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Zhang Y, Mo C, Ai P, He X, Xiao Q, Yang X. Pharmacomicrobiomics: a new field contributing to optimizing drug therapy in Parkinson's disease. Gut Microbes 2025; 17:2454937. [PMID: 39875349 PMCID: PMC11776486 DOI: 10.1080/19490976.2025.2454937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 11/19/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025] Open
Abstract
Gut microbiota, which act as a determinant of pharmacokinetics, have long been overlooked. In recent years, a growing body of evidence indicates that the gut microbiota influence drug metabolism and efficacy. Conversely, drugs also exert a substantial influence on the function and composition of the gut microbiota. Pharmacomicrobiomics, an emerging field focusing on the interplay of drugs and gut microbiota, provides a potential foundation for making certain advances in personalized medicine. Understanding the communication between gut microbiota and antiparkinsonian drugs is critical for precise treatment of Parkinson's disease. Here, we provide a historical overview of the interplay between gut microbiota and antiparkinsonian drugs. Moreover, we discuss potential mechanistic insights into the complex associations between gut microbiota and drug metabolism. In addition, we also draw attention to microbiota-based biomarkers for predicting antiparkinsonian drug efficacy and examine current state-of-the-art knowledge of microbiota-based strategies to optimize drug therapy in Parkinson's disease.
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Affiliation(s)
- Yi Zhang
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengjun Mo
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Penghui Ai
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoqin He
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qin Xiao
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaodong Yang
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Gabrielli M, Zileri Dal Verme L, Zocco MA, Nista EC, Ojetti V, Gasbarrini A. The Role of the Gastrointestinal Microbiota in Parkinson's Disease. Biomolecules 2024; 15:26. [PMID: 39858421 PMCID: PMC11764295 DOI: 10.3390/biom15010026] [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: 11/28/2024] [Revised: 12/19/2024] [Accepted: 12/26/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons leading to debilitating motor and non-motor symptoms. Beyond its well-known neurological features, emerging evidence underscores the pivotal role of the gut-brain axis and gastrointestinal microbiota in PD pathogenesis. Dysbiosis has been strongly linked to PD and is associated with increased intestinal permeability, chronic inflammation, and the production of neurotoxic metabolites that may exacerbate neuronal damage. METHODS This review delves into the complex interplay between PD and dysbiosis, shedding light on two peculiar subsets of dysbiosis, Helicobacter pylori infection and small-intestinal bacterial overgrowth. These conditions may not only contribute to PD progression but also influence therapeutic responses such as L-dopa efficacy. CONCLUSIONS The potential to modulate gut microbiota through probiotics, prebiotics, and synbiotics; fecal microbiota transplantation; and antibiotics represents a promising frontier for innovative PD treatments. Despite this potential, the current evidence is limited by small sample sizes and methodological variability across studies. Rigorous, large-scale, randomized placebo-controlled trials with standardized treatments in terms of composition, dosage, and duration are urgently needed to validate these findings and pave the way for microbiota-based therapeutic strategies in PD management.
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Affiliation(s)
- Maurizio Gabrielli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.Z.D.V.); (M.A.Z.); (E.C.N.); (A.G.)
| | - Lorenzo Zileri Dal Verme
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.Z.D.V.); (M.A.Z.); (E.C.N.); (A.G.)
| | - Maria Assunta Zocco
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.Z.D.V.); (M.A.Z.); (E.C.N.); (A.G.)
| | - Enrico Celestino Nista
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.Z.D.V.); (M.A.Z.); (E.C.N.); (A.G.)
| | - Veronica Ojetti
- Internal Medicine Department, San Carlo di Nancy Hospital, Università UniCamillus, 00131 Rome, Italy;
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.Z.D.V.); (M.A.Z.); (E.C.N.); (A.G.)
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Bano N, Khan S, Ahamad S, Kanshana JS, Dar NJ, Khan S, Nazir A, Bhat SA. Microglia and gut microbiota: A double-edged sword in Alzheimer's disease. Ageing Res Rev 2024; 101:102515. [PMID: 39321881 DOI: 10.1016/j.arr.2024.102515] [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: 04/23/2024] [Revised: 09/06/2024] [Accepted: 09/19/2024] [Indexed: 09/27/2024]
Abstract
The strong association between gut microbiota (GM) and brain functions such as mood, behaviour, and cognition has been well documented. Gut-brain axis is a unique bidirectional communication system between the gut and brain, in which gut microbes play essential role in maintaining various molecular and cellular processes. GM interacts with the brain through various pathways and processes including, metabolites, vagus nerve, HPA axis, endocrine system, and immune system to maintain brain homeostasis. GM dysbiosis, or an imbalance in GM, is associated with several neurological disorders, including anxiety, depression, and Alzheimer's disease (AD). Conversely, AD is sustained by microglia-mediated neuroinflammation and neurodegeneration. Further, GM and their products also affect microglia-mediated neuroinflammation and neurodegeneration. Despite the evidence connecting GM dysbiosis and AD progression, the involvement of GM in modulating microglia-mediated neuroinflammation in AD remains elusive. Importantly, deciphering the mechanism/s by which GM regulates microglia-dependent neuroinflammation may be helpful in devising potential therapeutic strategies to mitigate AD. Herein, we review the current evidence regarding the involvement of GM dysbiosis in microglia activation and neuroinflammation in AD. We also discuss the possible mechanisms through which GM influences the functioning of microglia and its implications for therapeutic intervention. Further, we explore the potential of microbiota-targeted interventions, such as prebiotics, probiotics, faecal microbiota transplantation, etc., as a novel therapeutic strategy to mitigate neuroinflammation and AD progression. By understanding and exploring the gut-brain axis, we aspire to revolutionize the treatment of neurodegenerative disorders, many of which share a common theme of microglia-mediated neuroinflammation and neurodegeneration.
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Affiliation(s)
- Nargis Bano
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Sameera Khan
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India.
| | - Jitendra Singh Kanshana
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburg, PA, USA.
| | - Nawab John Dar
- CNB, SALK Institute of Biological Sciences, La Jolla, CA 92037, USA.
| | - Sumbul Khan
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Aamir Nazir
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Academy of Scientific and Innovative Research, New Delhi, India.
| | - Shahnawaz Ali Bhat
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India.
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Abdelgalil A, Ismail D, Eskander A, Girgis M, Farouk A, Saeedi F, Shazly M, Hasnoon A. Effect of Helicobacter pylori Eradication on Serum Level of Valproic Acid in Children with Idiopathic Generalized Epilepsy. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1259. [PMID: 39457224 PMCID: PMC11506667 DOI: 10.3390/children11101259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/11/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND/OBJECTIVES The purpose of this study was to determine the influence of H. pylori eradication on the serum level of the orally administered valproic acid (VPA) in children with idiopathic generalized epilepsy; Methods: This prospective cohort observational study included 100 children with idiopathic generalized epilepsy, recruited from a neurology clinic from May 2021 to December 2021. The patients were divided into two groups, each containing 50 children. The first group had a positive H. pylori stool antigen and H. pylori-related symptoms, while the second group had a negative antigen. H. pylori Eradication therapy was given to the positive H. pylori group. The serum level of VPA was obtained at baseline and 4 weeks after eradication therapy. RESULTS Despite there being no significant difference between the H. pylori-positive and H. pylori-negative groups regarding the baseline VPA serum level (79.9 ± 13.9 and 77.9 ± 13.1 mcg/mL), respectively, the serum VPA level had significantly increased after H. pylori eradication therapy (99.4 ± 11 mcg/mL) (p value = 0.000), as opposed to the H. pylori-negative group (85.3 ± 10.9 mcg/mL) (p value = 0.142). Furthermore, there was a statistically significant association with a negative correlation between the VPA serum level after eradication and the number of epileptic attacks per month (p value = 0.033, R value = -0.301) and the dose of VPA (p value = 0.046, R value = -0.284). CONCLUSIONS The eradication of H. pylori resulted in a highly significant improvement in the serum level of the orally given VPA in children with idiopathic generalized epilepsy, as well as an indirect decrease in the frequency of epileptic events per month, allowing for dose reduction. Eradication therapy may have anticonvulsant properties and might indirectly aid in the management of epileptic activity. H. pylori screening for children with idiopathic generalized epilepsy can optimize serum VPA levels, potentially leading to better seizure control. To our knowledge, this is the first study in the literature to describe the effect of H. pylori eradication on the serum level of the orally administered VPA in children with idiopathic generalized epilepsy.
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Affiliation(s)
- Abobakr Abdelgalil
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo 12613, Egypt; (D.I.); (A.E.); (M.G.); (A.H.)
| | - Doaa Ismail
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo 12613, Egypt; (D.I.); (A.E.); (M.G.); (A.H.)
| | - Ayman Eskander
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo 12613, Egypt; (D.I.); (A.E.); (M.G.); (A.H.)
| | - Marian Girgis
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo 12613, Egypt; (D.I.); (A.E.); (M.G.); (A.H.)
| | - Ahmed Farouk
- Department of Clinical Pathology, Military Medical Academy, Cairo 12613, Egypt;
| | - Fajr Saeedi
- Department of Pediatrics, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Mohamed Shazly
- Department of Pediatrics, King Abdulaziz University Hospital, Jeddah 21589, Saudi Arabia;
- Department of Pediatrics, Mallwi Hospital, Minia 61631, Egypt
| | - Amera Hasnoon
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo 12613, Egypt; (D.I.); (A.E.); (M.G.); (A.H.)
