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van der Maden MM, Verbeek MM, Beckers M. Lactobacillaceae and Parkinson's disease: An apparent paradox. JOURNAL OF PARKINSON'S DISEASE 2025; 15:269-281. [PMID: 39973489 DOI: 10.1177/1877718x241312401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder predominantly known for its motor symptoms such as bradykinesia, rigidity and tremor, but the disorder is also increasingly recognized for its association with impaired gastrointestinal function. The composition of the gut microbiome is known to be different in PD compared with healthy individuals. One of the bacterial families with increased abundance in people with PD is Lactobacillaceae. Interestingly, opposite effects have been ascribed to Lactobacillaceae in PD. A number of studies have linked Lactobacillaceae spp. in the gut to worse motor function, and to premature degradation of levodopa. However, other studies have linked administration of Lactobacillaceae-containing probiotics to improved motor function and reduced gastrointestinal problems. In this narrative review, we investigate this apparent paradox. The key to its understanding appears to lie in the specific species of Lactobacillaceae. The species L. plantarum in particular seemed to show a correlation with improved motor symptoms, as well as a reduction in intestinal inflammation, whereas L. brevis, L. curvatus and L. fermentum have properties that might be detrimental to people with PD.
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Affiliation(s)
| | - Marcel M Verbeek
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboudumc Centre of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Milan Beckers
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboudumc Centre of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
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2
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Wang X, Jiang D, Zhang X, Wang R, Yang F, Xie C. Causal associations between Helicobacter Pylori infection and the risk and symptoms of Parkinson's disease: a Mendelian randomization study. Front Immunol 2024; 15:1412157. [PMID: 39165356 PMCID: PMC11333313 DOI: 10.3389/fimmu.2024.1412157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 07/22/2024] [Indexed: 08/22/2024] Open
Abstract
Background Increasing evidence suggests an association between Helicobacter pylori (HP) infection and Parkinson's disease (PD) and its clinical manifestations, but the causal relationship remain largely unknown. Objective To investigate the causal relationship between HP infection and PD risk, PD symptoms, and secondary parkinsonism, we conducted two-sample Mendelian randomization (MR). Methods We obtained summary data from genome-wide association studies for seven different antibodies specific to HP proteins and five PD-related phenotypes. The inverse-variance weighted (IVW), weighted median, weighted mode, and MR-Egger methods were used to assess the causal relationships. Sensitivity analyses were performed to examine the stability of the MR results and reverse MR analysis was conducted to evaluate the presence of reverse causality. Results Genetically predicted HP antibodies were not causally associated with an increased risk of PD. However, HP cytotoxin-associated gene-A (CagA) and outer membrane protein (OMP) antibody level were causally associated with PD motor subtype (tremor to postural instability/gait difficulty score ratio; β = -0.16 and 0.46, P = 0.002 and 0.048, respectively). HP vacuolating cytotoxin-A (VacA) antibody level was causally associated with an increased risk of PD dementia [odds ratio (OR) = 1.93, P = 0.040]. Additionally, HP OMP antibody level was identified as a risk factor for drug-induced secondary parkinsonism (OR = 2.08, P = 0.033). These results were stable, showed no evidence of heterogeneity or directional pleiotropy, and no evidence of a reverse causal relationship. Conclusions Our findings indicate that HP infection does not increase the risk of PD, but contributes to PD motor and cognitive symptoms. Different types of HP antibodies affect different symptoms of PD. Eradication of HP infection may help modulate and improve symptoms in PD patients.
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Affiliation(s)
- Xin Wang
- Department of Neurology, Beijing Huairou Hospital of Traditional Chinese Medicine, Beijing, China
| | - Deming Jiang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xiao Zhang
- Department of Neurology, Beijing Huairou Hospital of Traditional Chinese Medicine, Beijing, China
| | - Ran Wang
- Department of Neurology, Beijing Huairou Hospital of Traditional Chinese Medicine, Beijing, China
| | - Fengyi Yang
- Department of Neurology, Beijing Huairou Hospital of Traditional Chinese Medicine, Beijing, China
| | - Chunrong Xie
- Department of Neurology, Beijing Huairou Hospital of Traditional Chinese Medicine, Beijing, China
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3
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Jia X, Chen Q, Zhang Y, Asakawa T. Multidirectional associations between the gut microbiota and Parkinson's disease, updated information from the perspectives of humoral pathway, cellular immune pathway and neuronal pathway. Front Cell Infect Microbiol 2023; 13:1296713. [PMID: 38173790 PMCID: PMC10762314 DOI: 10.3389/fcimb.2023.1296713] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/27/2023] [Indexed: 01/05/2024] Open
Abstract
The human gastrointestinal tract is inhabited by a diverse range of microorganisms, collectively known as the gut microbiota, which form a vast and complex ecosystem. It has been reported that the microbiota-gut-brain axis plays a crucial role in regulating host neuroprotective function. Studies have shown that patients with Parkinson's disease (PD) have dysbiosis of the gut microbiota, and experiments involving germ-free mice and fecal microbiota transplantation from PD patients have revealed the pathogenic role of the gut microbiota in PD. Interventions targeting the gut microbiota in PD, including the use of prebiotics, probiotics, and fecal microbiota transplantation, have also shown efficacy in treating PD. However, the causal relationship between the gut microbiota and Parkinson's disease remains intricate. This study reviewed the association between the microbiota-gut-brain axis and PD from the perspectives of humoral pathway, cellular immune pathway and neuronal pathway. We found that the interactions among gut microbiota and PD are very complex, which should be "multidirectional", rather than conventionally regarded "bidirectional". To realize application of the gut microbiota-related mechanisms in the clinical setting, we propose several problems which should be addressed in the future study.
