The gut microbiota metabolite propionate ameliorates intestinal epithelial barrier dysfunction-mediated Parkinson's disease via the AKT signaling pathway.

OBJECTIVE: Parkinson's disease is a common neurodegenerative disease. Here, we investigated the protective effect and potential mechanisms of propionate on the intestinal epithelial barrier in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease. METHODS: Gas chromatography was used to determine short-chain fatty acids (SCFA) concentrations in the fecal samples of Parkinson's disease patients and healthy controls. The stepping test was used to analyze forelimb akinesia, whisker test was used to analyze sensorimotor injury, cylinder test was used to analyze sensorimotor function, and Western blotting was used to analyze protein expression. RESULTS: The concentrations of SCFAs, including acetate, butyrate and propionate, were significantly downregulated in the fecal samples of Parkinson's disease patients, and among the SCFAs, propionate decreased the most. Propionate administration improved the stepping test score, whisker test score and cylinder test score of MPTP-induced Parkinson's disease mice. Additionally, propionate administration increased the protein expression of zonula occludens-1 and occludin. Moreover, the effects of propionate on motor behavior and the intestinal epithelial barrier were dependent on the proteirrserinc-threonine kinases (AKT) signaling pathway. More importantly, treatment with SC79, a specific AKT agonist, abolished the effects of propionate on the intestinal epithelial barrier and motor behavior. CONCLUSION: Our results demonstrated that propionate, which was decreased in the fecal samples of Parkinson's disease patients, exerted beneficial effects on intestinal epithelial barrier function and improved motor behavior in MPTP-induced Parkinson's disease mice through the AKT signaling pathway.

Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series.

Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated with a novel TNF inhibitor XPro1595 (10 mg/kg, n = 3) or vehicle (n = 2) every three days starting 11 weeks after the initiation of MPTP to determine whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. The case studies revealed that earlier and robust [18F]FEPPA PET signals resulted in earlier and more severe parkinsonism, which was seen in male cases compared to female cases. Potential other sex differences were observed in circulating inflammation, microbiota diversity and their metabolites. Additional studies with larger group sizes of both sexes would enable confirmation and extension of these findings. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

[Epidemiological and clinical aspects of chronic neuroborreliosis with parkinsonism in the Yaroslavl region]. / Epidemiologicheskie i klinicheskie aspekty khronicheskogo neiroborrelioza s sindromom parkinsonizma v Yaroslavskoi oblasti.

OBJECTIVE: To study clinical and epidemiological features of chronic neuroborreliosis (CB) with parkinsonism (PS) in the Yaroslavl region. MATERIALS AND METHODS: The study included the main group of patients (n=5) with CB and PS of the average age of 61±3/4, the comparison group (n=6) with Parkinson's disease (PD) of the average age of 54.7±8.3 and a group of 6 healthy people. Diagnostic criteria of Lyme disease based on the recommendation of the US Centers for Disease Control and Prevention and criteria for the diagnosis of PS were used. PD was diagnosed by the criteria of the Parkinson's UK Brain Bank. Serological diagnosis of CB was carried out using immunoenzyme assay and immunoblotting in dynamics. The following scales were administered: HOEHN and YAHR, MMSE, MFI-20, CGI. All patients underwent MRI of the brain and spinal cord. RESULTS AND CONCLUSION: PS in patients with CB in the Yaroslavl region was observed in 2.17% of cases among patients with CB and amounted to 0.25% of all cases of the revealed PS. The features that complicate the diagnosis of PS within chronic borreliosis were: the absence of erythema migrans in the history of 80% of patients and in more than half of the cases of the acute period of the disease, the presence in most patients (60%) of asymmetric onset of the PS with rest tremor in 40% cases and a significant reduction in the severity of PS as a result of therapy with levodopa. The onset of complete regression of the clinical manifestations of PS and reduction of the titer of antibodies and obtaining the negative results during dynamic serological study in response to prolonged antibiotic therapy provided a basis to verify the diagnosis of borreliosis with PS in these patients.

Transient parkinsonism associated with acute Legionnaires' disease.

A 44-year-old right-handed man with a 5-day history of non-productive cough associated with subjective fevers/chills and night sweats presented to the emergency department with slurred speech. Radiography and urine antigen testing confirmed the diagnosis of Legionella pneumonia The hospital course was complicated by acute hypoxic respiratory failure that required 7 days of invasive mechanical ventilation. Following extubation, the patient had dysarthria and developed new parkinsonism features. Brain imaging revealed a non-specific focal lesion in the left frontal lobe of unclear significance. Ciprofloxacin was decided as the final antibiotic of choice for its favourable central nervous system profile. Levodopa-carbidopa was initiated to help activate the basal ganglia. The patient had complete resolution of pneumonia and transient parkinsonism. He was able to regain most of his baseline functional status with intensive rehabilitation.

