A punch in the gut – Intestinal inflammation links environmental factors to neurodegeneration in Parkinson's disease

Becker, Anouck; Faßbender, Klaus; Oertel, Wolfgang H.; Unger, Marcus M.

doi:10.1016/j.parkreldis.2018.09.032

Cited by 27 publications

(26 citation statements)

References 29 publications

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“…To date, although the by-standers effects, primarily through anti-inflammatory factors, have been widely examined in the brain, very few studies have ventured probing their potential actions peripherally [29], in particular the effects on the gut microbiome. Aberrant inflammation has been linked to exacerbation of dopaminergic cell depletions and worsened disease symptoms in animal models of PD [56–58], with auspicious contribution from the gut [17, 19, 59–61].…”

Section: Discussionmentioning

confidence: 99%

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A Gutsy Move for Cell-Based Regenerative Medicine in Parkinson’s Disease: Targeting the Gut Microbiome to Sequester Inflammation and Neurotoxicity

Lee

Tuazon

Corey

et al. 2019

Stem Cell Rev and Rep

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Pharmaceuticals and cell-based regenerative medicine for Parkinson’s disease (PD) offer palliative relief but do not arrest the disease progression. Cell therapy has emerged as an experimental treatment, but current cell sources such as human umbilical cord blood (hUCB) stem cells display only partial recapitulation of mature dopaminergic neuron phenotype and function. Nonetheless, stem cell grafts ameliorate PD-associated histological and behavioral deficits likely through stem cell graft-secreted therapeutic substances. We recently demonstrated the potential of hUCB-derived plasma in enhancing motor capabilities and gastrointestinal function, as well as preventing dopaminergic neuronal cell loss, in an 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) rodent model of PD. Recognizing the translational need to test in another PD model, we now examined here the effects of an intravenously transplanted combination of hUCB and plasma into the 6-hydroxydopamine (6-OHDA) lesioned adult rats. Animals received three separate doses of 4 × 10 6 hUCB cells with plasma beginning at 7 days after stereotaxic 6-OHDA lesion, then behaviorally and immunohistochemically evaluated over 56 days post-lesion. Whereas vehicle-treated lesioned animals exhibited the typical 6-OHDA neurobehavioral symptoms, hUCB and plasma-treated lesioned animals showed significant attenuation of motor function, gut motility, and nigral dopaminergic neuronal survival, combined with diminished pro-inflammatory microbiomes not only in the nigra, but also in the gut. Altogether these data support a regenerative medicine approach for PD by sequestering inflammation and neurotoxicity through correction of gut dysbiosis.

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Section: Discussionmentioning

confidence: 99%

“…Indeed, accumulating evidence has alluded to a pathological link between PD and gut microbiome [15–22]. The innovation here is that PD pathology may be affected by a non-CNS and non-dopaminergic organ [17, 19, 23] remote from substantia nigra, the conventionally targeted brain region of interest for PD.…”

Section: Introductionmentioning

confidence: 99%

A Gutsy Move for Cell-Based Regenerative Medicine in Parkinson’s Disease: Targeting the Gut Microbiome to Sequester Inflammation and Neurotoxicity

Lee

Tuazon

Corey

et al. 2019

Stem Cell Rev and Rep

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“…A53T α-Syn (B6C3F1/J-Tg-Prnp/SNCA*A53T/83Vle/J) heterozygous breeders (Jackson Laboratories, Bar Harbor, ME, USA) were used to produce A53T homozygous (SNCA) and Non-Tg littermates (WT). All mice were genotyped by SeqWright-DNA-Technology (Houston,TX, USA), and defined as WT (< 0), heterozygous (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and homozygous (> 20) of α-synuclein mutant. Animals were mix-housed in their home cages in the same shelf of the AAALAC accredited animal facilities at the National Institute of Environmental Health Sciences/NIH, with standard temperature (70 ± 2 °F), 12 h light:dark cycle (8:00 -8:00) and fed on standard rodent chow and tap water ad libitum.…”