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Affiliation(s)
- Xiaokang Jia
- School of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan, China
| | - Qiliang Chen
- School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuanyuan Zhang
- Department of Acupuncture and Moxibustion, The Affiliated Traditional Chinese Medicine (TCM) Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Tetsuya Asakawa
- Institute of Neurology, National Clinical Research Center for Infectious Diseases, the Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
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Brown GC, Camacho M, Williams‐Gray CH. The Endotoxin Hypothesis of Parkinson's Disease. Mov Disord 2023; 38:1143-1155. [PMID: 37157885 PMCID: PMC10947365 DOI: 10.1002/mds.29432] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/14/2023] [Accepted: 04/19/2023] [Indexed: 05/10/2023] Open
Abstract
The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Guy C. Brown
- Department of BiochemistryUniversity of CambridgeCambridgeUK
| | - Marta Camacho
- Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
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Xu K, Sheng S, Zhang F. Relationship Between Gut Bacteria and Levodopa Metabolism. Curr Neuropharmacol 2023; 21:1536-1547. [PMID: 36278467 PMCID: PMC10472813 DOI: 10.2174/1570159x21666221019115716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/26/2022] [Accepted: 09/02/2022] [Indexed: 11/22/2022] Open
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, characterized by the reduction of dopamine neurons in the substantia nigra. Levodopa, as a dopamine supplement, is the gold-standard therapeutic drug for PD. The metabolism of levodopa in the periphery not only decreases its bioavailability but also affects its efficacy. Thus, it is necessary to investigate how levodopa is metabolized. A growing number of studies have shown that intestinal bacteria, such as Enterococcus faecalis, Eggerthella lenta and Clostridium sporogenes, could metabolize levodopa in different ways. In addition, several pathways to reduce levodopa metabolism by gut microbiota were confirmed to improve levodopa efficacy. These pathways include aromatic amino acid decarboxylase (AADC) inhibitors, antibiotics, pH and (S)-α-fluoromethyltyrosine (AFMT). In this review, we have summarized the metabolic process of levodopa by intestinal bacteria and analyzed potential approaches to reduce the metabolism of levodopa by gut microbiota, thus improving the efficacy of levodopa.
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Affiliation(s)
- Kaifei Xu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Center, Zunyi Medical University, Zunyi, Guizhou, China
| | - Shuo Sheng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Center, Zunyi Medical University, Zunyi, Guizhou, China
| | - Feng Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Center, Zunyi Medical University, Zunyi, Guizhou, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou, China
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Sung YF, Yin JH, Lee KH, Tsai CL, Lin YK, Chen SY, Chung CH, Chien WC, Lee JT, Chou CH. Increased risk of sleep-related movement disorder in patients with Helicobacter pylori infection: A nationwide population-based study. Front Neurol 2022; 13:953821. [PMID: 36299273 PMCID: PMC9589275 DOI: 10.3389/fneur.2022.953821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background and purpose Evidence increasingly suggests that Helicobacter pylori infection (HPI) is associated with movement disorders such as Parkinson's disease (PD). However, the relationship between HPI and sleep-related movement disorders (SRMD) remains unknown. This nationwide population-based study tried to demonstrate whether patients with HPI have a higher risk of developing SRMD in a general adult population. Methods The study cohort enrolled 9,393 patients who were initially diagnosed with HPI between 2000 and 2013. Notably, 37,572 age- and sex-matched controls without prior HPI were selected as the reference. A Cox proportional hazard regression analysis was performed for multivariate adjustment. Results Patients with HPI had a higher risk of developing SRMD (adjusted hazard ratio [HR] = 2.18, 95% confidence interval [CI] = 1.26–3.82, p < 0.01). Patients with HPI aged ≥65 years exhibited the highest risk (HR = 3.01, 95% CI = 1.90–5.30, p < 0.001), followed by patients aged 45–64 years (HR = 1.69, 95% CI = 1.26–2.90, p <0.01) and <45 years (HR = 1.49, 95% CI = 1.12–2.49, p < 0.01). Patients were most likely to develop SRMD 5 years or more after diagnosis of HPI (HR = 3.33, 95% CI = 1.97–5.89, p < 0.001). The increased risk of SRMD in male patients with HPI (HR = 2.73, 95% CI = 1.53–4.79, p < 0.001) was greater than in female patients (HR = 1.14, 95% CI = 1.04–1.65, p < 0.05). Conclusion Patients with HPI were associated with an increased risk for SRMD, with a higher risk in men, aged ≥65 years, and diagnosed for more than 5 years.
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Affiliation(s)
- Yueh-Feng Sung
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jiu-Haw Yin
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Internal Medicine, Taipei Veterans General Hospital, Hsinchu, Taiwan
| | - Kuang-Heng Lee
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Lin Tsai
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Kai Lin
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Shao-Yuan Chen
- Department of Neurology, Cardinal Tien Hospital, New Taipei City, Taiwan
- Department of Hyperbaric Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan
- School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Chi-Hsiang Chung
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jiunn-Tay Lee
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Chung-Hsing Chou
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
- *Correspondence: Chung-Hsing Chou
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7
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Shamsdin SA, Khazraei H, Rahimi Jaberi A, Zamani M, Rafiee Monjezi M. Evaluation of Inflammatory Cytokine and Anti Helicobacter Pylori Antibodies in the Pathogenesis of Parkinson's Disease. Middle East J Dig Dis 2022; 14:96-102. [PMID: 36619735 PMCID: PMC9489332 DOI: 10.34172/mejdd.2022.261] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/24/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND: Parkinson's disease is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigari. Previous studies have shown that Helicobacter pylori (H. pylori) infection is associated with treatment and clinical response to Parkinson's disease. In the present study, we aimed to investigate the effect of H. pylori infection in the pathogenesis of Parkinson's disease. METHODS: 75 patients who suffered from Parkinson's disease and H. pylori infection and 91 healthy controls were recruited. All the subjects were evaluated for serum IgM, IgG, and IgA antibodies as well as TNF-α, IL-6, and IL-4 cytokines by Enzyme-Linked ImmunoSorbent Assay (ELISA)methods. RESULTS: The participants included 102 men and 64 women with a mean age of 66±10.2 and 52.6±10.7 years in the patients and control groups, respectively. The level of IgG, TNF-α, IL-6 in the patients with Parkinson's infected with H. pylori was significantly more than that in the control group. In contrast, IgA was significantly lower in patients with Parkinson's disease compared with the control group. CONCLUSION: Probably, persistent infection with H. pylori could be effective in the pathogenesis of Parkinson's disease by dominating the systemic inflammatory profile. It is suggested that pro-inflammatory cytokines followed by H. pylori infection through the promotion of immune response or neurotoxicity might have a role in the pathogenesis of Parkinson's disease.
