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Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease
Open accessAbstract
The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.
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“The increased level of inflammatory cytokines may be caused by disturbance of the gut microbiota, which may also disrupt the gut barrier. 241”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [241]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For example, one study showed that when α-synuclein over-expressing transgenic mice were raised in a germ-free environment they rarely developed the cardinal features of PD such as rest tremor, bradykinesia, and rigidity.”
From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [92]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“When these mice were either colonized with feces from wild-type mice or orally fed bacterial metabolites like short chain fatty acids (SCFAs) without colonization, they developed a PD-like phenotype [92].”
From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [92]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In contrast, FMT from PD patient donors worsens disease progression suggesting the presence of specific disease-promoting microbes (169).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [169]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“In addition, these mice showed changes in SCFAs, with lower concentrations of acetate and higher concentrations of propionate and butyrate, substantiating that the alteration of gut microbiota is a crucial risk factor for Parkinson's disease.50”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [50]
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“In addition, these mice showed changes in SCFAs, with lower concentrations of acetate and higher concentrations of propionate and butyrate, substantiating that the alteration of gut microbiota is a crucial risk factor for Parkinson's disease.50”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [50]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Prior work7,46,47, indicated that the biodiversity and composition of the gut microbiome are linked to various aspects of mouse cognition and behavior.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [7]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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“However, the presence of gut microbes is necessary to elicit pathophysiological alterations in a mouse model of αSyn overexpression, because elimination of the gut microbiota with antibiotics ameliorated the condition (169).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [169]
The cited source says what the claim attributes to it.
In the citing paper
“For instance, increased SCFA levels have been implicated in the pathophysiology of Parkinson's disease in mice (Sampson et al., 2016).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Sampson et al., 2016
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In the citing paper
“Intriguingly, the abundance of some gut microbiota increased in mice that were colonized by the faeces of patients with Parkinson's disease, including Proteus sp., Bilophila sp. and Roseburia sp., with a decrease in the Lachnospiracae, Rikenellae, Peptostreptococacae and Butyricicoccus sp.50”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [50]
The cited source says what the claim attributes to it.
In the citing paper
“In animal experiments, Sampson et al.50 found that the high expression of a-synuclein in mice that were colonized by the gut microbiota of patients with Parkinson's disease increased motor dysfunction.50”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as Sampson et al.50
The cited source says what the claim attributes to it.
In the citing paper
“These data suggest that as seen in Parkinson’s disease (PD) and PD models7, the gut microbiome might be a contributor to AD in humans and may play an important role in AD models as well.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [7]
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In the citing paper
“Despite variability introduced by diet and comorbid conditions, metabolomic biomarkers such as reduced docosahexaenoic acid (DHA) and elevated homocysteine have demonstrated clinical utility133,194, 195, 196, 197, 198, 199.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [195]
Experimental — accuracy not yet measuredIn the citing paper
“Moreover, studies on animal models have provided compelling evidence that the altered gut microbiome drives neurodegenerative disease pathogenesis, primarily through the modulation of microglial functions and activation.54–57”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [55]
In the citing paper
“Importantly, FMT from PD patients to GF ASO mice restored the main disease features, including α-synuclein-mediated motor dysfunction.55”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [55]
In the citing paper
“Of note, SCFA supplementation in GF ASO mice induced microglial activation, α-synuclein accumulation and motor dysfunction.55”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [55]
In the citing paper
“Changes in the F/B ratio have been found to be associated with various disorders, such as irritable bowel syndrome and inflammatory bowel disease (97), as well as with neurodegenerative diseases, such as PD, AD, and ALS (98).”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [98]
In the citing paper
“Intestinal microbes are closely related to neurological diseases such as AD, PD and ALS.”
From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Sampson et al. 2016
In the citing paper
“In addition, disturbed intestinal flora can affect neurogenesis, development, neurotransmission and neuroimmunity (Sampson et al. 2016), which ultimately affect the pathogenesis and progress of NDD.”
From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Sampson et al. 2016
In the citing paper
“Similarly, the abundance of Escherichia-Shigella, Proteus, and Enterococcus was increased, and the abundance of Blautia and Ruminococcus was decreased in the faecal samples of PD patients (Sampson et al. 2016).”
From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Sampson et al. 2016
In the citing paper
“Till now, a strong connection between intestinal microbiota and nervous diseases is evidenced, and the drug GV-971 has been conditionally approved by China’s State Drug Administration for AD treatment.”