Alterations of the gut microbiota with antibiotics protects dopamine neuron loss and improve motor deficits in a pharmacological rodent model of Parkinson's disease.

Parkinson's disease (PD) is a debilitating condition resulting in motor and non-motor symptoms affecting approximately 10 million people worldwide. Currently, there are no pharmacological treatments that can cure the condition or effectively halt its progression. The focus of PD research has been primarily on the neurobiological basis and consequences of dopamine (DA) neuron degeneration given that the loss of DA neurons projecting from the substantia nigra to the dorsal striatum results in the development of cardinal PD motor symptoms. Alternatively, gastrointestinal dysfunction is well recognized in PD patients, and often occurs prior to the development of motor symptoms. The gut microbiota, which contains thousands of bacterial species, play important roles in intestinal barrier integrity and function, metabolism, immunity and brain function. Pre-clinical and clinical studies suggest an important link between alterations in the composition of the gut microbiota and psychiatric and neurological conditions, including PD. Several reports have documented gut dysbiosis and alterations in the composition of the gut microbiota in PD patients. Therefore, the goal of this study was to explore the contribution of the gut microbiota to the behavioral and neurochemical alterations in a rodent toxin model of DA depletion that reproduces the motor symptoms associated with PD. We observed that chronic treatment of adult rats with non-absorbable antibiotics ameliorates the neurotoxicity of 6-hydroxydopamine (6-OHDA) in a unilateral lesion model. Specifically, immunohistochemistry against the dopaminergic neuron marker tyrosine hydroxylase (TH) showed an attenuation of the degree of 6-OHDA-induced dopaminergic neuron loss in antibiotic treated animals compared to control animals. In addition, we observed a reduction in the expression of pro-inflammatory markers in the striatum of antibiotic-treated animals. The degree of motor dysfunction after 6-OHDA was also attenuated in antibiotic-treated animals as measured by paw-rearing measurements in the cylinder test, forepaw stepping test, and ipsilateral rotations observed in the amphetamine-induced rotation test. These results implicate the gut microbiota as a potential contributor to pathology in the development of PD. Further studies are necessary to understand the specific mechanisms involved in transducing alterations in the gut microbiota to changes in dopaminergic neuron loss and motor dysfunction.

MitoPark transgenic mouse model recapitulates the gastrointestinal dysfunction and gut-microbiome changes of Parkinson's disease.

Gastrointestinal (GI) disturbances are one of the earliest symptoms affecting most patients with Parkinson's disease (PD). In many cases, these symptoms are observed years before motor impairments become apparent. Hence, the molecular and cellular underpinnings that contribute to this early GI dysfunction in PD have actively been explored using a relevant animal model. The MitoPark model is a chronic, progressive mouse model recapitulating several key pathophysiological aspects of PD. However, GI dysfunction and gut microbiome changes have not been categorized in this model. Herein, we show that decreased GI motility was one of the first non-motor symptoms to develop, evident as early as 8 weeks with significantly different transit times from 12 weeks onwards. These symptoms were observed well before motor symptoms developed, thereby paralleling PD progression in humans. At age 24 weeks, we observed increased colon transit time and reduced fecal water content, indicative of constipation. Intestinal inflammation was evidenced with increased expression of iNOS and TNFα in the small and large intestine. Specifically, iNOS was observed mainly in the enteric plexi, indicating enteric glial cell activation. A pronounced loss of tyrosine hydroxylase-positive neurons occurred at 24 weeks both in the mid-brain region as well as the gut, leading to a corresponding decrease in dopamine (DA) production. We also observed decreased DARPP-32 expression in the colon, validating the loss of DAergic neurons in the gut. However, the total number of enteric neurons did not significantly differ between the two groups. Metabolomic gas chromatography-mass spectrometry analysis of fecal samples showed increased sterol, glycerol, and tocopherol production in MitoPark mice compared to age-matched littermate controls at 20 weeks of age while 16 s microbiome sequencing showed a transient temporal increase in the genus Prevotella. Altogether, the data shed more light on the role of the gut dopaminergic system in maintaining intestinal health. Importantly, this model recapitulates the chronology and development of GI dysfunction along with other non-motor symptoms and can become an attractive translational animal model for pre-clinical assessment of the efficacy of new anti-Parkinsonian drugs that can alleviate GI dysfunction in PD.