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Zhang J, Ji X, Liu S, Sun Z, Cao X, Liu B, Li Y, Zhao H. Helicobacter pylori infection promotes liver injury through an exosome-mediated mechanism. Microb Pathog 2024; 195:106898. [PMID: 39208956 DOI: 10.1016/j.micpath.2024.106898] [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: 05/02/2024] [Revised: 08/12/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
Helicobacter pylori infection has been thought to be associated with liver diseases, although the exact mechanisms remain elusive. This study identified H. pylori-induced liver inflammation and tissue damage in infected mice and examined the exosome-mediated mechanism underlying H. pylori infection's impact on liver injury. Exosomes were isolated from H. pylori-infected gastric epithelial GES-1 cells (Hp-GES-EVs), and the crucial virulence factor CagA was identified within these exosomes. Fluorescent labeling demonstrated that Hp-GES-EVs can be absorbed by liver cells. Treatment with Hp-GES-EVs enhanced the proliferation, migration, and invasion of Hep G2 and Hep 3B cells. Additionally, exposure to Hp-GES-EVs activated NF-κB and PI3K/AKT signaling pathways, which provides a reasonable explanation for the liver inflammation and neoplastic traits. Using a mouse model established via tail vein injection of Hp-GES-EVs, exosome-driven liver injury was evidenced by slight hepatocellular erosion around the central hepatic vein and elevated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and IL-6. Administering the exosome inhibitor GW4869 via intraperitoneal injection in mice resulted in a reduction of liver damage caused by H. pylori infection. These findings illuminate the exosome-mediated pathogenesis of H. pylori-induced liver injury and offer valuable insights into the extra-gastrointestinal manifestations of H. pylori infection.
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Affiliation(s)
| | - Xiaofei Ji
- Binzhou Medical University, Yantai, China
| | | | - Zekun Sun
- Binzhou Medical University, Yantai, China
| | | | | | - Yizheng Li
- Binzhou Medical University, Yantai, China
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He X, Lai Y, Mo C, Zhang Y, Ai P, Xu S, Qian Y, Xiao Q, Yang X. Association between Fecal Bile Acids and Levodopa Response in Patients with Parkinson's Disease. Microorganisms 2024; 12:1432. [PMID: 39065200 PMCID: PMC11278915 DOI: 10.3390/microorganisms12071432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/24/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Levodopa is the mainstay of treatments for Parkinson's disease (PD), but large heterogeneity exists in patient response. Increasing evidence implicates bile acids (BAs) involved in the pathogenesis of PD. Furthermore, BAs have also participated in drug bioavailability. However, the impact of BAs on levodopa response (LR) has not been investigated. This study evaluated the association between fecal BAs and LR. Levodopa challenge test (LCT) was conducted in 92 PD patients to assess LR. A total of 36 fecal BAs and plasma levodopa concentrations were detected using LC-MS/MS. The difference of BAs between subgroups with bottom and top 30% LR were analyzed and fecal samples from the two groups were collected for metagenomic shotgun analysis. No fecal BAs were significantly correlated with LR, except for chenodeoxycholic acid-3-β-D-glucuronide (CDCA-3-β-glucuronide, R = -0.228, p-value = 0.039). We found no significant difference in BAs between subgroups with bottom and top 30% LR. What is more, no significant changes in bacterial species composition related to bile acids metabolism or in the proportional representation of genes encoding known bile acids enzymes were observed between the groups. Overall, our data do not support an association between fecal BAs and levodopa response in PD patients. More precise macro-metabolomic approaches are needed to reveal the potential association between gut microbial interactions and the treatment effect of levodopa.
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Affiliation(s)
- Xiaoqin He
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (X.H.); (C.M.); (P.A.); (Y.Q.)
| | - Yiqiu Lai
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (X.H.); (C.M.); (P.A.); (Y.Q.)
| | - Chengjun Mo
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (X.H.); (C.M.); (P.A.); (Y.Q.)
| | - Yi Zhang
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (X.H.); (C.M.); (P.A.); (Y.Q.)
| | - Penghui Ai
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (X.H.); (C.M.); (P.A.); (Y.Q.)
| | - Shaoqing Xu
- Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
| | - Yiwei Qian
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (X.H.); (C.M.); (P.A.); (Y.Q.)
| | - Qin Xiao
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (X.H.); (C.M.); (P.A.); (Y.Q.)
| | - Xiaodong Yang
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (X.H.); (C.M.); (P.A.); (Y.Q.)
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Menozzi E, Schapira AHV. The Gut Microbiota in Parkinson Disease: Interactions with Drugs and Potential for Therapeutic Applications. CNS Drugs 2024; 38:315-331. [PMID: 38570412 PMCID: PMC11026199 DOI: 10.1007/s40263-024-01073-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/14/2024] [Indexed: 04/05/2024]
Abstract
The concept of a 'microbiota-gut-brain axis' has recently emerged as an important player in the pathophysiology of Parkinson disease (PD), not least because of the reciprocal interaction between gut bacteria and medications. The gut microbiota can influence levodopa kinetics, and conversely, drugs administered for PD can influence gut microbiota composition. Through a two-step enzymatic pathway, gut microbes can decarboxylate levodopa to dopamine in the small intestine and then dehydroxylate it to m-tyramine, thus reducing availability. Inhibition of bacterial decarboxylation pathways could therefore represent a strategy to increase levodopa absorption. Other bacterial perturbations common in PD, such as small intestinal bacterial overgrowth and Helicobacter pylori infection, can also modulate levodopa metabolism, and eradication therapies may improve levodopa absorption. Interventions targeting the gut microbiota offer a novel opportunity to manage disabling motor complications and dopa-unresponsive symptoms. Mediterranean diet-induced changes in gut microbiota composition might improve a range of non-motor symptoms. Prebiotics can increase levels of short-chain fatty acid-producing bacteria and decrease pro-inflammatory species, with positive effects on clinical symptoms and levodopa kinetics. Different formulations of probiotics showed beneficial outcomes on constipation, with some of them improving dopamine levels; however, the most effective dosage and duration and long-term effects of these treatments remain unknown. Data from faecal microbiota transplantation studies are preliminary, but show encouraging trends towards improvement in both motor and non-motor outcomes.This article summarises the most up-to-date knowledge in pharmacomicrobiomics in PD, and discusses how the manipulation of gut microbiota represents a potential new therapeutic avenue for PD.
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Affiliation(s)
- Elisa Menozzi
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, NW3 2PF, UK
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Anthony H V Schapira
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, NW3 2PF, UK.
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
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Pereira QC, Fortunato IM, Oliveira FDS, Alvarez MC, dos Santos TW, Ribeiro ML. Polyphenolic Compounds: Orchestrating Intestinal Microbiota Harmony during Aging. Nutrients 2024; 16:1066. [PMID: 38613099 PMCID: PMC11013902 DOI: 10.3390/nu16071066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/20/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
In the aging process, physiological decline occurs, posing a substantial threat to the physical and mental well-being of the elderly and contributing to the onset of age-related diseases. While traditional perspectives considered the maintenance of life as influenced by a myriad of factors, including environmental, genetic, epigenetic, and lifestyle elements such as exercise and diet, the pivotal role of symbiotic microorganisms had been understated. Presently, it is acknowledged that the intestinal microbiota plays a profound role in overall health by signaling to both the central and peripheral nervous systems, as well as other distant organs. Disruption in this bidirectional communication between bacteria and the host results in dysbiosis, fostering the development of various diseases, including neurological disorders, cardiovascular diseases, and cancer. This review aims to delve into the intricate biological mechanisms underpinning dysbiosis associated with aging and the clinical ramifications of such dysregulation. Furthermore, we aspire to explore bioactive compounds endowed with functional properties capable of modulating and restoring balance in this aging-related dysbiotic process through epigenetics alterations.
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Affiliation(s)
- Quélita Cristina Pereira
- Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University, Av. Sao Francisco de Assis, 218, Braganca Paulista 12916-900, SP, Brazil; (Q.C.P.); (I.M.F.); (F.d.S.O.); (M.C.A.); (T.W.d.S.)
| | - Isabela Monique Fortunato
- Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University, Av. Sao Francisco de Assis, 218, Braganca Paulista 12916-900, SP, Brazil; (Q.C.P.); (I.M.F.); (F.d.S.O.); (M.C.A.); (T.W.d.S.)
| | - Fabricio de Sousa Oliveira
- Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University, Av. Sao Francisco de Assis, 218, Braganca Paulista 12916-900, SP, Brazil; (Q.C.P.); (I.M.F.); (F.d.S.O.); (M.C.A.); (T.W.d.S.)
| | - Marisa Claudia Alvarez
- Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University, Av. Sao Francisco de Assis, 218, Braganca Paulista 12916-900, SP, Brazil; (Q.C.P.); (I.M.F.); (F.d.S.O.); (M.C.A.); (T.W.d.S.)
- Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro, UNICAMP, Rua Carlos Chagas 480, Campinas 13083-878, SP, Brazil
| | - Tanila Wood dos Santos
- Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University, Av. Sao Francisco de Assis, 218, Braganca Paulista 12916-900, SP, Brazil; (Q.C.P.); (I.M.F.); (F.d.S.O.); (M.C.A.); (T.W.d.S.)
| | - Marcelo Lima Ribeiro
- Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University, Av. Sao Francisco de Assis, 218, Braganca Paulista 12916-900, SP, Brazil; (Q.C.P.); (I.M.F.); (F.d.S.O.); (M.C.A.); (T.W.d.S.)