From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Sampson et al. 2016
In the citing paper
“Sampson et al. demonstrated that fecal microbiota transplantation (FMT) from PD patients to mice led to the aggravation of motor deficits via the activation of microglia”
From Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway (2023) · cites this paper as [17]
In the citing paper
“Of note, the mice given fecal microbiota from PD patients exhibited even worse loss of TH+ neurons, corroborating previous findings [17].”
From Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway (2023) · cites this paper as [17]
In the citing paper
“FMT from PD patients can significantly worsen motor dysfunction in α-synuclein-overexpressing (ASO) mice compared to genotype-matched recipient mice receiving FMT from healthy human controls [17]”
From Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway (2023) · cites this paper as [17]
In the citing paper
“Second, dysbiosis is observed in several neurological conditions in which microglial dysfunction is thought to be a contributing factor to disease development, including ASD and PD (Table 1; Hsiao et al., 2013; Sampson et al., 2016).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Sampson et al., 2016
In the citing paper
“Support for the notion that the microbiota may drive the pathogenesis of PD was provided by studies in GF mice that overexpress human α-synuclein.”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Sampson et al., 2016
In the citing paper
“Feeding these GF transgenic mice a mixture of three SCFAs up-regulated microglial activation and induced motor deficits similar to those observed in colonized animals (Sampson et al., 2016).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Sampson et al., 2016
In the citing paper
“These mice display reduced motor deficits, GI dysfunction, and microglial activation when compared with mice with an intact gut microbiota (Sampson et al., 2016).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Sampson et al., 2016
In the citing paper
“This observation suggests that the gut microbiota, along with genetic predisposition, may be required for disease onset and/or progression.”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Sampson et al., 2016
In the citing paper
“Sampson et al. showed that microbiota-derived SCFAs are crucial for α-synuclein-mediated neuroinflammation, glial cell hyperactivation, and motor symptoms [10].”
From Neuroprotective Effects of Bifidobacterium breve CCFM1067 in MPTP-Induced Mouse Models of Parkinson’s Disease (2022) · cites this paper as [10]
In the citing paper
“recent studies have demonstrated that PD pathogenesis may be affected by alterations in the gut microbiota [5,6,7].”
From Neuroprotective Effects of Sodium Butyrate by Restoring Gut Microbiota and Inhibiting TLR4 Signaling in Mice with MPTP-Induced Parkinson’s Disease (2023) · cites this paper as [5]
In the citing paper
“There is an increase in proinflammatory microorganisms in the intestinal microbiota of PD patients [41]”
From Neuroprotective Effect of Ceftriaxone on MPTP‐Induced Parkinson’s Disease Mouse Model by Regulating Inflammation and Intestinal Microbiota (2021) · cites this paper as [41]
In the citing paper
“changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [95]
In the citing paper
“And the gut microbiome affects motor symptoms in an α-synuclein mouse model of PD, such that eliminating gut bacteria prevents motor deficits, while introducing the gut microbiome from PD patients exacerbates pathology [95].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [95]
In the citing paper
“In a PD model, antibiotic treatment ameliorates PD pathology, whereas oral administration of specific microbial metabolites promotes neuroinflammation and motor symptoms150.”