Unraveling gut microbiota in Parkinson's disease and atypical parkinsonism.

BACKGROUND: Although several studies have suggested that abnormalities in gut microbiota may play a critical role in the pathogenesis of PD, data are still extremely heterogeneous. METHODS: 16S gene ribosomal RNA sequencing was performed on fecal samples of 350 individuals, subdivided into idiopathic PD (n = 193, of whom 39 were drug naïve) stratified by disease duration, PSP (n = 22), MSA (n = 22), and healthy controls (HC; n = 113). Several confounders were taken into account, including dietary habits. RESULTS: Despite the fact that unadjusted comparison of PD and HC showed several differences in relative taxa abundances, the significant results were greatly reduced after adjusting for confounders. Although most of these differences were associated with disease duration, lower abundance in Lachnospiraceae was the only difference between de novo PD and HC (remaining lower across almost all PD duration strata). Decreased Lachnospiraceae and increased Lactobacillaceae and Christensenellaceae were associated with a worse clinical profile, including higher frequencies of cognitive impairment, gait disturbances, and postural instability. When compared with HC, MSA and PSP patients shared the changes in PD, with a few exceptions: in MSA, Lachnospiraceae were not lower, and Prevotellaceae were reduced; in PSP, Lactobacillaceae were similar, and Streptococcaceae were reduced. CONCLUSIONS: Gut microbiota may be an environmental modulator of the pathogenesis of PD and contribute to the interindividual variability of clinical features. Data are influenced by PD duration and several confounders that need to be taken into account in future studies. Prospective studies in de novo PD patients are needed to elucidate the net effect of dysbiosis on the progression of the disease. © 2018 International Parkinson and Movement Disorder Society.

The Prevalence and Distribution of Neurodegenerative Compound-Producing Soil Streptomyces spp.

Recent work from our labs demonstrated that a metabolite(s) from the soil bacterium Streptomyces venezuelae caused dopaminergic neurodegeneration in Caenorhabditis elegans and human neuroblastoma cells. To evaluate the capacity for metabolite production by naturally occurring streptomycetes in Alabama soils, Streptomyces were isolated from soils under different land uses (agriculture, undeveloped, and urban). More isolates were obtained from agricultural than undeveloped soils; there was no significant difference in the number of isolates from urban soils. The genomic diversity of the isolates was extremely high, with only 112 of the 1509 isolates considered clones. A subset was examined for dopaminergic neurodegeneration in the previously established C. elegans model; 28.3% of the tested Streptomyces spp. caused dopaminergic neurons to degenerate. Notably, the Streptomyces spp. isolates from agricultural soils showed more individual neuron damage than isolates from undeveloped or urban soils. These results suggest a common environmental toxicant(s) within the Streptomyces genus that causes dopaminergic neurodegeneration. It could also provide a possible explanation for diseases such as Parkinson's disease (PD), which is widely accepted to have both genetic and environmental factors.

Transient parkinsonism following mycoplasma pneumoniae infection with normal brain magnetic resonance imaging (MRI).

Parkinsonism caused by infection is uncommon in children. We report 2 previously healthy children with acute self-limiting parkinsonism following Mycoplasma pneumoniae infection, with normal brain magnetic resonance imaging (MRI). Our case report expands the phenotype of parkinsonism associated with M. pneumoniae infection. We recommend that children with acute parkinsonism preceded by a period of febrile illness, even with a normal brain MRI, should be investigated for M. pneumoniae infection.

Significantly higher frequency of Helicobacter suis in patients with idiopathic parkinsonism than in control patients.

BACKGROUND: There is increased proportional mortality from Parkinson's disease amongst livestock farmers. The hypokinesia of Parkinson's disease has been linked to Helicobacter pylori. H. suis is the most common zoonotic helicobacter in man. AIM: To compare the frequency of H. suis, relative to H. pylori, in gastric biopsies of patients with idiopathic parkinsonism (IP) and controls from gastroenterology services. METHODS: DNA extracts, archived at a Helicobacter Reference Laboratory, from IP patient and gastroenterology service biopsies were examined anonymously for H. suis, using species-specific RT-PCR. RESULTS: Relative risk of having H. suis in 60 IP patients compared with 256 controls was 10 times greater than that of having H. pylori. In patients with IP and controls, respectively, frequencies of H. suis were 27 (exact binomial 95% C.I. 15, 38) and 2 (0, 3)%, and of H. pylori, 28 (17, 40) and 16 (12, 21)%. Excess of H. suis in IP held when only the antral or corporal biopsy was considered. Of 16 IP patients with H. suis, 11 were from 19 with proven H. pylori eradication, 3 from 17 pre-H. pylori eradication, 2 from 24 H. pylori culture/PCR-negative. Frequency was different between groups (P = 0.001), greatest where H. pylori had been eradicated. Even without known exposure to anti-H. pylori therapy, H. suis was more frequent in IP patients (5/41) than in controls (1/155) (P = 0.002). Partial multilocus sequence typing confirmed that strains from IP patients (6) and control (1) differed from RT-PCR standard strain. CONCLUSIONS: Greater frequency of H. suis in idiopathic parkinsonism appears exaggerated following H. pylori eradication. Multilocus sequence testing comparison with porcine strains may clarify whether transmission is from pigs/porcine products or of human-adapted, H. suis-like, bacteria.