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Affiliation(s)
- Seyedeh Azra Shamsdin
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hajar Khazraei
- Colorectal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abass Rahimi Jaberi
- Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran,Corresponding Author: Abass Rahimi Jaberi, MD Assistant Professor, Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran Tel:+98 7136121065 Fax:+98 7136121065
| | - Mozhdeh Zamani
- Colorectal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Berlamont H, Bruggeman A, Bauwens E, Vandendriessche C, Clarebout E, Xie J, De Bruyckere S, Van Imschoot G, Van Wonterghem E, Ducatelle R, Santens P, Smet A, Haesebrouck F, Vandenbroucke RE. Gastric Helicobacter suis Infection Partially Protects against Neurotoxicity in A 6-OHDA Parkinson's Disease Mouse Model. Int J Mol Sci 2021; 22:ijms222111328. [PMID: 34768765 PMCID: PMC8582972 DOI: 10.3390/ijms222111328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 12/21/2022] Open
Abstract
The exact etiology of Parkinson’s disease (PD) remains largely unknown, but more and more research suggests the involvement of the gut microbiota. Interestingly, idiopathic PD patients were shown to have at least a 10 times higher prevalence of Helicobacter suis (H. suis) DNA in gastric biopsies compared to control patients. H. suis is a zoonotic Helicobacter species that naturally colonizes the stomach of pigs and non-human primates but can be transmitted to humans. Here, we investigated the influence of a gastric H. suis infection on PD disease progression through a 6-hydroxydopamine (6-OHDA) mouse model. Therefore, mice with either a short- or long-term H. suis infection were stereotactically injected with 6-OHDA in the left striatum and sampled one week later. Remarkably, a reduced loss of dopaminergic neurons was seen in the H. suis/6-OHDA groups compared to the control/6-OHDA groups. Correspondingly, motor function of the H. suis-infected 6-OHDA mice was superior to that in the non-infected 6-OHDA mice. Interestingly, we also observed higher expression levels of antioxidant genes in brain tissue from H. suis-infected 6-OHDA mice, as a potential explanation for the reduced 6-OHDA-induced cell loss. Our data support an unexpected neuroprotective effect of gastric H. suis on PD pathology, mediated through changes in oxidative stress.
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Affiliation(s)
- Helena Berlamont
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Arnout Bruggeman
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
- Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium;
| | - Eva Bauwens
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Charysse Vandendriessche
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Elien Clarebout
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Junhua Xie
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Sofie De Bruyckere
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Griet Van Imschoot
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Elien Van Wonterghem
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Richard Ducatelle
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Patrick Santens
- Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium;
| | - Annemieke Smet
- Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium;
| | - Freddy Haesebrouck
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; (H.B.); (E.B.); (S.D.B.); (R.D.); (F.H.)
| | - Roosmarijn E. Vandenbroucke
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (A.B.); (C.V.); (E.C.); (J.X.); (G.V.I.); (E.V.W.)
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
- Correspondence: ; Tel.: +32-9-3313730
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Zhang X, Han Y, Huang W, Jin M, Gao Z. The influence of the gut microbiota on the bioavailability of oral drugs. Acta Pharm Sin B 2021; 11:1789-1812. [PMID: 34386321 PMCID: PMC8343123 DOI: 10.1016/j.apsb.2020.09.013] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/27/2020] [Accepted: 08/20/2020] [Indexed: 02/07/2023] Open
Abstract
Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.
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Key Words
- 5-ASA, 5-aminosalicylic acid
- AA, ascorbic acid
- ABC, ATP-binding cassette
- ACS, amphipathic chitosan derivative
- AMI, amiodarone
- AQP4, aquaporin 4
- AR, azoreductase
- ASP, amisulpride
- BBR, berberine
- BCRP, breast cancer resistance protein
- BCS, biopharmaceutics classification system
- BDDCS, the biopharmaceutics drug disposition classification system
- BDEPT, the bacteria-directed enzyme prodrug therapy
- BSH, bile salt hydrolase
- Bioavailability
- CA, cholic acid
- CDCA, chenodeoxycholic acid
- CPP, cell-penetrating peptide
- CS, chitosan
- Colon-specific drug delivery system
- DCA, deoxycholic acid
- DRPs, digoxin reduction products
- EcN, Escherichia coli Nissle 1917
- FA, folate
- FAO, Food and Agriculture Organization of the United Nations
- GCDC, glycochenodeoxycholate
- GL, glycyrrhizic acid
- Gut microbiota
- HFD, high fat diet
- HTC, hematocrit
- IBD, inflammatory bowel disease
- LCA, lithocholic acid
- LPS, lipopolysaccharide
- MATEs, multidrug and toxin extrusion proteins
- MDR1, multidrug resistance gene 1
- MDR1a, multidrug resistance protein-1a
- MKC, monoketocholic acid
- MPA, mycophenolic acid
- MRP2, multidrug resistance-associated protein 2
- NEC, necrotizing enterocolitis
- NMEs, new molecular entities
- NRs, nitroreductases
- NSAIDs, non-steroidal anti-inflammatory drugs
- NaDC, sodium deoxycholate
- NaGC, sodium glycholate
- OATs, organic anion transporters
- OCTNs, organic zwitterion/cation
- OCTs, organic cation transporters
- Oral drugs
- P-gp, P-glycoprotein
- PD, Parkinson's disease
- PPIs, proton pump inhibitors
- PT, pectin
- PWSDs, poorly water-soluble drugs
- Probiotics
- RA, rheumatoid arthritis
- RBC, red blood cell
- SCFAs, short-chain fatty acids
- SGLT-1, sodium-coupled glucose transporter 1
- SLC, solute carrier
- SLN, solid lipid nanoparticle
- SP, sulfapyridine
- SSZ, sulfasalazine
- SVCT-1/2, the sodium-dependent vitamin C transporter-1/2
- T1D, type 1 diabetes
- T1DM, type 1 diabetes mellitus
- T2D, type 2 diabetes
- TCA, taurocholate
- TCDC, taurochenodeoxycholate
- TDCA, taurodeoxycholate
- TLCA, taurolithocholate
- TME, the tumor microenvironment
- UDC, ursodeoxycholic acid
- WHO, World Health Organization
- an OTC drug, an over-the-counter drug
- cgr operon, cardiac glycoside reductase operon
- dhBBR, dihydroberberine
- pKa, dissociation constant
- the GI tract, the gastrointestinal tract
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Affiliation(s)
- Xintong Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Ying Han
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Wei Huang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Mingji Jin
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zhonggao Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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10
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Liang Y, Cui L, Gao J, Zhu M, Zhang Y, Zhang HL. Gut Microbial Metabolites in Parkinson's Disease: Implications of Mitochondrial Dysfunction in the Pathogenesis and Treatment. Mol Neurobiol 2021; 58:3745-3758. [PMID: 33825149 PMCID: PMC8280023 DOI: 10.1007/s12035-021-02375-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 03/25/2021] [Indexed: 12/11/2022]
Abstract
The search for therapeutic targets for Parkinson's disease (PD) is hindered by the incomplete understanding of the pathophysiology of the disease. Mitochondrial dysfunction is an area with high potential. The neurobiological signaling connections between the gut microbiome and the central nervous system are incompletely understood. Multiple lines of evidence suggest that the gut microbiota participates in the pathogenesis of PD. Gut microbial dysbiosis may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The intervention of gut microbial metabolites via the microbiota-gut-brain axis may serve as a promising therapeutic strategy for PD. In this narrative review, we summarize the potential roles of gut microbial dysbiosis in PD, with emphasis on microbial metabolites and mitochondrial function. We then review the possible ways in which microbial metabolites affect the central nervous system, as well as the impact of microbial metabolites on mitochondrial dysfunction. We finally discuss the possibility of gut microbiota as a therapeutic target for PD.
