-Seq) significantly associated with Blautia genus. The gseGO showed that DEGs associated with Blautia genus (|r| > 0.3 and p < 0.05) were mainly targeted to inflammatory response and mitochondrial function (A). Blautia genus related DEGs enriched in inflammation were significantly increased in PD (B). Most of Blautia genus related DEGs involved in mitochondrial function were decreased (C). (D) Showed that the DEGs associated with mRNA binding were increased.
FIGURE 7
FIGURE 7
Interpretation and evaluation plot of the RF model in feces for detecting PD. An overview of the top 30 important features (genera) contributing to the predictive power of the random forest (RF) model for detecting PD were presented (A). It showed that Blautia genus was the 2nd important feature for the RF model in discriminating PD patients from controls, and was also decreased in the feces of PD patients, which was same to results found in the brain and blood samples (Supplementary Figures 12, 13). The receiver operating characteristic curve (ROC) was plotted and AUC value from five folds cross-validation (CV = 5) was 0.704 (B). The precision-recall Curve (PRC) and AUC value (0.787) was presented in (C). The cases and controls in the RF were not evenly distributed, and the AUC value in PRC was higher than that in ROC.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Aho V. T., Houser M. C., Pereira P. A., Chang J., Rudi K., Paulin L., et al. (2021). Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease. Mol. Neurodegener. 16 1–14. 10.1186/s13024-021-00427-6 - DOI - PMC - PubMed
    1. Al Mahi N., Najafabadi M. F., Pilarczyk M., Kouril M., Medvedovic M. (2019). GREIN: An interactive web platform for re-analyzing GEO RNA-seq data. Sci. Rep. 9:7580. 10.1038/s41598-019-43935-8 - DOI - PMC - PubMed
    1. Aron-Wisnewsky J., Vigliotti C., Witjes J., Le P., Holleboom A. G., Verheij J., et al. (2020). Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat. Rev. Gastroenterol. Hepatol. 17 279–297. 10.1038/s41575-020-0269-9 - DOI - PubMed
    1. Benítez-Páez A., Gómez del Pugar E. M., López-Almela I., Moya-Pérez Á, Codoñer-Franch P., Sanz Y. (2020). Depletion of Blautia species in the microbiota of obese children relates to intestinal inflammation and metabolic phenotype worsening. mSystems 5:e00857-19. 10.1128/mSystems.00857-19 - DOI - PMC - PubMed
    1. Bisanz J. (2018). qiime2R: importing QIIME2 artifacts and associated data into R sessions. Version 0.99 13.

LinkOut - more resources