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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, Matt 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. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20220706-965670000

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Abstract

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, though 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:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2022.06.27.497828DOIbioRxiv Discussion Paper
https://doi.org/10.5281/zenodo.6377704DOIData files
https://resolver.caltech.edu/CaltechAUTHORS:20221202-906989500.8Related ItemPublished Version
ORCID:
AuthorORCID
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, Matt0000-0003-1021-1234
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:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. 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. R.A. 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 S.K.M. 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. Data Availability. All datasets generated or analyzed in this study can be found through the Zenodo depository: https://doi.org/10.5281/zenodo.6377704 All experimental protocols can be found on protocols.io. Competing Interests. A.K., T.C-J., and B.R.H. have equity in RiteCarbs, a company developing prebiotic diets for Parkinson’s disease. S.K.M. has equity in Axial Therapeutics, a company developing gut-restricted drugs for Parkinson’s disease.
Group:Rosen Bioengineering Center, Heritage Medical Research Institute
Funders:
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 FoundationUNSPECIFIED
Aligning Science Across Parkinson’sASAP-000375
DOI:10.1101/2022.06.27.497828
Record Number:CaltechAUTHORS:20220706-965670000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220706-965670000
Official Citation:A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice Reem Abdel-Haq, Johannes C.M. Schlachetzki, Joseph C. Boktor, Thaisa M. Cantu-Jungles, Taren Thron, Mengying Zhang, John W. Bostick, Tahmineh Khazaei, Sujatha Chilakala, Livia H. Morais, Greg Humphrey, Ali Keshavarzian, Jonathan E. Katz, Matt Thomson, Rob Knight, Viviana Gradinaru, Bruce R. Hamaker, Christopher K. Glass, Sarkis K. Mazmanian bioRxiv 2022.06.27.497828; doi: https://doi.org/10.1101/2022.06.27.497828
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115357
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:08 Jul 2022 22:42
Last Modified:06 Dec 2022 16:03

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