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Affiliation(s)
- Yixuan Liang
- Department of Neurology, First Hospital of Jilin University, Changchun, 130021, China
| | - Li Cui
- Department of Neurology, First Hospital of Jilin University, Changchun, 130021, China
| | - Jiguo Gao
- Department of Neurology, First Hospital of Jilin University, Changchun, 130021, China
| | - Mingqin Zhu
- Department of Neurology, First Hospital of Jilin University, Changchun, 130021, China.,Departments of Laboratory Medicine and Pathology, Neurology and Immunology, Mayo Clinic, Rochester, MN, USA
| | - Ying Zhang
- Department of Neurology, First Hospital of Jilin University, Changchun, 130021, China.
| | - Hong-Liang Zhang
- Department of Life Sciences, National Natural Science Foundation of China, Shuangqing Road 83, Beijing, 100085, China.
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11
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Kline EM, Houser MC, Herrick MK, Seibler P, Klein C, West A, Tansey MG. Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation. Mov Disord 2021; 36:25-36. [PMID: 33314312 PMCID: PMC8285924 DOI: 10.1002/mds.28411] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/20/2020] [Accepted: 11/12/2020] [Indexed: 12/14/2022] Open
Abstract
Idiopathic Parkinson's disease (iPD) is a movement disorder characterized by the degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and non-motor symptoms, and extent of central and peripheral inflammation. Genetic and environmental factors are believed to act synergistically in iPD pathogenesis. We propose that environmental factors (pesticides and infections) increase the risk for iPD via the immune system and that the role of PD risk genes in immune cells is worthy of investigation. This review highlights the major PD-relevant genes expressed in immune cells and key environmental factors that activate immune cells and, alone or in combination with other factors, may contribute to iPD pathogenesis. By reviewing these interactions, we seek to enable the future development of immunomodulatory approaches to prevent or delay onset of iPD. © 2020 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Elizabeth M Kline
- Laney Graduate School, Emory University, Atlanta, Georgia, USA
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut, USA
| | - Madelyn C Houser
- Laney Graduate School, Emory University, Atlanta, Georgia, USA
- School of Nursing, Emory University, Atlanta, Georgia, USA
| | - Mary K Herrick
- Laney Graduate School, Emory University, Atlanta, Georgia, USA
- Departments of Neuroscience and Neurology, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Philip Seibler
- Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
| | - Christine Klein
- Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
| | - Andrew West
- Duke Center for Neurodegeneration and Neurotherapeutics, Duke University, Durham, North Carolina, USA
| | - Malú G Tansey
- Departments of Neuroscience and Neurology, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida, USA
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12
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Nyholm D, Hellström PM. Effects of Helicobacter pylori on Levodopa Pharmacokinetics. JOURNAL OF PARKINSON'S DISEASE 2021; 11:61-69. [PMID: 33164946 PMCID: PMC7990449 DOI: 10.3233/jpd-202298] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 10/08/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Infection with Helicobacter pylori seems overrepresented in Parkinson's disease. Clinical observations suggest a suboptimal treatment effect of levodopa in Helicobacter positive patients. OBJECTIVE Describe and explain the connection between a Helicobacter pylori infection of the upper gut and changes in pharmacokinetics of oral levodopa treatment in Parkinson's disease. METHODS PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: Bioavailability, drug metabolism, dyskinesia, Helicobacter, L-dopa, levodopa, motor control, pharmacodynamics, pharmacokinetics, prevalence, unified Parkinson's disease rating scale. RESULTS The prevalence of Helicobacter pylori in Parkinson's disease patients is reported to be about 1.6-fold higher than in a control population in some studies. Helicobacter has therefore been assumed to be linked to Parkinson's disease, but the mechanism is unclear. As regards symptoms and treatment, patients with Parkinson's disease on levodopa therapy and with Helicobacter pylori infection display worse motor control than those without Helicobacter infection. Eradication of the infection improves levodopa response in Parkinson's disease, likely as a consequence of an increased oral pre-systemic bioavailability of levodopa, likely to be explained by reduced Helicobacter-dependent levodopa consumption in the stomach. In addition, small intestinal bacterial overgrowth may also have an impact on the therapeutic setting for levodopa treatment but is less well established. CONCLUSION Eradication of Helicobacter pylori improves levodopa bioavailability resulting in improved motor control. Eradication of Helicobacter should be considered in patients with poor symptomatic control and considerable motor fluctuations.