Antimicrobial surveillance in idiopathic parkinsonism: indication-specific improvement in hypokinesia following Helicobacter pylori eradication and non-specific effect of antimicrobials for other indications in worsening rigidity.

BACKGROUND: Following Helicobacter pylori eradication in a placebo-controlled trial, the hypokinesia of idiopathic parkinsonism improved but flexor rigidity worsened. METHODS: We surveyed the effect of all antimicrobial prescriptions in 66 patients with idiopathic parkinsonism over a median of 1.9 (interquartile range 0.4, 3.5) years. Initial Helicobacter screening was followed (where positive) by gastric biopsy. Serial lactulose hydrogen breath tests (364 tests) for small intestinal bacterial overgrowth monitored the need to encourage fluid intake and bulk/osmotic laxatives. We measured hypokinesia (401 assessments of mean stride length at free walking speed in 58 patients) and upper limb flexor rigidity (396 assessments in 49). RESULTS: Following successful H. pylori eradication (12 cases) but not failed (2), stride increased in entire group (including those receiving levodopa), core group (those receiving only longer-t½ antiparkinsonian medication or untreated) and untreated (p = .001 each case). The effect was greater with less antiparkinsonian medication (19 (95% CI, 14, 25) cm/year in untreated). Flexor rigidity was unchanged. Following antimicrobials for other indications (75 courses), hypokinesia was unchanged. However, flexor rigidity increased cumulatively. It increased in core group only after a first course (by (10 (0, 20)%/year, p = .05)), but then in entire, core and untreated after a second course (18 (6, 31), 33 (19, 48) and 29 (12, 48)%/year respectively; p = .002, .001 and .001) and further still after a third (17 (2, 34), 23 (8, 41) and 38 (15, 65)%/year; p = .02, .003 and .001). Initially, 40/66 were lactulose hydrogen breath test positive. Odds for positivity fell with time (by 59 (46, 75)%/year, p = .001) and tended to be lower with Helicobacter positivity (28 (8, 104)%, p = .06), but were unrelated to other antimicrobial interventions. CONCLUSIONS: Improved hypokinesia following antimicrobials appeared unique to Helicobacter eradication. Rigidity increased following successive antimicrobial exposures for other indications, despite diminishing lactulose hydrogen breath test positivity.

Scrub typhus associated with transient parkinsonism and myoclonus.

Parkinsonism with myoclonus is rarely associated with infectious disease in adults. We present a 55-year-old man experiencing acute onset bilateral limb tremor, rigidity, and myoclonus with small-stepped gait, and skin rash involving the trunk and limbs, after a fever. Serum was positive for anti-Orientia tsutsugamushi immunoglobulin M antibody. Brain MRI revealed no abnormalities. The fever improved with oral doxycycline, and the parkinsonism and myoclonus improved with amantadine and clonazepam. This is a rare case of parkinsonism with myolonus associated with scrub typhus infection.

Asymmetry in parkinsonism, spreading pathogens and the nose.

Parkinson's disease, as well as many other parkinsonisms, including most toxic, neurodegenerative and familial types are typically asymmetric. No explanation for this phenomenon exists. A summary of the frequency of asymmetry in a spectrum of parkinsonian disorders is provided. Evidence against asymmetry being the result of normal asymmetries of the substantia nigrais reviewed. Asymmetry either results from a greater susceptibility on one side or a spreading pathology entering or starting on one side of the CNS. With the increasing evidence for spreading pathologies (toxins, viruses, α-synuclein), knowledge of neuroanatomical connections, and literature implicating spreading pathogens from the enteric and olfactory nerves, potential explanations can be theorized and explored, including the possibility of a pathogen preferentially entering or originating in the olfactory bulb on one side, with subsequent involvement of the other side.