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Pasricha TS, Guerrero-Lopez IL, Kuo B. Management of Gastrointestinal Symptoms in Parkinson's Disease: A Comprehensive Review of Clinical Presentation, Workup, and Treatment. J Clin Gastroenterol 2024; 58:211-220. [PMID: 38260966 PMCID: PMC10855995 DOI: 10.1097/mcg.0000000000001961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024]
Abstract
Gastrointestinal symptoms in Parkinson's disease (PD) are among the most prevalent and debilitating of complications and present unique diagnostic and management challenges. Patients with PD commonly experience dysphagia, nausea, bloating, and constipation related to pathologic involvement of the enteric nervous system. In turn, gastrointestinal complications may impact motor fluctuations and the efficacy of levodopa therapy. This review will explore the common gastrointestinal manifestations of PD with an emphasis on clinical presentation, workup, and treatment strategies.
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Affiliation(s)
- Trisha S. Pasricha
- Division of Gastroenterology, Massachusetts General Hospital
- Harvard Medical School, Boston, MA
| | | | - Braden Kuo
- Division of Gastroenterology, Massachusetts General Hospital
- Harvard Medical School, Boston, MA
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10
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Elangovan A, Dahiya B, Kirola L, Iyer M, Jeeth P, Maharaj S, Kumari N, Lakhanpal V, Michel TM, Rao KRSS, Cho SG, Yadav MK, Gopalakrishnan AV, Kadhirvel S, Kumar NS, Vellingiri B. Does gut brain axis has an impact on Parkinson's disease (PD)? Ageing Res Rev 2024; 94:102171. [PMID: 38141735 DOI: 10.1016/j.arr.2023.102171] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/04/2023] [Accepted: 12/13/2023] [Indexed: 12/25/2023]
Abstract
Parkinson's Disease (PD) is becoming a growing global concern by being the second most prevalent disease next to Alzheimer's Disease (AD). Henceforth new exploration is needed in search of new aspects towards the disease mechanism and origin. Evidence from recent studies has clearly stated the role of Gut Microbiota (GM) in the maintenance of the brain and as a root cause of various diseases and disorders including other neurological conditions. In the case of PD, with an unknown etiology, the GM is said to have a larger impact on the disease pathophysiology. Although GM and its metabolites are crucial for maintaining the normal physiology of the host, it is an undeniable fact that there is an influence of GM in the pathophysiology of PD. As such the Enteroendocrine Cells (EECs) in the epithelium of the intestine are one of the significant regulators of the gut-brain axis and act as a communication mediator between the gut and the brain. The communication is established via the molecules of neuroendocrine which are said to have a crucial part in neurological diseases such as AD, PD, and other psychiatry-related disorders. This review is focused on understanding the proper role of GM and EECs in PD. Here, we also focus on some of the metabolites and compounds that can interact with the PD genes causing various dysfunctions in the cell and facilitating the disease conditions using bioinformatical tools. Various mechanisms concerning EECs and PD, their identification, the latest studies, and available current therapies have also been discussed.
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Affiliation(s)
- Ajay Elangovan
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Bhawna Dahiya
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Laxmi Kirola
- Department of Biotechnology, School of Health Sciences and Technology (SoHST), UPES University, Dehradun, Uttarakhand 248007, India
| | - Mahalaxmi Iyer
- Department of Microbiology, Central University of Punjab, Bathinda 151401, Punjab, India; Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore 641021, Tamil Nadu, India
| | - Priyanka Jeeth
- Department of Computational Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Sakshi Maharaj
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Nikki Kumari
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Vikas Lakhanpal
- Department of Neurology, All India Institute of Medical Sciences, Bathinda 151005, Punjab, India
| | - Tanja Maria Michel
- Research Unit of Psychiatry, Dept. of Psychiatry Odense, Clinical Institute, University of Southern Denmark, J.B. Winslowsvej 20, Indg. 220B, Odense, Denmark
| | - K R S Sambasiva Rao
- Mangalayatan University - Jabalpur, Jabalpur - 481662, Madhya Pradesh, India
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Mukesh Kumar Yadav
- Department of Microbiology, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632 014, India
| | - Saraboji Kadhirvel
- Department of Computational Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Nachimuthu Senthil Kumar
- Department of Biotechnology, Mizoram University (A Central University), Aizawl, 796 004 Mizoram, India
| | - Balachandar Vellingiri
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India.
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11
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Higinbotham AS, Kilbane CW. The gastrointestinal tract and Parkinson's disease. Front Cell Infect Microbiol 2024; 13:1158986. [PMID: 38292855 PMCID: PMC10825967 DOI: 10.3389/fcimb.2023.1158986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 12/14/2023] [Indexed: 02/01/2024] Open
Affiliation(s)
- Alissa S. Higinbotham
- Parkinson's disease and Movement Disorders Center, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
- Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Camilla W. Kilbane
- Parkinson's disease and Movement Disorders Center, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
- Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
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12
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Huang G, Khan R, Zheng Y, Lee PC, Li Q, Khan I. Exploring the role of gut microbiota in advancing personalized medicine. Front Microbiol 2023; 14:1274925. [PMID: 38098666 PMCID: PMC10720646 DOI: 10.3389/fmicb.2023.1274925] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 11/15/2023] [Indexed: 12/17/2023] Open
Abstract
Ongoing extensive research in the field of gut microbiota (GM) has highlighted the crucial role of gut-dwelling microbes in human health. These microbes possess 100 times more genes than the human genome and offer significant biochemical advantages to the host in nutrient and drug absorption, metabolism, and excretion. It is increasingly clear that GM modulates the efficacy and toxicity of drugs, especially those taken orally. In addition, intra-individual variability of GM has been shown to contribute to drug response biases for certain therapeutics. For instance, the efficacy of cyclophosphamide depends on the presence of Enterococcus hirae and Barnesiella intestinihominis in the host intestine. Conversely, the presence of inappropriate or unwanted gut bacteria can inactivate a drug. For example, dehydroxylase of Enterococcus faecalis and Eggerthella lenta A2 can metabolize L-dopa before it converts into the active form (dopamine) and crosses the blood-brain barrier to treat Parkinson's disease patients. Moreover, GM is emerging as a new player in personalized medicine, and various methods are being developed to treat diseases by remodeling patients' GM composition, such as prebiotic and probiotic interventions, microbiota transplants, and the introduction of synthetic GM. This review aims to highlight how the host's GM can improve drug efficacy and discuss how an unwanted bug can cause the inactivation of medicine.
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Affiliation(s)
- Gouxin Huang
- Clinical Research Center, Shantou Central Hospital, Shantou, China
| | - Raees Khan
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Yilin Zheng
- Clinical Research Center, Shantou Central Hospital, Shantou, China
| | - Ping-Chin Lee
- Biotechnology Research Institute, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
- Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
| | - Qingnan Li
- Clinical Research Center, Shantou Central Hospital, Shantou, China
- Department of Pharmacy, Shantou Central Hospital, Shantou, China
| | - Imran Khan
- Department of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University Mardan, Mardan, Pakistan
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13
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Miyaue N, Yabe H, Nagai M. Concomitant use of magnesium oxide significantly decreases absorption of levodopa preparations in patients with Parkinson's disease. Clin Park Relat Disord 2023; 9:100227. [PMID: 38021340 PMCID: PMC10656210 DOI: 10.1016/j.prdoa.2023.100227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 10/20/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Constipation is one of the most frequent non-motor symptoms of Parkinson's disease (PD), and magnesium oxide (MgO) is a frequently used laxative. This study aimed to investigate the effect of concomitant use of MgO on the pharmacokinetics of levodopa preparations in patients with PD. Methods We prospectively enrolled 35 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and motor symptoms with and without MgO. The impact of alterations in pH and the addition of MgO on the solubility of levodopa formulations were also evaluated under in vitro conditions. Results Concomitant use of MgO significantly reduced the maximum plasma concentration of levodopa (Cmax) (from 7.66 ± 3.74 μmol/L to 5.82 ± 3.69 μmol/L; p = 0.006) and area under the plasma concentration-time curve 3 h after drug administration (AUC3h, from 9.64 ± 3.23 μmol·h/L to 7.39 ± 3.15 μmol·h/L; p < 0.001), and further decreased carbidopa Cmax (from 64.02 ± 27.02 ng/mL to 38.83 ± 21.94 μmol/L; p < 0.001) and AUC3h (from 130.58 ± 65.64 ng/mL to 76.48 ± 52.24 ng·h/mL; p < 0.001). The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III score also deteriorated significantly (from 30.71 ± 11.34 to 32.06 ± 11.22; p = 0.007). MgO significantly affected the pharmacokinetics of levodopa and carbidopa. This also applied when the findings were analyzed by sex and age. In vitro dissolution experiments revealed a decrease in the relative concentrations of levodopa, carbidopa, and benserazide as the pH increased and in the presence of MgO suspension, with the most prominent impact on benserazide. Conclusions Concomitant use of MgO and levodopa should be discouraged to improve levodopa absorption.