Section: Animals and Exposuresmentioning

confidence: 99%

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice

Song

Liu

Zhang

et al. 2020

Sci Rep

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This study examined the genetic mutation and toxicant exposure in producing gut microbiota alteration and neurotoxicity. Homozygous α-synuclein mutant (SNCA) mice that overexpress human A53T protein and littermate wild-type mice received a single injection of LPS (2 mg/kg) or a selective norepinephrine depleting toxin DSP-4 (50 mg/kg), then the motor activity, dopaminergic neuron loss, colon gene expression and gut microbiome were examined 13 months later. LPS and DSP-4 decreased rotarod and wirehang activity, reduced dopaminergic neurons in substantia nigra pars compacta (SNpc), and SNCA mice were more vulnerable. SNCA mice had 1,000-fold higher human SNCA mRNA expression in the gut, and twofold higher gut expression of NADPH oxidase (NOX2) and translocator protein (TSPO). LPS further increased expression of TSPO and IL-6 in SNCA mice. Both LPS and DSP-4 caused microbiome alterations, and SNCA mice were more susceptible. The altered colon microbiome approximated clinical findings in PD patients, characterized by increased abundance of Verrucomicrobiaceae, and decreased abundance of Prevotellaceae, as evidenced by qPCR with 16S rRNA primers. The Firmicutes/Bacteroidetes ratio was increased by LPS in SNCA mice. This study demonstrated a critical role of α-synuclein and toxins interactions in producing gut microbiota disruption, aberrant gut pro-inflammatory gene expression, and dopaminergic neuron loss.

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“…Growing awareness of communication between the intestinal environment and central nervous system activity through the brain–gut axis has led to the hypothesis that chronic intestinal inflammation may result in neurodegeneration in PD [21]. It has been confirmed that IBD and PD share common genetic risk profiles, such as NOD2 , LRRK2 and MAPT genes [22,23,24,25,26].…”

Section: Introductionmentioning

confidence: 99%

Patients with Inflammatory Bowel Disease Are at an Increased Risk of Parkinson’s Disease: A South Korean Nationwide Population-Based Study

Park

Kim

Chun

et al. 2019

JCM

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Background and Aims: It is not known whether inflammatory bowel disease (IBD) enhances the risk of Parkinson’s disease (PD) or whether PD diagnosis is the result of increased health care use. We determined the risk of developing PD among patients with IBD in terms of health care and medication use. Methods: A nationwide population-based study was conducted using claims data from the Korean National Health care Insurance service. From 2010 to 2013, patients with Crohn’s disease (CD) and ulcerative colitis (UC) were identified through both International Classification of Disease, Tenth Revision (ICD-10) and national rare intractable disease (RID) registration program codes. We compared 38,861 IBD patients with age and sex-matched non-IBD individuals at a ratio of 1:3. Patients with newly diagnosed PD were identified through both ICD-10 and RID codes. Results: The incidence of PD among patients with IBD was 49 per 100,000 person-years. The risk of developing PD in patients with IBD was significantly higher than controls even after adjustment for health care use (adjusted hazard ratio (aHR), 1.87; P < 0.001). Compared to controls, the risk of PD was significantly higher in patients with CD (aHR, 2.23; P = 0.023) and UC (aHR, 1.85; P < 0.001). Corticosteroid use showed a preventive effect on developing PD in patients with CD (aHR 0.08; P < 0.001), but not UC (aHR, 0.75; P = 0.213). Among 2110 patients receiving anti-tumor necrosis factor (anti-TNF), none of the treated patients experienced PD during 9950 person-years. Conclusion: Patients with IBD are at an increased risk of PD, regardless of health care use. Corticosteroid and anti-TNF use may prevent PD in patients with IBD.

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A punch in the gut – Intestinal inflammation links environmental factors to neurodegeneration in Parkinson's disease

Cited by 27 publications

References 29 publications

A Gutsy Move for Cell-Based Regenerative Medicine in Parkinson’s Disease: Targeting the Gut Microbiome to Sequester Inflammation and Neurotoxicity

A Gutsy Move for Cell-Based Regenerative Medicine in Parkinson’s Disease: Targeting the Gut Microbiome to Sequester Inflammation and Neurotoxicity

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice

Patients with Inflammatory Bowel Disease Are at an Increased Risk of Parkinson’s Disease: A South Korean Nationwide Population-Based Study

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