Dimethyl itaconate ameliorates cognitive impairment induced by a high-fat diet via the gut-brain axis in mice
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Study information
-
Quality control
- Retracted paper
- Contamination issues suspected
- Batch effect issues suspected
- Uncontrolled confounding suspected
- Results are suspect (various reasons)
- Tags applied
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI
Authors
Pan W, Zhao J, Wu J, Xu D, Meng X, Jiang P, Shi H, Ge X, Yang X, Hu M, Zhang P, Tang R, Nagaratnam N, Zheng K, Huang XF, Yu Y
Journal
Microbiome
Year
2023
Keywords:
Cognition, Gut microbiome, Gut-brain axis, Itaconate, Microglia, Obesity
BACKGROUND: Gut homeostasis, including intestinal immunity and microbiome, is essential for cognitive function via the gut-brain axis. This axis is altered in high-fat diet (HFD)-induced cognitive impairment and is closely associated with neurodegenerative diseases. Dimethyl itaconate (DI) is an itaconate derivative and has recently attracted extensive interest due to its anti-inflammatory effect. This study investigated whether intraperitoneal administration of DI improves the gut-brain axis and prevents cognitive deficits in HF diet-fed mice. RESULTS: DI effectively attenuated HFD-induced cognitive decline in behavioral tests of object location, novel object recognition, and nesting building, concurrent with the improvement of hippocampal RNA transcription profiles of genes associated with cognition and synaptic plasticity. In agreement, DI reduced the damage of synaptic ultrastructure and deficit of proteins (BDNF, SYN, and PSD95), the microglial activation, and neuroinflammation in the HFD-fed mice. In the colon, DI significantly lowered macrophage infiltration and the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in mice on the HF diet, while upregulating the expression of immune homeostasis-related cytokines (IL-22, IL-23) and antimicrobial peptide Reg3γ. Moreover, DI alleviated HFD-induced gut barrier impairments, including elevation of colonic mucus thickness and expression of tight junction proteins (zonula occludens-1, occludin). Notably, HFD-induced microbiome alteration was improved by DI supplementation, characterized by the increase of propionate- and butyrate-producing bacteria. Correspondingly, DI increased the levels of propionate and butyrate in the serum of HFD mice. Intriguingly, fecal microbiome transplantation from DI-treated HF mice facilitated cognitive variables compared with HF mice, including higher cognitive indexes in behavior tests and optimization of hippocampal synaptic ultrastructure. These results highlight the gut microbiota is necessary for the effects of DI in improving cognitive impairment. CONCLUSIONS: The present study provides the first evidence that DI improves cognition and brain function with significant beneficial effects via the gut-brain axis, suggesting that DI may serve as a novel drug for treating obesity-associated neurodegenerative diseases. Video Abstract.
Experiment 1
Reviewed Marked as Reviewed by Svetlana up on 2024-8-12
Subjects
- Location of subjects
- China
- Host species Species from which microbiome was sampled. Contact us to have more species added.
- Mus musculus
- Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
- Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces
- Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
- Metabolite Metabolite,metabolite
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- HF+Veh (High fat and Vehicle treated mice)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- HF+DI (High fat and Dimethyl Itaconate treated mice)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Mice in this group received a high-fat diet (30% fat by weight) to induce cognitive impairment. Then, they were intraperitoneally injected with Dimethy Itaconate (25mg/kg) twice a week.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 12
- Group 1 sample size Number of subjects in the case (exposed) group
- 12
Lab analysis
- Sequencing type
- 16S
- 16S variable region One or more hypervariable region(s) of the bacterial 16S gene
- V3-V4
- Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
- Illumina
Statistical Analysis
- Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
- relative abundances
- Statistical test
- LEfSe
- Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
- 0.05
- MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
- No
- LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
- 3
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- increased
- Chao1 Abundance-based estimator of species richness
- increased
Signature 1
Reviewed Marked as Reviewed by Svetlana up on 2024-8-12
Source: Fig. 5g
Description: A Linear discriminant analysis (LDA) effect size (LEfSe) showing the most significantly abundant taxa enriched in microbiome from the HF+DI group compared to the HF+Veh group.
Abundance in Group 1: increased abundance in HF+DI (High fat and Dimethyl Itaconate treated mice)
Revision editor(s): Victoria
Signature 2
Reviewed Marked as Reviewed by Svetlana up on 2024-8-12
Source: Fig. 5g
Description: A Linear discriminant analysis (LDA) effect size (LEfSe) showing the most significantly abundant taxa enriched in microbiome from the HF+DI group compared to the HF+Veh group.
Abundance in Group 1: decreased abundance in HF+DI (High fat and Dimethyl Itaconate treated mice)
Revision editor(s): Victoria
Experiment 2
Reviewed Marked as Reviewed by Svetlana up on 2024-8-12
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- FMT-HF+Veh (Fecal microbiome transplantation-High fat and Vehicle treated mice)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- FMT-HF+DI (Fecal microbiome transplantation-High fat and Dimethyl Itaconate treated mice)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Mice in this group received a high-fat diet (30% fat by weight) to induce cognitive impairment. Then, they were intraperitoneally injected with Dimethy Itaconate (25mg/kg) twice a week. Afterward, they received fecal microbiome transplantation.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 8
- Group 1 sample size Number of subjects in the case (exposed) group
- 8
Lab analysis
Statistical Analysis
Alpha Diversity
- Shannon Estimator of species richness and species evenness: more weight on species richness
- increased
- Chao1 Abundance-based estimator of species richness
- increased
Signature 1
Reviewed Marked as Reviewed by Svetlana up on 2024-8-12
Source: Supplemental Figure S5
Description: Linear discriminant analysis (LDA) effect size (LEfSe) showing the most significantly abundant taxa enriched in microbiome from the FMT-HF+DI group compared to the FMT-HF+Veh group.
Abundance in Group 1: increased abundance in FMT-HF+DI (Fecal microbiome transplantation-High fat and Dimethyl Itaconate treated mice)
Revision editor(s): Victoria
Signature 2
Reviewed Marked as Reviewed by Svetlana up on 2024-8-12
Source: Supplemental Figure S5
Description: Linear discriminant analysis (LDA) effect size (LEfSe) showing the most significantly abundant taxa enriched in microbiome from the FMT-HF+DI group compared to the FMT-HF+Veh group.
Abundance in Group 1: decreased abundance in FMT-HF+DI (Fecal microbiome transplantation-High fat and Dimethyl Itaconate treated mice)
| NCBI | Quality Control | Links |
|---|---|---|
| Pseudochrobactrum | ||
| Hyphomicrobiales | ||
| Rhizobiaceae | ||
| Ileibacterium | ||
| Bacillota | ||
| Bacilli | ||
| Dubosiella | ||
| Erysipelotrichaceae | ||
| Erysipelotrichales |
Revision editor(s): Victoria
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