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Affiliation(s)
- Noriyuki Miyaue
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan
- Department of Neurology, Saiseikai Matsuyama Hospital, Matsuyama, Ehime, Japan
| | - Hayato Yabe
- Department of Neurology, Saiseikai Matsuyama Hospital, Matsuyama, Ehime, Japan
| | - Masahiro Nagai
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan
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14
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Peng R, Zhang Z, Qu Y, Chen W. The impact of Helicobacter pylori eradication with vonoprazan-amoxicillin dual therapy combined with probiotics on oral microbiota: a randomized double-blind placebo-controlled trial. Front Microbiol 2023; 14:1273709. [PMID: 37849923 PMCID: PMC10577438 DOI: 10.3389/fmicb.2023.1273709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 09/11/2023] [Indexed: 10/19/2023] Open
Abstract
Background Helicobacter pylori infection and eradication have been reported to cause dysbiosis of the oral microbiota. Probiotics are increasingly being used to maintain the balance of the oral microbiota. We aimed to investigate the effects of H. pylori infection, H. pylori eradication with vonoprazan-amoxicillin dual therapy, and probiotics supplementation on the oral microbiota. Methods H. pylori positive patients were randomly assigned to a vonoprazan-amoxicillin regimen plus probiotics (BtT group) or the placebo (PT group) for 14 days. H. pylori negative population served as normal controls. Tongue coating samples were collected from 60 H. pylori positive patients at three time points (before H. pylori eradication, after H. pylori eradication, and at confirmation of H. pylori infection cure) and 20 H. pylori negative subjects. 16S rRNA gene sequencing was used to analyze the oral microbiota. Results H. pylori was detected in the oral cavity in positive (34/60), negative (7/20), and eradicated (1/60) subjects using high-throughput sequencing. Compared with normal controls, H. pylori positive patients exhibited higher richness (p = 0.012) and comparable diversity (p = 0.075) of oral microbiota. Beta diversity and KEGG analysis showed oral flora composition and function differences in H. pylori positive and negative subjects. Alpha diversity dramatically decreased after H. pylori eradication and modestly increased with confirmation of H. pylori eradication. Beta diversity and LEfSe analysis revealed distinct structures, and KEGG analysis showed distinct signaling pathways of tongue coating flora at three time points. There was a significant reduction of Firmicutes and Lactobacillus after H. pylori erdication. The PT group and BtT group had identical compositional and functional differences of oral microbiota at three time points. Conclusion No substantial link existed between oral and stomach H. pylori, while removing gastric H. pylori helped eliminate oral H. pylori. H. pylori infection and vonoprazan-amoxicillin dual therapy affected oral microbiota diversity, structure, and function. H. pylori eradication demonstrated a suppressive impact on the proliferation of oral pathogens, specifically Firmicutes and Lactobacillus. Nevertheless, probiotics supplementation did not reduce the oral microbial disturbance caused by H. pylori eradication. Clinical trial registration https://www.chictr.org.cn/, identifiers CHICTR2200060023.
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Affiliation(s)
| | - Zhenyu Zhang
- Department of Gastroenterology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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15
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Fernández-Espejo E. Microorganisms associated with increased risk of Parkinson's disease. Neurologia 2023; 38:495-503. [PMID: 35644845 DOI: 10.1016/j.nrleng.2020.08.023] [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: 06/03/2020] [Accepted: 08/26/2020] [Indexed: 11/25/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder that affects more than 7 million people worldwide. Its aetiology is unknown, although the hypothesis of a genetic susceptibility to environmental agents is accepted. These environmental agents include fungi, bacteria, and viruses. Three microorganisms are directly associated with a significantly increased risk of developing Parkinson's disease: the fungal genus Malassezia, the bacterium Helicobacter pylori, and the hepatitis C virus. If the host is vulnerable due to genetic susceptibility or immune weakness, these microorganisms can access and infect the nervous system, causing chronic neuroinflammation with neurodegeneration. Other microorganisms show an epidemiological association with the disease, including the influenza type A, Japanese encephalitis type B, St Louis, and West Nile viruses. These viruses can affect the nervous system, causing encephalitis, which can result in parkinsonism. This article reviews the role of all these microorganisms in Parkinson's disease.
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Affiliation(s)
- E Fernández-Espejo
- Laboratorio de Neurología Molecular, Universidad de Sevilla, Sevilla, Spain; Red Andaluza de Investigación Clínica y Traslacional en Neurología (Neuro-RECA), Málaga, Spain.
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16
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Justich MB, Rojas OL, Fasano A. The Role of Helicobacter pylori and Small Intestinal Bacterial Overgrowth in Parkinson's Disease. Semin Neurol 2023; 43:553-561. [PMID: 37562451 DOI: 10.1055/s-0043-1771468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder whose etiology remains largely unexplained. Several studies have aimed to describe a causative effect in the interactions between the gastrointestinal tract and the brain, for both PD pathogenesis and disease course. However, the results have been controversial. Helicobacter pylori and small intestinal bacterial overgrowth (SIBO) are theorized to be agents capable of triggering chronic proinflammatory changes with a possible neurotoxic effect, as well as a cause of erratic L-dopa response in PD patients. This review evaluates the individual and possibly synergistic influence of H. pylori and SIBO on PD, to provide an opportunity to consider prospective therapeutic approaches.
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Affiliation(s)
- Maria Belen Justich
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
- Division of Neurology, University of Toronto, Toronto, Ontario, Canada
| | - Olga L Rojas
- Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Ontario, Canada
| | - Alfonso Fasano
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
- Division of Neurology, University of Toronto, Toronto, Ontario, Canada
- Department of Parkinson's Disease and Movement Disorders Rehabilitation, Moriggia-Pelascini Hospital - Gravedona ed Uniti, Como, Italy
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17
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Quigley EMM. Constipation in Parkinson's Disease. Semin Neurol 2023; 43:562-571. [PMID: 37579786 DOI: 10.1055/s-0043-1771457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2023]
Abstract
Constipation is one of the most common gastrointestinal features of Parkinson's disease (PD), occurring in over 50% of all PD patients during the course of their disease. Furthermore, constipation is now recognized as an important, prodromal symptom and may predate the onset of the classical motor symptoms by decades. Thereafter, the prevalence and severity of constipation in PD tend to parallel the course of both motor and nonmotor phenomena such as cognitive decline and depression. Difficult defecation (obstructed defecation, dyssynergia) is the primary pathophysiology underlying constipation and likely reflects involvement by the PD process of one or more of the many skeletal muscle groups that are involved in effecting defecation. Management of constipation in PD may be complicated by several patient factors including dysphagia, cognitive impairment, depression, and weak sphincter tone. While the armamentarium available to those who treat constipation, in general, has expanded considerably in recent years, the evidence supporting any therapy in the management of this symptom in PD has remained slim.
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Affiliation(s)
- Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas
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18
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Talman L, Safarpour D. An Overview of Gastrointestinal Dysfunction in Parkinsonian Syndromes. Semin Neurol 2023; 43:583-597. [PMID: 37703887 DOI: 10.1055/s-0043-1771461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
Gastrointestinal (GI) dysfunction is a common nonmotor symptom in Parkinson's disease (PD) as well as other parkinsonian syndromes and may precede the onset of motor symptoms by decades. Involvement of all segments of the GI tract can lead to altered responses to medications and worsened quality of life for patients. While some GI symptoms occur in isolation, others overlap. Therefore, understanding the changes in different segments of the GI tract and how they relate to altered responses to PD treatment can guide both diagnostic and pharmacological interventions. Gut microbiota plays a critical role in immune activity and modulation of the enteric and central nervous systems. Understanding this bidirectional relationship helps to elucidate the pathogenesis of neurodegeneration. This review will describe the current understanding of how GI dysfunction develops in parkinsonian syndromes, common symptoms in PD and related disorders, and available treatments.
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Affiliation(s)
- Lauren Talman
- Department of Neurology School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Delaram Safarpour
- Department of Neurology School of Medicine, Oregon Health & Science University, Portland, Oregon
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19
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Zhong Z, Ye M, Yan F. A review of studies on gut microbiota and levodopa metabolism. Front Neurol 2023; 14:1046910. [PMID: 37332996 PMCID: PMC10272754 DOI: 10.3389/fneur.2023.1046910] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 05/02/2023] [Indexed: 06/20/2023] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease globally. Levodopa (L-dopa) has been the cornerstone for treating Parkinson's since the 1960s. However, complications such as "wearing-off" and dyskinesia inevitably appear with disease progression. With the further development of microbiomics in recent years, It has been recognized that gut microbiota plays a crucial role in Parkinson's disease pathogenesis. However, Little is known about the impact of gut microbiota in PD treatment, especially in levodopa metabolism. This review examines the possible mechanisms of gut microbiota, such as Helicobacter pylori, Enterobacter faecalis, and Clostridium sporogenes, affecting L-dopa absorption. Furthermore, we review the current status of gut microbiota intervention strategies, providing new insights into the treatment of PD.
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Affiliation(s)
- Zhe Zhong
- Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Research Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Min Ye
- Department of Neurology, Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fuling Yan
- Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Research Institution of Neuropsychiatry, Southeast University, Nanjing, China
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20
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Tan AH, Chuah KH, Beh YY, Schee JP, Mahadeva S, Lim SY. Gastrointestinal Dysfunction in Parkinson's Disease: Neuro-Gastroenterology Perspectives on a Multifaceted Problem. J Mov Disord 2023; 16:138-151. [PMID: 37258277 DOI: 10.14802/jmd.22220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/21/2023] [Indexed: 06/02/2023] Open
Abstract
Patients with Parkinson's disease (PD) face a multitude of gastrointestinal (GI) symptoms, including nausea, bloating, reduced bowel movements, and difficulties with defecation. These symptoms are common and may accumulate during the course of PD but are often under-recognized and challenging to manage. Objective testing can be burdensome to patients and does not correlate well with symptoms. Effective treatment options are limited. Evidence is often based on studies in the general population, and specific evidence in PD is scarce. Upper GI dysfunction may also interfere with the pharmacological treatment of PD motor symptoms, which poses significant management challenges. Several new less invasive assessment tools and novel treatment options have emerged in recent years. The current review provides an overview and a practical approach to recognizing and diagnosing common upper and lower GI problems in PD, e.g., dyspepsia, gastroparesis, small bowel dysfunction, chronic constipation, and defecatory dysfunction. Management aspects are discussed based on the latest evidence from the PD and general populations, with insights for future research pertaining to GI dysfunction in PD.