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Affiliation(s)
- Dag Nyholm
- Department of Neuroscience, Neurology; and Department of Medical Sciences, Gastroenterology, Uppsala University, Sweden
| | - Per M. Hellström
- Department of Neuroscience, Neurology; and Department of Medical Sciences, Gastroenterology, Uppsala University, Sweden
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13
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Affiliation(s)
- Yogesh Bhattarai
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Purna C. Kashyap
- Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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14
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Tucker RM, Augustin AD, Hayee BH, Bjarnason I, Taylor D, Weller C, Charlett A, Dobbs SM, Dobbs RJ. Role of Helicobacters in Neuropsychiatric Disease: A Systematic Review in Idiopathic Parkinsonism. J Clin Med 2020; 9:jcm9072159. [PMID: 32650535 PMCID: PMC7408992 DOI: 10.3390/jcm9072159] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/03/2020] [Accepted: 07/05/2020] [Indexed: 12/14/2022] Open
Abstract
Interest in an aetiopathogenic role for Helicobacter in neuropsychiatric diseases started with idiopathic parkinsonism (IP), where the cardinal signs can be assessed objectively. This systematic review, using an EMBASE database search, addresses Oxford Centre for Evidence-Based Medicine based questions on the inter-relationship of Helicobacter and IP, the benefits of eradicating Helicobacter in IP and the outcome of not treating. The search strategy was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines: 21 of 204 articles met the inclusion criteria. The results show that the assumption that any benefit of Helicobacter eradication results from improved levodopa bioavailability is unjustified. The inter-relationship between Helicobacter and IP is well-established. H. pylori virulence markers (associated with autoimmunity and immune tolerance) influence the risk, severity and progression of IP. The birth cohort effect for virulence marker antibodies, seen in controls, is obliterated in IP, suggesting causality. Successful H. pylori eradication in IP is disease-modifying (even in anti-parkinsonian treatment-naïve patients) but not preventive. Hypokinesia regresses with eradication and overall motor severity lessens. Eradication may influence gastrointestinal microbiota adversely, unlocking the next stage in the natural history, the development of rigidity. Failed eradication worsens hypokinesia, as does the presence/persistence of H. pylori at molecular level only. Adequate prognostic assessment of the consequences of not treating Helicobacter, for IP, is prevented by a short follow-up. We conclude that Helicobacter is a pathophysiological driver of IP.
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Affiliation(s)
- Rosalind M. Tucker
- Pharmaceutical Sciences, King’s College, London SE1 9NH, UK; (R.M.T.); (A.D.A.); (D.T.); (C.W.); (A.C.); (R.J.D.)
- The Maudsley Hospital, London SE5 8AZ, UK
| | - Aisha D. Augustin
- Pharmaceutical Sciences, King’s College, London SE1 9NH, UK; (R.M.T.); (A.D.A.); (D.T.); (C.W.); (A.C.); (R.J.D.)
- The Maudsley Hospital, London SE5 8AZ, UK
| | - Bu’ Hussain Hayee
- Gastroenterology, King’s College Hospital, London SE5 9RS, UK; (B.H.H.); (I.B.)
| | - Ingvar Bjarnason
- Gastroenterology, King’s College Hospital, London SE5 9RS, UK; (B.H.H.); (I.B.)
| | - David Taylor
- Pharmaceutical Sciences, King’s College, London SE1 9NH, UK; (R.M.T.); (A.D.A.); (D.T.); (C.W.); (A.C.); (R.J.D.)
- The Maudsley Hospital, London SE5 8AZ, UK
| | - Clive Weller
- Pharmaceutical Sciences, King’s College, London SE1 9NH, UK; (R.M.T.); (A.D.A.); (D.T.); (C.W.); (A.C.); (R.J.D.)
| | - André Charlett
- Pharmaceutical Sciences, King’s College, London SE1 9NH, UK; (R.M.T.); (A.D.A.); (D.T.); (C.W.); (A.C.); (R.J.D.)
- Statistics, Modelling and Economics, National Infection Service, Public Health England, London NW9 5EQ, UK
| | - Sylvia M Dobbs
- Pharmaceutical Sciences, King’s College, London SE1 9NH, UK; (R.M.T.); (A.D.A.); (D.T.); (C.W.); (A.C.); (R.J.D.)
- The Maudsley Hospital, London SE5 8AZ, UK
- Gastroenterology, King’s College Hospital, London SE5 9RS, UK; (B.H.H.); (I.B.)
- Correspondence:
| | - R John Dobbs
- Pharmaceutical Sciences, King’s College, London SE1 9NH, UK; (R.M.T.); (A.D.A.); (D.T.); (C.W.); (A.C.); (R.J.D.)
- The Maudsley Hospital, London SE5 8AZ, UK
- Gastroenterology, King’s College Hospital, London SE5 9RS, UK; (B.H.H.); (I.B.)
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15
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Abstract
As one of the most prevalent infections globally, Helicobacter pylori (H. pylori) continues to present diagnostic and therapeutic challenges for clinicians worldwide. Diagnostically, the "test-and-treat" strategy is the recommended approach for healthcare practitioners when managing this potentially curable disease. The choice of testing method should be based on several factors including patient age, presenting symptoms, and medication use, as well as test reliability, availability, and cost. With rising antibiotic resistance, particularly of macrolides, care must be taken to ensure that therapy is selected based on regional resistance patterns and prior antibiotic exposure. In the USA, macrolide antibiotic resistance rates in some areas have reached or exceeded a generally accepted threshold, such that clarithromycin triple therapy may no longer be an appropriate first-line empiric treatment. Instead, bismuth quadruple therapy should be considered, while levofloxacin-based or alternative macrolide-containing therapies are also options. Once treated, it is essential to test for eradication as untreated H. pylori is associated with serious complications including peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. This review article aims to consolidate current knowledge of H. pylori infection with a particular emphasis on diagnostic and treatment strategies.
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Affiliation(s)
- Bernardo Guevara
- Department of Internal Medicine, University of California Davis School of Medicine, 4150 V Street, Suite 1100, Sacramento, CA, 95817, USA
| | - Asha Gupta Cogdill
- Division of Gastroenterology and Hepatology, UC Davis Medical Center, University of California Davis School of Medicine, 4150 V Street, Suite 3500, Sacramento, CA, 95817, USA.
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16
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Fu P, Gao M, Yung KKL. Association of Intestinal Disorders with Parkinson's Disease and Alzheimer's Disease: A Systematic Review and Meta-Analysis. ACS Chem Neurosci 2020; 11:395-405. [PMID: 31876406 DOI: 10.1021/acschemneuro.9b00607] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative disorders, with an overall global incidence of 40 million. Many studies have revealed the association of intestinal disorders and bacterial infections with PD, but few studies have found such a relationship with AD. In this meta-analysis, related articles published up to September 2018 were searched in PubMed. Of the 2121 related articles screened initially, 56 were found to be eligible. Data on the risks of PD and AD due to five intestinal disorders and infection with Helicobacter pylori, as a representative intestinal microbe, were obtained, and a fixed- or random-effects model was used to pool the odds ratios (ORs) with 95% confidence interval (CIs) from individual studies. The combined OR for all types of intestinal disorders with an increased risk of PD was 3.36 (95% CI: 2.70-4.17). The ORs for each category were as follows: constipation, 4.05 (95% CI, 3.24-5.06); inflammatory bowel disease (IBD), 1.16 (95% CI, 0.89-1.52); irritable bowel syndrome (IBS), 1.75 (95% CI, 0.55-5.56); small intestinal bacterial overgrowth, 5.15 (95% CI, 3.33-7.96); and diarrhea, 1.27 (95% CI, 0.28-5.75). The combined OR of all types of intestinal disorders with an increased risk of AD was 1.52 (95% CI, 1.09-2.13). The ORs for IBS and IBD were 1.42 (95% CI, 1.02-1.99) and 2.40 (95% CI, 1.00-5.76), respectively. The risk estimates of H. pylori infection in PD and AD patients were as follows: OR, 1.65 (95% CI, 1.43-1.91) and OR, 1.40 (95% CI, 1.12-1.76), respectively. These findings suggest that PD and AD are significantly associated with intestinal disorders. The negative roles of H. pylori in the development of PD or AD should be evaluated to shed new light on the diagnosis and treatment of PD and AD. National governments should periodically inspect the intestinal condition of residents and extend health plans to improve intestinal health to prevent potential neurological disorders.