From Microglia in neurodegeneration (2018) · cites this paper as [150]
In the citing paper
“it has been reported that α-synuclein-dependent activation of microglia may be linked to changes in the microbiome in both animal models and patients162.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [162]
In the citing paper
“Concerning PD, dysbiosis followed by GI symptoms and gut discomfort far precedes the onset of motor dysfunctions and it is linked to neuroinflammation, as well as to alterations in dopamine, serotonin, and kynurenine metabolism through the gut-brain axis [40,41,42,43,44,45,46]”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [40]
In the citing paper
“Early evidence came in 2016 from the work of Sampson et al., who first reported that the transfer of fecal matter from human PD patients to α-synuclein overexpressing mice substantially worsened their physical symptoms in comparison with mice receiving feces from healthy human donors [40].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [40]
In the citing paper
“Concerning PD, consistent preclinical studies and a handful of human case reports have shown that FMT might be exploited to reduce motor and non-motor symptoms, as well as constipation, at least in the short term [40,465,469,470,471,472,473,474,475,476,477] (Table 4).”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [40]
In the citing paper
“Mice overexpressing α-synuclein given antibiotic treatment or raised under GF conditions displayed improved motor functions and reduced amount of α-synuclein deposits.”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [404]
In the citing paper
“FMT from patients with Parkinson's disease to mice overexpressing α-synuclein aggravated the problems in motor functions more profoundly than gut bacteria derived from healthy subjects, which suggested that the manifestation of disease symptoms is related to the shift in gut microbiota [404].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [404]
In the citing paper
“Furthermore, recent studies have shown dramatic changes in the GM of patients with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and schizophrenia (73–77).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [75]
In the citing paper
“Oral administration of SCFAs to germ-free α-synuclein mice promoted neuroinflammation and motor dysfunction, and FMT with Parkinson’s disease-affected patients enhanced the Parkinsonism compared to FMT from healthy human donors.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [75]
In the citing paper
“Oral administration of SCFAs to germ-free α-synuclein mice promoted neuroinflammation and motor dysfunction, and FMT with Parkinson’s disease-affected patients enhanced the Parkinsonism compared to FMT from healthy human donors.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [75]
In the citing paper
“In a mouse model that overexpresses the protein α-synuclein, resulting in Parkinsonism, Sampson et al. were able to show that MGB axis signaling is required for motor deficits, microglia activation, and synucleinopathies (75).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [75]
In the citing paper
“The microbiota composition differs significantly between healthy controls and patients affected by neurodegenerative disorders (such as multiple sclerosis (MS), Alzheimer’s (AD) and Parkinson’s (PD) diseases) (20, 22, 23, 32, 111–115), and neuropsychiatric disorders (NPS) (30), like major depressive and mood disorders.”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [111]
In the citing paper
“GF mice colonized with microbiota from PD patients display physical impairments compared to GF mice colonized with microbiota from healthy human donors (111).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [111]
In the citing paper
“The differences in the microbiome profile, in SCFAs amount, and motor dysfunctions (increase in propionate and butyrate) were transferred and maintained in vivo too (111).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [111]
In the citing paper
“Likewise, in GF mice the administration of an SCFA mixture resulted in microglia activation and motor deficits (369), hallmark symptoms of Parkinson's disease”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [369]
In the citing paper
“Second, animal studies have shown effects of the gut microbiota on neurodevelopment, suggesting that intestinally derived lipopolysaccharides can increase anxiety-like behavior in mice (69–71).”
From Association Between Gut Microbiota and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis (2019) · cites this paper as [70]
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Self-citation
Metadata
- Authors
- Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., Gradinaru, V., Chesselet, M.-F., Keshavarzian, A., Shannon, K. M., Krajmalnik-Brown, R., Wittung-Stafshede, P., Knight, R., & Mazmanian, S. K.
- Affiliations
- California Institute of Technology (US)
- University of California San Diego (US)
- Arizona State University (US)
- Chalmers University of Technology (SE)
- Rush University Medical Center (US)
- Corresponding author
- Sampson, Timothy R.
- Mazmanian, Sarkis K.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 167
- Issue
- 6
- Pages
- 1469-1480.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5718049
- OpenAlex
- W2558041282
- Cited by
- 3,622
- References
- 75
- Citations by year
- 2026: 363 · 2025: 414 · 2024: 421 · 2023: 410 · 2022: 455 · 2021: 450 · 2020: 385 · 2019: 300 · 2018: 247 · 2017: 171 · 2016: 5
- FWCI
- 181.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Chalmers Research (Chalmers University of Technology) (submittedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- HAL (submittedVersion)
- PUB – Publications at Bielefeld University (Bielefeld University) (submittedVersion)
- Chalmers Publication Library (Chalmers University of Technology) (submittedVersion)
- Funders
- Caltech Beckman Institute
- Arnold and Mabel Beckman Foundation
- Larry L. Hillblom Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Research Council
- Mrs. and Mr. Larry Field
- Heritage Medical Research Institute
- NIH (NS085910)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- gut microbiota, Parkinson's disease, alpha-synuclein, synucleinopathies, motor impairment, neuroinflammation, microglial activation, microbiota transplantation, germ-free mice, antibiotic therapy, microbial metabolites, gut-brain axis, neurodegeneration
- MeSH terms
- Gastrointestinal Microbiome, Animals, Brain, Fatty Acids, Humans, Inflammation, Parkinson Disease, Microglia, Gastrointestinal Tract, Mice, alpha-Synuclein, Dysbiosis
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