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Affiliation(s)
- Ai Huey Tan
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kee Huat Chuah
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Yuan Ye Beh
- Department of Medicine, Hospital Pulau Pinang, Penang, Malaysia
| | - Jie Ping Schee
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Sanjiv Mahadeva
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Shen-Yang Lim
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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21
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Džidić-Krivić A, Kusturica J, Sher EK, Selak N, Osmančević N, Karahmet Farhat E, Sher F. Effects of intestinal flora on pharmacokinetics and pharmacodynamics of drugs. Drug Metab Rev 2023; 55:126-139. [PMID: 36916327 DOI: 10.1080/03602532.2023.2186313] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Gut microbiota is known as unique collection of microorganisms (including bacteria, archaea, eukaryotes and viruses) that exist in a complex environment of the gut. Recently, this has become one of the most popular areas of research in medicine because this plays not only an important role in disease development, but gut microbiota also influences drug pharmacokinetics. These alterations in drug pharmacokinetic pathways and drug concentration in plasma and blood often lead to an increase in the incidence of toxicological events in patients. This review aims to present current knowledge of the most commonly used drugs in clinical practice and their dynamic interplay with the host's gut microbiota as well as the mechanisms underlying these metabolic processes and the consequent effect on their therapeutic efficacy and safety. These new findings set a foundation for the development of personalized treatments specific to each metabolism, maximizing drugs' therapeutic effects and minimizing the side effects because they are one of the major limiting factors in treating patients.
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Affiliation(s)
- Amina Džidić-Krivić
- Zenica Cantonal Hospital, Zenica, Bosnia and Herzegovina.,International Society of Engineering Science and Technology, Nottingham, UK
| | - Jasna Kusturica
- Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Emina Karahmet Sher
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Nejra Selak
- Dom zdravlja Zenica, Zenica, Bosnia and Herzegovina
| | | | - Esma Karahmet Farhat
- International Society of Engineering Science and Technology, Nottingham, UK.,Department of Food and Nutrition Research, Faculty of Food Technology, Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Farooq Sher
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, UK
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22
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Abstract
Abnormalities in gut microbiota have been suggested to be involved in the pathophysiology and progression of Parkinson's disease (PD). Gastrointestinal nonmotor symptoms often precede the onset of motor features in PD, suggesting a role for gut dysbiosis in neuroinflammation and α-synuclein (α-syn) aggregation. In the first part of this chapter, we analyze critical features of healthy gut microbiota and factors (environmental and genetic) that modify its composition. In the second part, we focus on the mechanisms underlying the gut dysbiosis and how it alters anatomically and functionally the mucosal barrier, triggering neuroinflammation and subsequently α-syn aggregation. In the third part, we describe the most common alterations in the gut microbiota of PD patients, dividing the gastrointestinal system in higher and lower tract to examine the association between microbiota abnormalities and clinical features. In the final section, we report on current and future therapeutic approaches to gut dysbiosis aiming to either reduce the risk for PD, modify the disease course, or improve the pharmacokinetic profile of dopaminergic therapies. We also suggest that further studies will be needed to clarify the role of the microbiome in PD subtyping and of pharmacological and nonpharmacological interventions in modifying specific microbiota profiles in individualizing disease-modifying treatments in PD.
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Affiliation(s)
- Salvatore Bonvegna
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Clinical Neurosciences, Parkinson and Movement Disorders Unit, Milan, Italy
| | - Roberto Cilia
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Clinical Neurosciences, Parkinson and Movement Disorders Unit, Milan, Italy.
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23
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Leta V, Klingelhoefer L, Longardner K, Campagnolo M, Levent HÇ, Aureli F, Metta V, Bhidayasiri R, Chung-Faye G, Falup-Pecurariu C, Stocchi F, Jenner P, Warnecke T, Ray Chaudhuri K. Gastrointestinal barriers to levodopa transport and absorption in Parkinson's disease. Eur J Neurol 2023; 30:1465-1480. [PMID: 36757008 DOI: 10.1111/ene.15734] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/29/2023] [Accepted: 01/31/2023] [Indexed: 02/10/2023]
Abstract
Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.
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Affiliation(s)
- Valentina Leta
- Parkinson's Foundation Center of Excellence at King's College Hospital, London, UK.,Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London and National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre, Institute of Psychology, Psychiatry and Neurosciences, King's College London, London, UK
| | | | - Katherine Longardner
- Parkinson and Other Movement Disorders Center, Department of Neurosciences, University of California San Diego, La Jolla, California, USA
| | - Marta Campagnolo
- Department of Neurosciences (DNS), University of Padova, Padova, Italy
| | | | - Federico Aureli
- Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Vinod Metta
- Parkinson's Foundation Center of Excellence at King's College Hospital, London, UK.,Kings College Hospital London, Dubai, United Arab Emirates
| | - Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Academy of Science, Royal Society of Thailand, Bangkok, Thailand
| | - Guy Chung-Faye
- Parkinson's Foundation Center of Excellence at King's College Hospital, London, UK.,Kings College Hospital London, Dubai, United Arab Emirates
| | | | - Fabrizio Stocchi
- Department of Neurology, University San Raffaele Roma and IRCCS San Raffaele Pisana, Rome, Italy
| | - Peter Jenner
- Institute of Pharmaceutical Sciences, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Tobias Warnecke
- Department of Neurology and Neurorehabilitation, Klinikum Osnabrueck-Academic Teaching Hospital of the WWU Muenster, Osnabrueck, Germany
| | - K Ray Chaudhuri
- Parkinson's Foundation Center of Excellence at King's College Hospital, London, UK.,Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London and National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre, Institute of Psychology, Psychiatry and Neurosciences, King's College London, London, UK
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24
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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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25
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Gulnaz A, Chang JE, Maeng HJ, Shin KH, Lee KR, Chae YJ. A mechanism-based understanding of altered drug pharmacokinetics by gut microbiota. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2022. [DOI: 10.1007/s40005-022-00600-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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26
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Manfready RA, Goetz CG, Keshavarzian A. Intestinal microbiota and neuroinflammation in Parkinson's disease: At the helm of the gut-brain axis. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 167:81-99. [PMID: 36427960 DOI: 10.1016/bs.irn.2022.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Emerging data suggest that disrupted intestinal microbiota, or dysbiosis, may be responsible for multiple features of Parkinson's disease (PD), from initiation, to progression, to therapeutic response. We have progressed greatly in our understanding of microbial signatures associated with PD, and have gained important insights into how dysbiosis and intestinal permeability promote neurodegeneration through neuroinflammation and Lewy body formation. These insights underscore the potential of microbiota-directed therapies, which include dietary, pharmacologic, and lifestyle interventions.
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Affiliation(s)
- Richard A Manfready
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, United States
| | - Christopher G Goetz
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
| | - Ali Keshavarzian
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, United States; Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States.
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27
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Fan HX, Sheng S, Zhang F. New hope for Parkinson's disease treatment: Targeting gut microbiota. CNS Neurosci Ther 2022; 28:1675-1688. [PMID: 35822696 PMCID: PMC9532916 DOI: 10.1111/cns.13916] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/21/2022] [Accepted: 06/25/2022] [Indexed: 12/14/2022] Open
Abstract
There might be more than 10 million confirmed cases of Parkinson's disease (PD) worldwide by 2040. However, the pathogenesis of PD is still unclear. Host health is closely related to gut microbiota, which are affected by factors such as age, diet, and exercise. Recent studies have found that gut microbiota may play key roles in the progression of a wide range of diseases, including PD. Changes in the abundance of gut bacteria, such as Helicobacter pylori, Enterococcus faecalis, and Desulfovibrio, might be involved in PD pathogenesis or interfere with PD therapy. Gut microbiota and the distal brain achieve action on each other through a gut‐brain axis composed of the nervous system, endocrine system, and immune system. Here, this review focused on the current understanding of the connection between Parkinson's disease and gut microbiota, to provide potential therapeutic targets for PD.
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Affiliation(s)
- Hong-Xia Fan
- Laboratory Animal Center and 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, Zunyi Medical University, Zunyi, Guizhou, China
| | - Shuo Sheng
- Laboratory Animal Center and 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, Zunyi Medical University, Zunyi, Guizhou, China
| | - Feng Zhang
- Laboratory Animal Center and 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, Zunyi Medical University, Zunyi, Guizhou, China
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28
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Di Luca DG, Reyes NGD, Fox SH. Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease. Drugs 2022; 82:1027-1053. [PMID: 35841520 PMCID: PMC9287529 DOI: 10.1007/s40265-022-01747-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2022] [Indexed: 12/11/2022]
Abstract
Motor symptoms are a core feature of Parkinson's disease (PD) and cause a significant burden on patients' quality of life. Oral levodopa is still the most effective treatment, however, the motor benefits are countered by inherent pharmacologic limitations of the drug. Additionally, with disease progression, chronic levodopa leads to the appearance of motor complications including motor fluctuations and dyskinesia. Furthermore, several motor abnormalities of posture, balance, and gait may become less responsive to levodopa. With these unmet needs and our evolving understanding of the neuroanatomic and pathophysiologic underpinnings of PD, several advances have been made in defining new therapies for motor symptoms. These include newer levodopa formulations and drug delivery systems, refinements in adjunctive medications, and non-dopaminergic treatment strategies. Although some are in early stages of development, these novel treatments potentially widen the available options for the management of motor symptoms allowing clinicians to provide an individually tailored care for PD patients. Here, we review the existing and emerging interventions for PD with focus on newly approved and investigational drugs for motor symptoms, motor fluctuations, dyskinesia, and balance and gait dysfunction.