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Affiliation(s)
- Pengfei Fu
- Department of Biology, Hong Kong Baptist University, Kowloon Tong 999077, Hong Kong SAR, China
| | - Meng Gao
- Department of Geography, Hong Kong Baptist University, Kowloon Tong 999077, Hong Kong SAR, China
| | - Ken Kin Lam Yung
- Department of Biology, Hong Kong Baptist University, Kowloon Tong 999077, Hong Kong SAR, China
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17
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Ilie OD, Ciobica A, McKenna J, Doroftei B, Mavroudis I. Minireview on the Relations between Gut Microflora and Parkinson's Disease: Further Biochemical (Oxidative Stress), Inflammatory, and Neurological Particularities. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4518023. [PMID: 32089768 PMCID: PMC7025076 DOI: 10.1155/2020/4518023] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 12/20/2019] [Accepted: 01/04/2020] [Indexed: 02/07/2023]
Abstract
The aetiology of Parkinson's disease (PD) is a highly debated topic. Despite the progressive increase in the number of patients diagnosed with PD over the last couple of decades, the causes remain largely unknown. This report is aimed at highlighting the main features of the microbial communities which have been termed "the second brain" that may be a major participant in the etiopathophysiology of PD. It is possible that dysbiosis could be caused by an overactivity of proinflammatory cytokines which act on the gastrointestinal tract as well as infections. The majority of patients who are diagnosed with PD display gastrointestinal symptoms as one of the earliest features. In addition, an unbalanced cycle of oxidative stress caused by dysbacteriosis may have the effect of gradually promoting PD's specific phenotype. Thus, it seems that bacteria possess the ability to manipulate the brain by initiating specific responses, defining their capability to configure the human body, with oxidative stress playing a pivotal role in preventing infections but also in activating related signalling pathways.
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Affiliation(s)
- Ovidiu-Dumitru Ilie
- Department of Research, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, no. 11, 700505 Iasi, Romania
| | - Alin Ciobica
- Department of Research, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, no. 11, 700505 Iasi, Romania
| | - Jack McKenna
- Leeds Teaching Hospitals NHS Trust, Great George St., Leeds LS1 3EX, UK
| | - Bogdan Doroftei
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no. 16, 700115 Iasi, Romania
- Origyn Fertility Center, Palace Street, no. 3C, 700032 Iasi, Romania
| | - Ioannis Mavroudis
- Leeds Teaching Hospitals NHS Trust, Great George St., Leeds LS1 3EX, UK
- Laboratory of Neuropathology and Electron Microscopy, School of Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
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18
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Abstract
The endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid β and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer's disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer's disease. Intestinal permeability increases early in Parkinson's disease, and injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson's disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.
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Affiliation(s)
- Guy C Brown
- Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QW, UK.
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19
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McGee DJ, Lu XH, Disbrow EA. Stomaching the Possibility of a Pathogenic Role for Helicobacter pylori in Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2018; 8:367-374. [PMID: 29966206 PMCID: PMC6130334 DOI: 10.3233/jpd-181327] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 05/14/2018] [Indexed: 12/20/2022]
Abstract
While a small subset of Parkinson's disease cases have genetic causes, most cases are sporadic and may have an environmental contributor that has largely remained enigmatic. Remarkably, gastrointestinal symptoms in PD patients serve as a prodrome for the eventual motor dysfunctions. Herein, we review studies exploring a possible link between the gastric human pathogen Helicobacter pylori and PD. We provide plausible and testable hypotheses for how this organism might contribute to PD: 1) a toxin(s) produced by the bacteria; 2) disruption of the intestinal microbiome; 3) local inflammation that crosses the gut-brain axis, leading to neuroinflammation; and 4) manipulation of the pharmacokinetics of the PD drug levodopa by H. pylori, even in those not receiving exogenous levodopa. Key findings are: 1) people with PD are 1.5-3-fold more likely to be infected with H. pylori than people without PD; 2) H. pylori-infected PD patients display worse motor functions than H. pylori-negative PD patients; 3) eradication of H. pylori improves motor function in PD patients over PD patients whose H. pylori was not eradicated; and 4) eradication of H. pylori improves levodopa absorption in PD patients compared to that of PD patients whose H. pylori was not eradicated. Evidence is accumulating that H. pylori has a link with PD, but the mechanism is unclear. Future work should explore the effects of H. pylori on development of PD in defined PD animal models, focusing on the roles of H. pylori toxins, inflammation, levodopa absorption, and microbiome dysbiosis.
