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| Status |
Public on Apr 01, 2021 |
| Title |
The gut microbiota modulates environmental risk for cognitive impairment |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Cognitive impairment (CI) is a prevalent neurological condition characterized deficient attention, causal reasoning, learning and/or memory. Many genetic and environmental factors increase risk for CI, and the gut microbiome is increasingly implicated. However, the identity of gut microbes associated with CI risk, their effects on CI, and their mechanisms of action remain unclear. Here we examine the gut microbiome in response to restricted diet and intermittent hypoxia, known environmental risk factors for CI. Modeling the environmental factors together in mice potentiates CI and alters the gut microbiota. Depleting the microbiome by antibiotic treatment or germ-free rearing prevents the adverse effects of environmental risk on CI, whereas transplantation of the risk-associated microbiome into naïve mice confers CI. Parallel sequencing and gnotobiotic approaches identify the pathobiont Bilophila wadsworthia as enriched by the environmental risk factors for CI and as sufficient to induce CI. Consistent with CI-related behavioral abnormalities, B. wadsworthia and the risk-associated microbiome disrupt hippocampal activity, neurogenesis and gene expression. The CI induced by B. wadsworthia and by environmental risk factors is associated with microbiome-dependent increases in intestinal IFNy-producing Th1 cells. Inhibiting Th1 cells abrogates the adverse effects of both B. wadsworthia and environmental risk factors on CI. Together, these findings identify select gut bacteria that contribute to environmental risk for CI in mice by promoting inflammation and hippocampal dysfunction.
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| Overall design |
For each group, n=6 was dissected and analyzed as biological replicates. Hippocampi were microdissected and RNA extracted using the Qiagen RNEasy Mini Kit. RNA quality was assessed to be RIN>8.9 using the 4200 Tapestation (Agilent). RNA libraries were prepared using the QuantSeq FWD’ mRNA-Seq Library Prep Kit (Lexogen) and sequenced via the Illumina HiSeq platform by the UCLA Neuroscience Genomics Core. Sequences were filtered using FastQC v. 0.11.9 (Andrews, 2010) for quality control, followed by Trimmomatic (Bolger et al.)to remove barcodes and reads with an average phred score of 33 (parameters: illuminaclip:2:30:6, slidingwindow:5:30, leading:30, trailing:30, crop:65, minlen:20). Parsed reads were then aligned to the mouse genome mm10 using HISAT2 (Kim et al.; Kim et al.). Read counts were obtained using HTSeq-count (Anders et al.). Differential gene expression was determined using DESeq2 (Love et al.). Heatmaps were constructed using the R package (Team, 2013) pheatmap (Kolde, 2015), GO term enrichment analysis was conducted using DAVID (Huang da et al., 2009a, b) and Protein-Protein network analysis using STRING (Szklarczyk et al., 2019).
Definitions:
KD = KD diet is a ketogenic 6:1 fat to carbohydrate ratio diet from Harlan Teklad (TD.1150300).
"SPF, then Abx" = mice are raised specific pathogen free (SPF), and then treated with a heavy dosage of antibiotics (Abx) to deplete the gut microbiota.
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| Contributor(s) |
Iñiguez AJ, Olson CA, Hsiao EY |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Dec 13, 2020 |
| Last update date |
Apr 03, 2021 |
| Contact name |
Christine Olson |
| E-mail(s) |
olsonca@g.ucla.edu
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| Organization name |
UCLA
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| Department |
Integrative Biology and Physiology
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| Lab |
Elaine Hsiao
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| Street address |
609 Charles E Young Dr
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90095 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (36)
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| GSM4972045 |
CA3 isolated from hippocampus SPF KD Mock_1 |
| GSM4972046 |
CA3 isolated from hippocampus SPF KD Mock_2 |
| GSM4972047 |
CA3 isolated from hippocampus SPF KD Mock_3 |
| GSM4972048 |
CA3 isolated from hippocampus SPF KD Mock_4 |
| GSM4972049 |
CA3 isolated from hippocampus SPF KD Mock_5 |
| GSM4972050 |
CA3 isolated from hippocampus SPF KD Mock_6 |
| GSM4972051 |
CA3 isolated from hippocampus SPF KD Hyp_1 |
| GSM4972052 |
CA3 isolated from hippocampus SPF KD Hyp_2 |
| GSM4972053 |
CA3 isolated from hippocampus SPF KD Hyp_3 |
| GSM4972054 |
CA3 isolated from hippocampus SPF KD Hyp_4 |
| GSM4972055 |
CA3 isolated from hippocampus SPF KD Hyp_5 |
| GSM4972056 |
CA3 isolated from hippocampus SPF KD Hyp_6 |
| GSM4972057 |
CA3 isolated from hippocampus GF KD Hyp_1 |
| GSM4972058 |
CA3 isolated from hippocampus GF KD Hyp_2 |
| GSM4972059 |
CA3 isolated from hippocampus GF KD Hyp_3 |
| GSM4972060 |
CA3 isolated from hippocampus GF KD Hyp_4 |
| GSM4972061 |
CA3 isolated from hippocampus GF KD Hyp_5 |
| GSM4972062 |
CA3 isolated from hippocampus GF KD Hyp_6 |
| GSM4972063 |
CA3 isolated from hippocampus GF+Clos_1 |
| GSM4972064 |
CA3 isolated from hippocampus GF+Clos_2 |
| GSM4972065 |
CA3 isolated from hippocampus GF+Clos_3 |
| GSM4972066 |
CA3 isolated from hippocampus GF+Clos_4 |
| GSM4972067 |
CA3 isolated from hippocampus GF+Clos_5 |
| GSM4972068 |
CA3 isolated from hippocampus GF+Clos_6 |
| GSM4972069 |
CA3 isolated from hippocampus GF+Bilo_1 |
| GSM4972070 |
CA3 isolated from hippocampus GF+Bilo_2 |
| GSM4972071 |
CA3 isolated from hippocampus GF+Bilo_3 |
| GSM4972072 |
CA3 isolated from hippocampus GF+Bilo_4 |
| GSM4972073 |
CA3 isolated from hippocampus GF+Bilo_5 |
| GSM4972074 |
CA3 isolated from hippocampus GF+Bilo_6 |
| GSM4972075 |
CA3 isolated from hippocampus Abx KD Hyp_1 |
| GSM4972076 |
CA3 isolated from hippocampus Abx KD Hyp_2 |
| GSM4972077 |
CA3 isolated from hippocampus Abx KD Hyp_3 |
| GSM4972078 |
CA3 isolated from hippocampus Abx KD Hyp_4 |
| GSM4972079 |
CA3 isolated from hippocampus Abx KD Hyp_5 |
| GSM4972080 |
CA3 isolated from hippocampus Abx KD Hyp_6 |
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| Relations |
| BioProject |
PRJNA684902 |
| SRA |
SRP297787 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE163099_RAW.tar |
3.1 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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