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Affiliation(s)
- Daniel Garbin Di Luca
- Edmond J. Safra Program in Parkinson’s Disease, Movement Disorders Clinic, Krembil Brain Institute, Toronto Western Hospital, Toronto, ON Canada
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON Canada
| | - Nikolai Gil D. Reyes
- Edmond J. Safra Program in Parkinson’s Disease, Movement Disorders Clinic, Krembil Brain Institute, Toronto Western Hospital, Toronto, ON Canada
| | - Susan H. Fox
- Edmond J. Safra Program in Parkinson’s Disease, Movement Disorders Clinic, Krembil Brain Institute, Toronto Western Hospital, Toronto, ON Canada
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29
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Tan AH, Lim SY, Lang AE. The microbiome-gut-brain axis in Parkinson disease - from basic research to the clinic. Nat Rev Neurol 2022; 18:476-495. [PMID: 35750883 DOI: 10.1038/s41582-022-00681-2] [Citation(s) in RCA: 159] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2022] [Indexed: 12/12/2022]
Abstract
Evidence for a close bidirectional link between the brain and the gut has led to a paradigm shift in neurology, especially in the case of Parkinson disease (PD), in which gastrointestinal dysfunction is a prominent feature. Over the past decade, numerous high-quality preclinical and clinical publications have shed light on the highly complex relationship between the gut and the brain in PD, providing potential for the development of new biomarkers and therapeutics. With the advent of high-throughput sequencing, the role of the gut microbiome has been specifically highlighted. Here, we provide a critical review of the literature on the microbiome-gut-brain axis in PD and present perspectives that will be useful for clinical practice. We begin with an overview of the gut-brain axis in PD, including the potential roles and interrelationships of the vagus nerve, α-synuclein in the enteric nervous system, altered intestinal permeability and inflammation, and gut microbes and their metabolic activities. The sections that follow synthesize the proposed roles of gut-related factors in the development and progression of, in responses to PD treatment, and as therapeutic targets. Finally, we summarize current knowledge gaps and challenges and delineate future directions for the field.
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Affiliation(s)
- Ai Huey Tan
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. .,Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
| | - Shen Yang Lim
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.,Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Anthony E Lang
- Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Ontario, Canada.,Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
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30
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Exploring the multifactorial aspects of Gut Microbiome in Parkinson's Disease. Folia Microbiol (Praha) 2022; 67:693-706. [PMID: 35583791 PMCID: PMC9526693 DOI: 10.1007/s12223-022-00977-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 05/02/2022] [Indexed: 02/06/2023]
Abstract
Advanced research in health science has broadened our view in approaching and understanding the pathophysiology of diseases and has also revolutionised diagnosis and treatment. Ever since the establishment of Braak’s hypothesis in the propagation of alpha-synuclein from the distant olfactory and enteric nervous system towards the brain in Parkinson’s Disease (PD), studies have explored and revealed the involvement of altered gut microbiota in PD. This review recapitulates the gut microbiome associated with PD severity, duration, motor and non-motor symptoms, and antiparkinsonian treatment from recent literature. Gut microbial signatures in PD are potential predictors of the disease and are speculated to be used in early diagnosis and treatment. In brief, the review also emphasises on implications of the prebiotic, probiotic, faecal microbiota transplantation, and dietary interventions as alternative treatments in modulating the disease symptoms in PD.
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31
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Gubert C, Gasparotto J, H. Morais L. Convergent pathways of the gut microbiota-brain axis and neurodegenerative disorders. Gastroenterol Rep (Oxf) 2022; 10:goac017. [PMID: 35582476 PMCID: PMC9109005 DOI: 10.1093/gastro/goac017] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 03/22/2022] [Accepted: 04/01/2022] [Indexed: 11/14/2022] Open
Abstract
Recent research has been uncovering the role of the gut microbiota for brain health and disease. These studies highlight the role of gut microbiota on regulating brain function and behavior through immune, metabolic, and neuronal pathways. In this review we provide an overview of the gut microbiota axis pathways to lay the groundwork for upcoming sessions on the links between the gut microbiota and neurogenerative disorders. We also discuss how the gut microbiota may act as an intermediate factor between the host and the environment to mediate disease onset and neuropathology. Based on the current literature, we further examine the potential for different microbiota-based therapeutic strategies to prevent, to modify, or to halt the progress of neurodegeneration.
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Affiliation(s)
- Carolina Gubert
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
| | - Juciano Gasparotto
- Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva, Alfenas, Minas Gerais, Brasil
| | - Livia H. Morais
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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32
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Warnecke T, Schäfer KH, Claus I, Del Tredici K, Jost WH. Gastrointestinal involvement in Parkinson's disease: pathophysiology, diagnosis, and management. NPJ Parkinsons Dis 2022; 8:31. [PMID: 35332158 PMCID: PMC8948218 DOI: 10.1038/s41531-022-00295-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Growing evidence suggests an increasing significance for the extent of gastrointestinal tract (GIT) dysfunction in Parkinson's disease (PD). Most patients suffer from GIT symptoms, including dysphagia, sialorrhea, bloating, nausea, vomiting, gastroparesis, and constipation during the disease course. The underlying pathomechanisms of this α-synucleinopathy play an important role in disease development and progression, i.e., early accumulation of Lewy pathology in the enteric and central nervous systems is implicated in pharyngeal discoordination, esophageal and gastric motility/peristalsis impairment, chronic pain, altered intestinal permeability and autonomic dysfunction of the colon, with subsequent constipation. Severe complications, including malnutrition, dehydration, insufficient drug effects, aspiration pneumonia, intestinal obstruction, and megacolon, frequently result in hospitalization. Sophisticated diagnostic tools are now available that permit more detailed examination of specific GIT impairment patterns. Furthermore, novel treatment approaches have been evaluated, although high-level evidence trials are often missing. Finally, the burgeoning literature devoted to the GIT microbiome reveals its importance for neurologists. We review current knowledge about GIT pathoanatomy, pathophysiology, diagnosis, and treatment in PD and provide recommendations for management in daily practice.
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Affiliation(s)
- T Warnecke
- Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, 48149, Münster, Germany
| | - K-H Schäfer
- Research and Transfer Working Group Enteric Nervous System (AGENS), University of Applied Sciences Kaiserslautern, Campus Zweibrücken, 66482, Zweibrücken, Germany
| | - I Claus
- Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, 48149, Münster, Germany
| | - K Del Tredici
- Clinical Neuroanatomy, Department of Neurology, Center for Biomedical Research, University of Ulm, 89081, Ulm, Germany
| | - W H Jost
- Parkinson-Klinik Ortenau, 77709, Wolfach, Germany.
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33
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Madla CM, Gavins FKH, Trenfield SJ, Basit AW. Special Populations. BIOPHARMACEUTICS 2022:205-237. [DOI: 10.1002/9781119678366.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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34
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35
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Markulin I, Matasin M, Turk VE, Salković-Petrisic M. Challenges of repurposing tetracyclines for the treatment of Alzheimer's and Parkinson's disease. J Neural Transm (Vienna) 2022; 129:773-804. [PMID: 34982206 DOI: 10.1007/s00702-021-02457-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/20/2021] [Indexed: 12/13/2022]
Abstract
The novel antibiotic-exploiting strategy in the treatment of Alzheimer's (AD) and Parkinson's (PD) disease has emerged as a potential breakthrough in the field. The research in animal AD/PD models provided evidence on the antiamyloidogenic, anti-inflammatory, antioxidant and antiapoptotic activity of tetracyclines, associated with cognitive improvement. The neuroprotective effects of minocycline and doxycycline in animals initiated investigation of their clinical efficacy in AD and PD patients which led to inconclusive results and additionally to insufficient safety data on a long-standing doxycycline and minocycline therapy in these patient populations. The safety issues should be considered in two levels; in AD/PD patients (particularly antibiotic-induced alteration of gut microbiota and its consequences), and as a world-wide threat of development of bacterial resistance to these antibiotics posed by a fact that AD and PD are widespread incurable diseases which require daily administered long-lasting antibiotic therapy. Recently proposed subantimicrobial doxycycline doses should be thoroughly explored for their effectiveness and long-term safety especially in AD/PD populations. Keeping in mind the antibacterial activity-related far-reaching undesirable effects both for the patients and globally, further work on repurposing these drugs for a long-standing therapy of AD/PD should consider the chemically modified tetracycline compounds tailored to lack antimicrobial but retain (or introduce) other activities effective against the AD/PD pathology. This strategy might reduce the risk of long-term therapy-related adverse effects (particularly gut-related ones) and development of bacterial resistance toward the tetracycline antibiotic agents but the therapeutic potential and desirable safety profile of such compounds in AD/PD patients need to be confirmed.
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Affiliation(s)
- Iva Markulin
- Community Health Centre Zagreb-Centre, Zagreb, Croatia
| | | | - Viktorija Erdeljic Turk
- Division of Clinical Pharmacology, Department of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Melita Salković-Petrisic
- Department of Pharmacology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia.
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36
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Menozzi E, Macnaughtan J, Schapira AHV. The gut-brain axis and Parkinson disease: clinical and pathogenetic relevance. Ann Med 2021; 53:611-625. [PMID: 33860738 PMCID: PMC8078923 DOI: 10.1080/07853890.2021.1890330] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/10/2021] [Indexed: 12/16/2022] Open
Abstract
Gastrointestinal disorders are one of the most significant non-motor problems affecting people with Parkinson disease (PD). Pathogenetically, the gastrointestinal tract has been proposed to be the initial site of pathological changes in PD. Intestinal inflammation and alterations in the gut microbiota may contribute to initiation and progression of pathology in PD. However, the mechanisms underlying this "gut-brain" axis in PD remain unclear. PD patients can display a large variety of gastrointestinal symptoms, leading to reduced quality of life and psychological distress. Gastrointestinal disorders can also limit patients' response to medications, and consequently negatively impact on neurological outcomes. Despite an increasing research focus, gastrointestinal disorders in PD remain poorly understood and their clinical management often suboptimal. This review summarises our understanding of the relevance of the "gut-brain" axis to the pathogenesis of PD, discusses the impact of gastrointestinal disorders in patients with PD, and provides clinicians with practical guidance to their management.