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Affiliation(s)
- David J. McGee
- Department of Microbiology and Immunology, LSU Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Xiao-Hong Lu
- Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Elizabeth A. Disbrow
- Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center-Shreveport, Shreveport, LA, USA
- Department of Neurology, LSU Health Sciences Center-Shreveport, Shreveport, LA, USA
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20
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Som Chaudhury S, Das Mukhopadhyay C. Functional amyloids: interrelationship with other amyloids and therapeutic assessment to treat neurodegenerative diseases. Int J Neurosci 2017; 128:449-463. [PMID: 29076790 DOI: 10.1080/00207454.2017.1398153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Sutapa Som Chaudhury
- Centre for Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, Shibpur, West Bengal, India
| | - Chitrangada Das Mukhopadhyay
- Centre for Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, Shibpur, West Bengal, India
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21
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Mukherjee A, Biswas A, Das SK. Gut dysfunction in Parkinson's disease. World J Gastroenterol 2016; 22:5742-5752. [PMID: 27433087 PMCID: PMC4932209 DOI: 10.3748/wjg.v22.i25.5742] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/30/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Early involvement of gut is observed in Parkinson’s disease (PD) and symptoms such as constipation may precede motor symptoms. α-Synuclein pathology is extensively evident in the gut and appears to follow a rostrocaudal gradient. The gut may act as the starting point of PD pathology with spread toward the central nervous system. This spread of the synuclein pathology raises the possibility of prion-like propagation in PD pathogenesis. Recently, the role of gut microbiota in PD pathogenesis has received attention and some phenotypic correlation has also been shown. The extensive involvement of the gut in PD even in its early stages has led to the evaluation of enteric α-synuclein as a possible biomarker of early PD. The clinical manifestations of gastrointestinal dysfunction in PD include malnutrition, oral and dental disorders, sialorrhea, dysphagia, gastroparesis, constipation, and defecatory dysfunction. These conditions are quite distressing for the patients and require relevant investigations and adequate management. Treatment usually involves both pharmacological and non-pharmacological measures. One important aspect of gut dysfunction is its contribution to the clinical fluctuations in PD. Dysphagia and gastroparesis lead to inadequate absorption of oral anti-PD medications. These lead to response fluctuations, particularly delayed-on and no-on, and there is significant relationship between levodopa pharmacokinetics and gastric emptying in patients with PD. Therefore, in such cases, alternative routes of administration or drug delivery systems may be required.
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22
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Augmentation of Autoantibodies by Helicobacter pylori in Parkinson's Disease Patients May Be Linked to Greater Severity. PLoS One 2016; 11:e0153725. [PMID: 27100827 PMCID: PMC4839651 DOI: 10.1371/journal.pone.0153725] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 04/01/2016] [Indexed: 12/20/2022] Open
Abstract
Parkinson's disease (PD) is the second most common chronic and progressive neurodegenerative disorder. Its etiology remains elusive and at present only symptomatic treatments exists. Helicobacter pylori chronically colonizes the gastric mucosa of more than half of the global human population. Interestingly, H. pylori positivity has been found to be associated with greater of PD motor severity. In order to investigate the underlying cause of this association, the Sengenics Immunome protein array, which enables simultaneous screening for autoantibodies against 1636 human proteins, was used to screen the serum of 30 H. pylori-seropositive PD patients (case) and 30 age- and gender-matched H. pylori-seronegative PD patients (control) in this study. In total, 13 significant autoantibodies were identified and ranked, with 8 up-regulated and 5 down-regulated in the case group. Among autoantibodies found to be elevated in H. pylori-seropositive PD were included antibodies that recognize Nuclear factor I subtype A (NFIA), Platelet-derived growth factor B (PDGFB) and Eukaryotic translation initiation factor 4A3 (eIFA3). The presence of elevated autoantibodies against proteins essential for normal neurological functions suggest that immunomodulatory properties of H. pylori may explain the association between H. pylori positivity and greater PD motor severity.
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23
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Csoti I, Jost WH, Reichmann H. Parkinson's disease between internal medicine and neurology. J Neural Transm (Vienna) 2016; 123:3-17. [PMID: 26298728 PMCID: PMC4713462 DOI: 10.1007/s00702-015-1443-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 08/10/2015] [Indexed: 02/07/2023]
Abstract
General medical problems and complications have a major impact on the quality of life in all stages of Parkinson's disease. To introduce an effective treatment, a comprehensive analysis of the various clinical symptoms must be undertaken. One must distinguish between (1) diseases which arise independently of Parkinson's disease, and (2) diseases which are a direct or indirect consequence of Parkinson's disease. Medical comorbidity may induce additional limitations to physical strength and coping strategies, and may thus restrict the efficacy of the physical therapy which is essential for treating hypokinetic-rigid symptoms. In selecting the appropriate medication for the treatment of any additional medical symptoms, which may arise, its limitations, contraindications and interactions with dopaminergic substances have to be taken into consideration. General medical symptoms and organ manifestations may also arise as a direct consequence of the autonomic dysfunction associated with Parkinson's disease. As the disease progresses, additional non-parkinsonian symptoms can be of concern. Furthermore, the side effects of Parkinson medications may necessitate the involvement of other medical specialists. In this review, we will discuss the various general medical aspects of Parkinson's disease.
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Affiliation(s)
- Ilona Csoti
- Gertrudis-Clinic Parkinson-Center, Karl-Ferdinand-Broll-Str. 2-4, 35638, Leun, Germany.
| | - Wolfgang H Jost
- Parkinson-Klinik Wolfach, Kreuzbergstr.12-24, 77709, Wolfach, Germany.
| | - Heinz Reichmann
- Department of Neurology, University of Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
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Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson's disease. World J Gastroenterol 2015; 21:10609-10620. [PMID: 26457021 PMCID: PMC4588083 DOI: 10.3748/wjg.v21.i37.10609] [Citation(s) in RCA: 385] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 05/28/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Parkinson’s disease (PD) is characterized by alpha-synucleinopathy that affects all levels of the brain-gut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological, neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding. Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gut-microbiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.
