Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse models
Abstract The contribution of the gut microbiome to neuroinflammation, cognition, and Alzheimer’s disease progression has been highlighted over the past few years. Additionally, inhibition of various components of the complement system has repeatedly been demonstrated to reduce neuroinflammation and...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02885-9 |
| _version_ | 1797451998422892544 |
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| author | Tiffany J. Petrisko Matthew Gargus Shu-Hui Chu Purnika Selvan Katrine L. Whiteson Andrea J. Tenner |
| author_facet | Tiffany J. Petrisko Matthew Gargus Shu-Hui Chu Purnika Selvan Katrine L. Whiteson Andrea J. Tenner |
| author_sort | Tiffany J. Petrisko |
| collection | DOAJ |
| description | Abstract The contribution of the gut microbiome to neuroinflammation, cognition, and Alzheimer’s disease progression has been highlighted over the past few years. Additionally, inhibition of various components of the complement system has repeatedly been demonstrated to reduce neuroinflammation and improve cognitive performance in AD mouse models. Whether the deletion of these complement components is associated with distinct microbiome composition, which could impact neuroinflammation and cognitive performance in mouse models has not yet been examined. Here, we provide a comprehensive analysis of conditional and constitutive knockouts, pharmacological inhibitors, and various housing paradigms for the animal models and wild-type controls at various ages. We aimed to determine the impact of C1q or C5aR1 inhibition on the microbiome in the Arctic and Tg2576 mouse models of AD, which develop amyloid plaques at different ages and locations. Analysis of fecal samples from WT and Arctic mice following global deletion of C1q demonstrated significant alterations to the microbiomes of Arctic but not WT mice, with substantial differences in abundances of Erysipelotrichales, Clostridiales and Alistipes. While no differences in microbiome diversity were detected between cohoused wildtype and Arctic mice with or without the constitutive deletion of the downstream complement receptor, C5aR1, a difference was detected between the C5aR1 sufficient (WT and Arctic) and deficient (C5ar1KO and ArcticC5aR1KO) mice, when the mice were housed segregated by C5aR1 genotype. However, cohousing of C5aR1 sufficient and deficient wildtype and Arctic mice resulted in a convergence of the microbiomes and equalized abundances of each identified order and genus across all genotypes. Similarly, pharmacologic treatment with the C5aR1 antagonist, PMX205, beginning at the onset of beta-amyloid plaque deposition in the Arctic and Tg2576 mice, demonstrated no impact of C5aR1 inhibition on the microbiome. This study demonstrates the importance of C1q in microbiota homeostasis in neurodegenerative disease. In addition, while demonstrating that constitutive deletion of C5aR1 can significantly alter the composition of the fecal microbiome, these differences are not present when C5aR1-deficient mice are cohoused with C5aR1-sufficient animals with or without the AD phenotype and suggests limited if any contribution of the microbiome to the previously observed prevention of cognitive and neuronal loss in the C5aR1-deficient AD models. |
| first_indexed | 2024-03-09T15:02:29Z |
| format | Article |
| id | doaj.art-ec8ea2d255f74df3a4c5afdf98427e7e |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-09T15:02:29Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-ec8ea2d255f74df3a4c5afdf98427e7e2023-11-26T13:51:57ZengBMCJournal of Neuroinflammation1742-20942023-09-0120111610.1186/s12974-023-02885-9Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse modelsTiffany J. Petrisko0Matthew Gargus1Shu-Hui Chu2Purnika Selvan3Katrine L. Whiteson4Andrea J. Tenner5Department of Molecular Biology & Biochemistry, University of California, IrvineDepartment of Molecular Biology & Biochemistry, University of California, IrvineDepartment of Molecular Biology & Biochemistry, University of California, IrvineDepartment of Molecular Biology & Biochemistry, University of California, IrvineDepartment of Molecular Biology & Biochemistry, University of California, IrvineDepartment of Molecular Biology & Biochemistry, University of California, IrvineAbstract The contribution of the gut microbiome to neuroinflammation, cognition, and Alzheimer’s disease progression has been highlighted over the past few years. Additionally, inhibition of various components of the complement system has repeatedly been demonstrated to reduce neuroinflammation and improve cognitive performance in AD mouse models. Whether the deletion of these complement components is associated with distinct microbiome composition, which could impact neuroinflammation and cognitive performance in mouse models has not yet been examined. Here, we provide a comprehensive analysis of conditional and constitutive knockouts, pharmacological inhibitors, and various housing paradigms for the animal models and wild-type controls at various ages. We aimed to determine the impact of C1q or C5aR1 inhibition on the microbiome in the Arctic and Tg2576 mouse models of AD, which develop amyloid plaques at different ages and locations. Analysis of fecal samples from WT and Arctic mice following global deletion of C1q demonstrated significant alterations to the microbiomes of Arctic but not WT mice, with substantial differences in abundances of Erysipelotrichales, Clostridiales and Alistipes. While no differences in microbiome diversity were detected between cohoused wildtype and Arctic mice with or without the constitutive deletion of the downstream complement receptor, C5aR1, a difference was detected between the C5aR1 sufficient (WT and Arctic) and deficient (C5ar1KO and ArcticC5aR1KO) mice, when the mice were housed segregated by C5aR1 genotype. However, cohousing of C5aR1 sufficient and deficient wildtype and Arctic mice resulted in a convergence of the microbiomes and equalized abundances of each identified order and genus across all genotypes. Similarly, pharmacologic treatment with the C5aR1 antagonist, PMX205, beginning at the onset of beta-amyloid plaque deposition in the Arctic and Tg2576 mice, demonstrated no impact of C5aR1 inhibition on the microbiome. This study demonstrates the importance of C1q in microbiota homeostasis in neurodegenerative disease. In addition, while demonstrating that constitutive deletion of C5aR1 can significantly alter the composition of the fecal microbiome, these differences are not present when C5aR1-deficient mice are cohoused with C5aR1-sufficient animals with or without the AD phenotype and suggests limited if any contribution of the microbiome to the previously observed prevention of cognitive and neuronal loss in the C5aR1-deficient AD models.https://doi.org/10.1186/s12974-023-02885-9Alzheimer’s diseaseMicrobiomeComplementC1qC5aR1Neuroprotection |
| spellingShingle | Tiffany J. Petrisko Matthew Gargus Shu-Hui Chu Purnika Selvan Katrine L. Whiteson Andrea J. Tenner Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse models Journal of Neuroinflammation Alzheimer’s disease Microbiome Complement C1q C5aR1 Neuroprotection |
| title | Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse models |
| title_full | Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse models |
| title_fullStr | Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse models |
| title_full_unstemmed | Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse models |
| title_short | Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse models |
| title_sort | influence of complement protein c1q or complement receptor c5ar1 on gut microbiota composition in wildtype and alzheimer s mouse models |
| topic | Alzheimer’s disease Microbiome Complement C1q C5aR1 Neuroprotection |
| url | https://doi.org/10.1186/s12974-023-02885-9 |
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