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Affiliation(s)
- Elisa Menozzi
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Jane Macnaughtan
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Anthony H. V. Schapira
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
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37
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Shen S, Zhang C, Xu YM, Shi CH. The Role of Pathogens and Anti-Infective Agents in Parkinson's Disease, from Etiology to Therapeutic Implications. JOURNAL OF PARKINSONS DISEASE 2021; 12:27-44. [PMID: 34719435 PMCID: PMC8842782 DOI: 10.3233/jpd-212929] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Parkinson's disease is a debilitating neurodegenerative disorder whose etiology is still unclear, hampering the development of effective treatments. There is an urgent need to identify the etiology and provide further effective treatments. Recently, accumulating evidence has indicated that infection may play a role in the etiology of Parkinson's disease. The infective pathogens may act as a trigger for Parkinson's disease, the most common of which are hepatitis C virus, influenza virus, and Helicobacter pylori. In addition, gut microbiota is increasingly recognized to influence brain function through the gut-brain axis, showing an important role in the pathogenesis of Parkinson's disease. Furthermore, a series of anti-infective agents exhibit surprising neuroprotective effects via various mechanisms, such as interfering with α-synuclein aggregation, inhibiting neuroinflammation, attenuating oxidative stress, and preventing from cell death, independent of their antimicrobial effects. The pleiotropic agents affect important events in the pathogenesis of Parkinson's disease. Moreover, most of them are less toxic, clinically safe and have good blood-brain penetrability, making them hopeful candidates for the treatment of Parkinson's disease. However, the use of antibiotics and subsequent gut dysbiosis may also play a role in Parkinson's disease, making the long-term effects of anti-infective drugs worthy of further consideration and exploration. This review summarizes the current evidence for the association between infective pathogens and Parkinson's disease and subsequently explores the application prospects of anti-infective drugs in Parkinson's disease treatment, providing novel insights into the pathogenesis and treatment of Parkinson's disease.
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Affiliation(s)
- Si Shen
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Chan Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Yu-Ming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.,Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China
| | - Chang-He Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.,Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.,Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China
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38
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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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Deidda G, Biazzo M. Gut and Brain: Investigating Physiological and Pathological Interactions Between Microbiota and Brain to Gain New Therapeutic Avenues for Brain Diseases. Front Neurosci 2021; 15:753915. [PMID: 34712115 PMCID: PMC8545893 DOI: 10.3389/fnins.2021.753915] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Brain physiological functions or pathological dysfunctions do surely depend on the activity of both neuronal and non-neuronal populations. Nevertheless, over the last decades, compelling and fast accumulating evidence showed that the brain is not alone. Indeed, the so-called "gut brain," composed of the microbial populations living in the gut, forms a symbiotic superorganism weighing as the human brain and strongly communicating with the latter via the gut-brain axis. The gut brain does exert a control on brain (dys)functions and it will eventually become a promising valuable therapeutic target for a number of brain pathologies. In the present review, we will first describe the role of gut microbiota in normal brain physiology from neurodevelopment till adulthood, and thereafter we will discuss evidence from the literature showing how gut microbiota alterations are a signature in a number of brain pathologies ranging from neurodevelopmental to neurodegenerative disorders, and how pre/probiotic supplement interventions aimed to correct the altered dysbiosis in pathological conditions may represent a valuable future therapeutic strategy.
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Affiliation(s)
- Gabriele Deidda
- The BioArte Limited, Life Sciences Park, San Gwann, Malta
- Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
| | - Manuele Biazzo
- The BioArte Limited, Life Sciences Park, San Gwann, Malta
- SienabioACTIVE, University of Siena, Siena, Italy
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40
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Ivan IF, Irincu VL, Diaconu Ș, Falup-Pecurariu O, Ciopleiaș B, Falup-Pecurariu C. Gastro-intestinal dysfunctions in Parkinson's disease (Review). Exp Ther Med 2021; 22:1083. [PMID: 34447476 DOI: 10.3892/etm.2021.10517] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 06/16/2021] [Indexed: 12/14/2022] Open
Abstract
In patients with Parkinson's disease (PD), gastrointestinal dysfunction occurs from the early stages of the disease and even in the pre-motor phase. This condition can include the entire digestive tract, with symptoms ranging from delays in gastric emptying to dysphagia, constipation and even malnutrition. Excess saliva accumulates in the mouth due to the low frequency of swallowing. Dysphagia develops in about 50% of patients and may be a reflection of both central nervous system and enteric nervous system disorder. Gastroparesis can cause a variety of symptoms, including nausea, and also may be responsible for some of the motor fluctuations observed with levodopa therapy. Intestinal dysfunction in PD may be the result of both delayed colon transit and impaired anorectal muscle coordination. In addition, recent studies have demonstrated the role of Helicobacter pylori infection in the pathogenesis of diseases but also the occurrence of motor fluctuations by affecting the absorption of anti-parkinsonian medication. In this review, the main gastrointestinal dysfunctions associated with PD are presented.
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Affiliation(s)
- Irina-Florina Ivan
- Department of Neurology, County Emergency Clinic Hospital, 500365 Brașov, Romania
| | | | - Ștefania Diaconu
- Faculty of Medicine, Transilvania University, 500036 Brașov, Romania
| | | | - Bogdan Ciopleiaș
- Department of Neurology, County Emergency Clinic Hospital, 500365 Brașov, Romania
| | - Cristian Falup-Pecurariu
- Department of Neurology, County Emergency Clinic Hospital, 500365 Brașov, Romania.,Faculty of Medicine, Transilvania University, 500036 Brașov, Romania
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Jan A, Gonçalves NP, Vaegter CB, Jensen PH, Ferreira N. The Prion-Like Spreading of Alpha-Synuclein in Parkinson's Disease: Update on Models and Hypotheses. Int J Mol Sci 2021; 22:8338. [PMID: 34361100 PMCID: PMC8347623 DOI: 10.3390/ijms22158338] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 12/11/2022] Open
Abstract
The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson's disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.
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Affiliation(s)
- Asad Jan
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (N.P.G.); (C.B.V.); (P.H.J.)
| | - Nádia Pereira Gonçalves
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (N.P.G.); (C.B.V.); (P.H.J.)
- International Diabetic Neuropathy Consortium (IDNC), Aarhus University Hospital, 8200 Aarhus, Denmark
| | - Christian Bjerggaard Vaegter
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (N.P.G.); (C.B.V.); (P.H.J.)
- International Diabetic Neuropathy Consortium (IDNC), Aarhus University Hospital, 8200 Aarhus, Denmark
| | - Poul Henning Jensen
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (N.P.G.); (C.B.V.); (P.H.J.)
| | - Nelson Ferreira
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; (N.P.G.); (C.B.V.); (P.H.J.)
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Lotz SK, Blackhurst BM, Reagin KL, Funk KE. Microbial Infections Are a Risk Factor for Neurodegenerative Diseases. Front Cell Neurosci 2021; 15:691136. [PMID: 34305533 PMCID: PMC8292681 DOI: 10.3389/fncel.2021.691136] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/08/2021] [Indexed: 12/13/2022] Open
Abstract
Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, comprise a family of disorders characterized by progressive loss of nervous system function. Neuroinflammation is increasingly recognized to be associated with many neurodegenerative diseases but whether it is a cause or consequence of the disease process is unclear. Of growing interest is the role of microbial infections in inciting degenerative neuroinflammatory responses and genetic factors that may regulate those responses. Microbial infections cause inflammation within the central nervous system through activation of brain-resident immune cells and infiltration of peripheral immune cells. These responses are necessary to protect the brain from lethal infections but may also induce neuropathological changes that lead to neurodegeneration. This review discusses the molecular and cellular mechanisms through which microbial infections may increase susceptibility to neurodegenerative diseases. Elucidating these mechanisms is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of neurodegenerative diseases.
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Affiliation(s)
| | | | | | - Kristen E. Funk
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States
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Bai F, Li X. Association of Helicobacter pylori treatment with Parkinsonism and related disorders: A systematic review and meta-analysis. Life Sci 2021; 281:119767. [PMID: 34216625 DOI: 10.1016/j.lfs.2021.119767] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/17/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022]
Abstract
AIMS Previous studies have suggested that Helicobacter pylori (H. pylori) infections may be the cause of or worsen Parkinson's disease symptoms. In this meta-analysis, all relevant studies were reviewed to assess whether H. pylori treatment would benefit patients with Parkinson's disease. MAIN METHODS Systemically searches were carried out in MEDLINE and other popular databases. The software RevMan 5.2 was used for meta-analysis. The mean difference (MD) was used as the effect size to draw forest plots. KEY FINDINGS A total of 10 qualified studies were included. For bradykinesia, the pooled MD value of stride length was -75.76, 95% CI [-109.37, -42.15, P < 0.05]; for myotonia, the pooled MD value of torque to flex was 75.24, 95% CI [27.36, 123.13, P < 0.05]. The pooled MD value of Unified Parkinson's Disease Rating Scale (UPDRS)-III scores before and after treatment was 6.27, 95% CI [1.30, 11.24, P < 0.05], suggesting that UPDRS-III scores improved in response to H. pylori treatment. The pooled MD value of levodopa onset time (min) was 14.91, 95% CI [8.92, 20.90, P < 0.05]. SIGNIFICANCE H. pylori treatment may improve the stride length in the bradykinesia index and significantly improve UPDRS-III scores.
