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A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice

Abdel-Haq, Reem and Schlachetzki, Johannes C. M. and Boktor, Joseph C. and Cantu-Jungles, Thaisa M. and Thron, Taren and Zhang, Mengying and Bostick, John W. and Khazaei, Tahmineh and Chilakala, Sujatha and Morais, Livia H. and Humphrey, Greg and Keshavarzian, Ali and Katz, Jonathan E. and Thomson, Matthew and Knight, Rob and Gradinaru, Viviana and Hamaker, Bruce R. and Glass, Christopher K. and Mazmanian, Sarkis K. (2022) A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice. eLife, 11 . Art. No. e81453. ISSN 2050-084X. PMCID PMC9668333. doi:10.7554/elife.81453.

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Parkinson’s disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.

Item Type:Article
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URLURL TypeDescription CentralArticle ItemDiscussion Paper
Abdel-Haq, Reem0000-0002-7418-5736
Schlachetzki, Johannes C. M.0000-0002-7801-9743
Boktor, Joseph C.0000-0003-2456-1913
Cantu-Jungles, Thaisa M.0000-0001-8928-9717
Thron, Taren0000-0001-9577-2617
Bostick, John W.0000-0001-8925-2447
Khazaei, Tahmineh0000-0002-4743-2383
Chilakala, Sujatha0000-0003-1581-3381
Morais, Livia H.0000-0002-5738-2658
Keshavarzian, Ali0000-0002-7969-3369
Thomson, Matthew0000-0003-1021-1234
Knight, Rob0000-0002-0975-9019
Gradinaru, Viviana0000-0001-5868-348X
Hamaker, Bruce R.0000-0001-6591-942X
Glass, Christopher K.0000-0003-4344-3592
Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:We thank members of the Mazmanian laboratory and Dr. Catherine Oikonomou for critical review of this manuscript. We thank the Caltech Office of Laboratory Animal Research (OLAR) for animal husbandry, Dr. Wei-Li Wu for assistance with SCFA brain measurements, Dr. Sisi Chen and the Caltech Single-Cell Profiling and Engineering Center (SPEC) for technical assistance and support, the Caltech Flow Cytometry and Cell Sorting Facility for technical assistance, the Caltech Bioinformatics Center for data analysis support, and the Caltech Biological Imaging Facility (BIF) for training and use of confocal microscopes. We thank Prof. Chen-Chih Hsu’s laboratory in the Department of Chemistry at National Taiwan University and BIOTOOLS Co, Ltd. for the feces and brain SCFA measurements. RA was supported by the U.S. Department of Defense, the Donna and Benjamin M Rosen Bioengineering Center, and the Biotechnology Leadership Program at Caltech. This study was funded by grants to SKM from the U.S. Department of Defense (PD160030), Heritage Medical Research Institute (HMRI-15-09-01), and by the joint efforts of the Michael J Fox Foundation for Parkinson’s Research (MJFF) and the Aligning Science Across Parkinson’s (ASAP) initiative. MJFF administers the grant (ASAP-000375) on behalf of ASAP and itself. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Data availability. All datasets generated or analyzed in this study can be found through the Zenodo depository: All experimental protocols can be found on
Group:Rosen Bioengineering Center, Heritage Medical Research Institute
Funding AgencyGrant Number
Department of DefensePD160030
Donna and Benjamin M. Rosen Bioengineering CenterUNSPECIFIED
Caltech Biotechnology Leadership ProgramUNSPECIFIED
Heritage Medical Research InstituteHMRI-15-09-01
Michael J Fox Foundation for Parkinson’s ResearchUNSPECIFIED
Aligning Science Across Parkinson’sASAP-000375
PubMed Central ID:PMC9668333
Record Number:CaltechAUTHORS:20221202-906989500.8
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:118212
Deposited By: Research Services Depository
Deposited On:08 Dec 2022 23:46
Last Modified:08 Dec 2022 23:46

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