Parkinsonism induced by sepsis: a case report.

BACKGROUND: Parkinson's disease (PD) is a slowly progressive neurodegenerative disease that appears essentially as a sporadic condition with no identifiable cause. Parkinsonism is used for syndromes where the aetiolobgy is known such as Parkinsonism due to stroke, infection, neuroleptic drugs and toxic agents. Parkinson's disease and Parkinsonism present with the tetrad of tremor at rest, slowness of voluntary movement (bradykinesia), rigidity and a characteristic disturbance of gait and posture. A report of Parkinsonism induced by sepsis is rare. This report aims to create awareness of Parkinsonism as a manifestation of sepsis. METHOD: The case note of a patient with Parkinsonism induced by sepsis managed in the medical unit of the University of Port Harcourt Teaching Hospital and a review of the literature on the subject with Medline search was used. RESULT: A 71-year-old Nigerian male presented with Parkinsonism on a background of Gram negative sepsis which resolved with antibiotic therapy. Antiparkinoinian drugs were not used. CONCLUSION: Parkinsonism is a rarely reported neurological complication of sepsis. There is a need for physicians to be aware of this clinical manifestation.

Nocardia otitidiscaviarum (GAM-5) induces parkinsonian-like alterations in mouse.

Parkinson's disease, a major neurodegenerative disorder in humans whose etiology is unknown, may be associated with some environmental factors. Nocardia otitidiscaviarum (GAM-5) isolated from a patient with an actinomycetoma produced signs similar to Parkinson's disease following iv injection into NMRI mice. NMRI mice were infected intravenously with a non-lethal dose of 5 x 10(6) colony forming units of N. otitidiscaviarum (GAM-5). Fourteen days after bacterial infection, most of the 60 mice injected exhibited parkinsonian features characterized by vertical head tremor, akinesia/bradykinesia, flexed posture and postural instability. There was a peak of nocardial growth in the brain during the first 24 h followed by a decrease, so that by 14 days nocardiae could no longer be cultured. At 24 h after infection, Gram staining showed nocardiae in neurons in the substantia nigra and occasionally in the brain parenchyma in the frontal and parietal cortex. At 21 days post-infection, tyrosine hydroxylase immunolabeling showed a 58% reduction of tyrosine hydroxylase in the substantia nigra, and a 35% reduction of tyrosine hydroxylase in the ventral tegmental region. Dopamine levels were reduced from 110 +/- 32.5 to 58 +/- 16.5 ng/mg protein (47.2% reduction) in brain from infected mice exhibiting impaired movements, whereas serotonin levels were unchanged (191 +/- 44 protein in control and 175 +/- 39 ng/mg protein in injected mice). At later times, intraneuronal inclusion bodies were observed in the substantia nigra. Our observations emphasize the need for further studies of the potential association between Parkinson's disease or parkinsonism-like disease and exposure to various nocardial species.

Neuroinvasive Nocardia asteroides GUH-2 induces apoptosis in the substantia nigra in vivo and dopaminergic cells in vitro.

Neurodegenerative diseases such as Parkinson's disease are increasingly prevalent in the aging population worldwide. The causes of these disorders are unknown, but many studies have suggested that the etiology is likely multifactorial and may involve exposure to something in the environment combined with the normal aging process. Nocardia asteroides are bacteria commonly found in the soil, and neuroinvasive strains of nocardiae have been described. N. asteroides strain GUH-2 invades the brains of experimentally infected animals and selectively affects dopaminergic neurons of the substantia nigra (SN), causing an L-DOPA-responsive movement disorder resembling parkinsonism. Furthermore, dopaminergic neurons undergo morphological changes characteristic of apoptosis following nocardial infection. Apoptosis has been implicated in dopaminergic neuronal dropout in Parkinson's patients as well as other parkinsonian models. Thus, in this study, in vivo and in vitro models were utilized to measure the ability of GUH-2 to induce the apoptotic death of dopaminergic cells. Following infection with GUH-2, dopaminergic apoptotic cells were identified in the SN of animals by in situ end labeling, which detects DNA fragmentation, combined with fluorescent immunolabeling of tyrosine hydroxylase-positive cells. In addition, apoptosis was observed in PC12 cell cultures incubated with GUH-2 by both in situ end labeling and the annexin V assay, which detects externalization of phosphatidylserine of the plasma membrane, indicating apoptotic death. Based on the results of these studies, it appears that experimental infection with N. asteroides provides a general model for studying apoptosis in parkinsonian disorders.