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Affiliation(s)
- Fusheng Bai
- Department of Neurology, Liaoning Province Jinqiu Hospital, No. 317 Xiaonan Street, Shenyang 110016, Liaoning Province, China
| | - Xinming Li
- Key Lab of Environmental Pollution and Microecology of Liaoning Province, Shenyang Medical College, No. 146 North Huanghe Street, Shenyang 110034, Liaoning Province, China.
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Abstract
The gut microbiota is known to play a role in various disease states through inflammatory, immune and endocrinologic response. Parkinson's Disease is of particular interest as gastrointestinal involvement is one of the earlier features seen in this disease. This paper examines the relationship between gut microbiota and Parkinson's Disease, which has a growing body of literature. Inflammation caused by gut dysbiosis is thought to increase a-synuclein aggregation and worsen motor and neurologic symptoms of Parkinson's disease. We discuss potential treatment and supplementation to modify the microbiota. Some of these treatments require further research before recommendations can be made, such as cord blood transplant, antibiotic use, immunomodulation and fecal microbiota transplant. Other interventions, such as increasing dietary fiber, polyphenol and fermented food intake, can be made with few risks and may have some benefit for symptom relief and speed of disease progression.
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Affiliation(s)
- Amy Gallop
- Department of Psychiatry and Behavioral Neuroscience, 7547Saint Louis University, MO, USA
| | - James Weagley
- Division of Biological Sciences, 7548Washington University, Saint Louis, MO, USA
| | - Saif-Ur-Rahman Paracha
- Department of Psychiatry and Behavioral Neuroscience, 7547Saint Louis University, MO, USA
| | - George Grossberg
- Samuel W. Fordyce Professor and Director of Geriatric Psychiatry, Department of Psychiatry and Behavioral Neuroscience, 7547Saint Louis University, Saint Louis, MO, USA
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45
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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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Tsunoda SM, Gonzales C, Jarmusch AK, Momper JD, Ma JD. Contribution of the Gut Microbiome to Drug Disposition, Pharmacokinetic and Pharmacodynamic Variability. Clin Pharmacokinet 2021; 60:971-984. [PMID: 33959897 PMCID: PMC8332605 DOI: 10.1007/s40262-021-01032-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 12/20/2022]
Abstract
The trillions of microbes that make up the gut microbiome are an important contributor to health and disease. With respect to xenobiotics, particularly orally administered compounds, the gut microbiome interacts directly with drugs to break them down into metabolic products. In addition, microbial products such as bile acids interact with nuclear receptors on host drug-metabolizing enzyme machinery, thus indirectly influencing drug disposition and pharmacokinetics. Gut microbes also influence drugs that undergo enterohepatic recycling by reversing host enzyme metabolic processes and increasing exposure to toxic metabolites as exemplified by the chemotherapy agent irinotecan and non-steroidal anti-inflammatory drugs. Recent data with immune checkpoint inhibitors demonstrate the impact of the gut microbiome on drug pharmacodynamics. We summarize the clinical importance of gut microbe interaction with digoxin, irinotecan, immune checkpoint inhibitors, levodopa, and non-steroidal anti-inflammatory drugs. Understanding the complex interactions of the gut microbiome with xenobiotics is challenging; and highly sensitive methods such as untargeted metabolomics with molecular networking along with other in silico methods and animal and human in vivo studies will uncover mechanisms and pathways. Incorporating the contribution of the gut microbiome to drug disposition, pharmacokinetics, and pharmacodynamics is vital in this era of precision medicine.
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Affiliation(s)
- Shirley M Tsunoda
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0657, La Jolla, San Diego, CA, 90293-0657, USA.
| | - Christopher Gonzales
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0657, La Jolla, San Diego, CA, 90293-0657, USA
| | - Alan K Jarmusch
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0657, La Jolla, San Diego, CA, 90293-0657, USA.,Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, San Diego, CA, USA
| | - Jeremiah D Momper
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0657, La Jolla, San Diego, CA, 90293-0657, USA
| | - Joseph D Ma
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0657, La Jolla, San Diego, CA, 90293-0657, USA
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Lolekha P, Sriphanom T, Vilaichone RK. Helicobacter pylori eradication improves motor fluctuations in advanced Parkinson's disease patients: A prospective cohort study (HP-PD trial). PLoS One 2021; 16:e0251042. [PMID: 33945559 PMCID: PMC8096108 DOI: 10.1371/journal.pone.0251042] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 04/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Helicobacter pylori (HP) is a bacterium associated with many gastrointestinal (GI) diseases and has shown a high prevalence in Parkinson's disease (PD). As HP-associated GI dysfunction could affect L-dopa (levodopa) absorption, HP eradication might improve the clinical response and decrease motor fluctuations. METHODS A prospective cohort study was conducted on the clinical symptoms of PD patients with motor fluctuations. The 13C-urea breath test was used to diagnose a current HP infection. All patients with HP infection received a 2-week regimen of triple therapy. The changes in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, L-dopa onset time, wearing-off symptoms, mean daily on-off time, GI symptom scores, and quality of life score were measured at baseline and at a 6-week follow-up. RESULTS A total of 163 PD patients were assessed, of whom 40 were enrolled. Fifty-five percent of the enrolled patients (22/40) had a current HP infection, whereas HP eradication was identified in 17 of 22 (77.3%) patients who received eradication therapy. Patients with HP eradication showed a significant decrease in daily 'off' time (4.0 vs. 4.7 h, p = 0.040) and an increase in daily 'on' time (11.8 vs. 10.9 h, p = 0.009). Total wearing-off score (4.4 vs. 6.0, p = 0.001) and the GI symptom score (8.1 vs. 12.8, p = 0.007) were significantly improved. There was no significant improvement in L-dopa onset time, UPDRS motor score, or quality of life score. CONCLUSIONS HP eradication leads to significant clinical improvement in the symptoms of PD. Eradication of HP not only increases the total daily 'on' time but also decreases wearing-off symptoms and improves GI symptoms.
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Affiliation(s)
- Praween Lolekha
- Faculty of Medicine, Division of Neurology, Department of Internal Medicine, Thammasat University, Pathumthani, Thailand
| | - Thanakarn Sriphanom
- Faculty of Medicine, Division of Neurology, Department of Internal Medicine, Thammasat University, Pathumthani, Thailand
| | - Ratha-Korn Vilaichone
- Faculty of Medicine, Department of Internal Medicine, Gastroenterology Unit, Thammasat University, Pathumthani, Thailand
- Department of Medicine, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
- Faculty of Medicine, Division of Gastroentero-Hepatology, Department of Internal Medicine, Universitas Airlangga, Surabaya, Indonesia
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Furuto Y, Kawamura M, Yamashita J, Yoshikawa T, Namikawa A, Isshiki R, Takahashi H, Shibuya Y. Relationship Between Helicobacter pylori Infection and Arteriosclerosis. Int J Gen Med 2021; 14:1533-1540. [PMID: 33935515 PMCID: PMC8079247 DOI: 10.2147/ijgm.s303071] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 04/01/2021] [Indexed: 12/19/2022] Open
Abstract
It is reported that Helicobacter pylori (H. pylori) infection may be linked to non-digestive tract diseases, such as arteriosclerosis including dyslipidemia, diabetes, obesity, hypertension, and cardiovascular disease. Therefore, we reviewed recent studies available in PubMed dealing with the mechanisms of arteriosclerosis due to H. pylori infection and the effects of H. pylori eradication. Conventional studies suggested that H. pylori infection may increase the risk of arteriosclerosis. A large interventional study is required to clarify the causal relationships and the effects of bacterial eradication.
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Affiliation(s)
- Yoshitaka Furuto
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Mariko Kawamura
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Jumpei Yamashita
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Takahiro Yoshikawa
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Akio Namikawa
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Rei Isshiki
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Hiroko Takahashi
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
| | - Yuko Shibuya
- Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan
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Helicobacter pylori infection is associated with a poor response to levodopa in patients with Parkinson's disease: a systematic review and meta-analysis. J Neurol 2021; 269:703-711. [PMID: 33616741 DOI: 10.1007/s00415-021-10473-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/13/2021] [Accepted: 02/13/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Helicobacter pylori (HP) infection has been reported to be associated with increased severity of Parkinson's disease (PD) and have negative effects on drug response in patients. We aimed to investigate the influence of HP infection on patients with PD using a systematic review and meta-analysis approach. METHODS PubMed and EMBASE databases for relevant articles published before October 2020 were searched. Two authors independently screened records, extracted data, and evaluated the quality of the included studies. The odds ratios (ORs) or standardized mean differences (SMDs) with their corresponding 95% confidence intervals (CIs) were used to calculate the pooled results by employing a random or fixed-effects model. Sensitivity analyses were conducted, and potential publication bias was assessed. RESULTS A total of 13 studies were included in our meta-analysis. Overall, PD patients with HP infection had significantly higher levodopa equivalent daily dose (UPDRS) motor scores (SMD = 0.266; 95% CI 0.065-0.467; P = 0.009) and more units of levodopa equivalent daily dose (LEDD) (SMD = 0.178; 95% CI 0.004-0.353; P = 0.046) than those of patients without HP infection. Additionally, the time to achieve 'ON' state was significantly longer (SMD = 0.778; 95% CI 0.337-1.220; P = 0.001) and the duration of 'ON' state was significantly shorter (SMD = -0.539; 95% CI = -0.801 to -0.227; P = 0.001) in patients with HP infection than in those without HP infection. CONCLUSION Our pooled results of this meta-analysis demonstrated that HP infection was associated with worse motor symptoms, higher LEDD, and worse response to drugs in patients with PD. This evidence emphasizes the importance of considering subsequent eradication of HP infection in patients with PD.
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50
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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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