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The association between infectious burden and Parkinson's disease: A case-control study. Parkinsonism Relat Disord 2015; 21:877-81. [DOI: 10.1016/j.parkreldis.2015.05.015] [Citation(s) in RCA: 123] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 05/16/2015] [Accepted: 05/25/2015] [Indexed: 11/21/2022]
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Tan AH, Mahadeva S, Marras C, Thalha AM, Kiew CK, Yeat CM, Ng SW, Ang SP, Chow SK, Loke MF, Vadivelu JS, Ibrahim N, Yong HS, Tan CT, Fox SH, Lang AE, Lim SY. Helicobacter pylori infection is associated with worse severity of Parkinson's disease. Parkinsonism Relat Disord 2015; 21:221-5. [DOI: 10.1016/j.parkreldis.2014.12.009] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 12/10/2014] [Accepted: 12/11/2014] [Indexed: 02/08/2023]
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Scheperjans F, Aho V, Pereira PAB, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola‐Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord 2014; 30:350-8. [DOI: 10.1002/mds.26069] [Citation(s) in RCA: 1068] [Impact Index Per Article: 97.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 08/21/2014] [Accepted: 10/08/2014] [Indexed: 12/11/2022] Open
Affiliation(s)
- Filip Scheperjans
- Department of NeurologyHelsinki University Central Hospitaland Department of Neurological SciencesUniversity of HelsinkiHelsinki Finland
| | - Velma Aho
- Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of HelsinkiHelsinki Finland
| | - Pedro A. B. Pereira
- Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of HelsinkiHelsinki Finland
| | - Kaisa Koskinen
- Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of HelsinkiHelsinki Finland
| | - Lars Paulin
- Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of HelsinkiHelsinki Finland
| | - Eero Pekkonen
- Department of NeurologyHelsinki University Central Hospitaland Department of Neurological SciencesUniversity of HelsinkiHelsinki Finland
| | - Elena Haapaniemi
- Department of NeurologyHelsinki University Central Hospitaland Department of Neurological SciencesUniversity of HelsinkiHelsinki Finland
| | - Seppo Kaakkola
- Department of NeurologyHelsinki University Central Hospitaland Department of Neurological SciencesUniversity of HelsinkiHelsinki Finland
| | - Johanna Eerola‐Rautio
- Department of NeurologyHelsinki University Central Hospitaland Department of Neurological SciencesUniversity of HelsinkiHelsinki Finland
| | - Marjatta Pohja
- Department of NeurologyHelsinki University Central Hospitaland Department of Neurological SciencesUniversity of HelsinkiHelsinki Finland
| | - Esko Kinnunen
- Department of NeurologyHyvinkää HospitalHyvinkää Finland
| | - Kari Murros
- Department of NeurologyHelsinki University Central Hospitaland Department of Neurological SciencesUniversity of HelsinkiHelsinki Finland
| | - Petri Auvinen
- Institute of Biotechnology, DNA Sequencing and Genomics Laboratory, University of HelsinkiHelsinki Finland
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Hashim H, Azmin S, Razlan H, Yahya NW, Tan HJ, Manaf MRA, Ibrahim NM. Eradication of Helicobacter pylori infection improves levodopa action, clinical symptoms and quality of life in patients with Parkinson's disease. PLoS One 2014; 9:e112330. [PMID: 25411976 PMCID: PMC4239049 DOI: 10.1371/journal.pone.0112330] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Accepted: 10/05/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Previous studies have demonstrated a higher prevalence of Helicobacter pylori (H. pylori) infection in patients with Parkinson's disease (PD) compared to controls. H. pylori infection affects levodopa absorption and its eradication significantly improves clinical response to levodopa. Here, we studied the prevalence of H. pylori infection and its eradication effects among our PD patients. METHODS A prospective study involving idiopathic PD patients on levodopa therapy. 13C-urea breath test (UBT) was used to detect H. pylori. UBT-positive patients were given standard eradication therapy and followed up at 6 and 12 weeks in an open label single arm design. Repeat UBT was performed at 12 weeks. The UPDRS, PD NMQ, PD NMSS and PDQ-39 were administered at baseline and post-eradication (6 and 12 weeks). Levodopa 'onset' time and ON-duration were recorded. RESULTS Of 82 patients recruited, 27 (32.9%) had positive UBT. H. pylori-positive patients had significantly poorer total UPDRS (p = 0.005) and PDQ39 (p<0.0001) scores compared to H. pylori-negative patients. At 12 weeks post-eradication, the mean levodopa onset time shortened by 14 minutes (p = 0.011). The mean ON duration time increased by 56 minutes at week 6 (p = 0.041) and 38 minutes at week 12 (p = 0.035). The total UPDRS scores (p<0.0001), scores for parts II (p = 0.001), III (p<0.0001) and IV (p = 0.009) were significantly better. The total PDQ-39 scores (p = 0.001) and subdomains mobility (p = 0.002), ADL (p = 0.001), emotional well being (p = 0.026) and stigma (p = 0.034) significantly improved. The PD NMSQ did not show significant improvement. CONCLUSIONS H. pylori eradication improved levodopa onset time, ON duration, motor severity and quality of life parameters. Screening and eradication of H. pylori is inexpensive and should be recommended in PD patients, particularly those with erratic response to levodopa. TRIAL REGISTRATION ClinicalTrials.gov NCT02112812.
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Affiliation(s)
- Hasriza Hashim
- Neurology Unit, Department of Medicine, UKM Medical Center, Kuala Lumpur, Malaysia
| | - Shahrul Azmin
- Neurology Unit, Department of Medicine, UKM Medical Center, Kuala Lumpur, Malaysia
| | - Hamizah Razlan
- Neurology Unit, Department of Medicine, UKM Medical Center, Kuala Lumpur, Malaysia
| | - Nafisah Wan Yahya
- Neurology Unit, Department of Medicine, UKM Medical Center, Kuala Lumpur, Malaysia
| | - Hui Jan Tan
- Neurology Unit, Department of Medicine, UKM Medical Center, Kuala Lumpur, Malaysia
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Motor fluctuations and Helicobacter pylori in Parkinson's disease. J Neurol 2013; 260:2974-80. [PMID: 24002418 DOI: 10.1007/s00415-013-7089-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Revised: 08/20/2013] [Accepted: 08/21/2013] [Indexed: 12/13/2022]
Abstract
The presence of Helicobacter pylori (HP) in the gastrointestinal tract may limit the absorption of levodopa. The objectives of this study were to investigate whether HP infection may affect the clinical response to levodopa as well as levodopa dose requirement in patients with Parkinson's disease (PD) as well as to investigate whether HP infection may affect plasma levels of vitamin B12, folic acid, and homocysteine. Seventy-five patients with PD diagnosed at least 4 years ago were included. Symptom fluctuations were assessed by UPDRS-IV and the WOQ9 wearing-off-scale. Plasma levels of vitamin B12, folic acid, and homocysteine were analyzed. Screening for HP was performed with a 13C-labeled urea breath test (Diabact UBT). A propensity-matched analysis was made where each patient in the HP-infected group was matched with one patient in the non-infected group with respect to age and gender. Of the 75 included patients, 20 were HP infected (27 %). Median Hoehn & Yahr scores were 3 in both HP infected patients and the matched group (n = 20). HP-infected patients had decreased "complications of therapy" with average total UPDRS-IV score of 4.8 ± 3.0 vs. 7.7 ± 3.8 (p < 0.05), despite no significant difference in levodopa equivalent dose. Wearing-off and sleep disturbance were significantly less common in the HP group (p < 0.05). There were no differences regarding vitamin B12, folic acid, or homocysteine values. HP infection in patients with PD may result in a decreased occurrence of symptom fluctuations according to this small study. This finding may be due to altered absorption of levodopa in the gastrointestinal tract in patients with HP infection, but further studies are required.
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