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Templeton HN, Tobet SA, Schwerdtfeger LA. Gut neuropeptide involvement in Parkinson's disease. Am J Physiol Gastrointest Liver Physiol 2025; 328:G716-G733. [PMID: 40279198 DOI: 10.1152/ajpgi.00383.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/09/2025] [Accepted: 04/21/2025] [Indexed: 04/27/2025]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder affecting over 10 million people. A key pathological feature of PD is the accumulation of misfolded α-synuclein (aSyn) protein in the substantia nigra pars compacta. Aggregation of aSyn can form Lewy bodies that contribute to dopaminergic neuron degeneration and motor symptoms, such as tremor, rigidity, and bradykinesia. Beyond the central nervous system, aSyn aggregates have been detected in the gastrointestinal (GI) tract, suggesting a link between peripheral aSyn and nonmotor PD symptoms. GI symptoms, often preceding motor symptoms by up to 20 years, highlight the bidirectional communication between the central nervous system and the enteric nervous system (gut-brain axis) in PD. Although microbiome alterations and intestinal inflammation have been associated with PD, functional impacts on gut-brain signaling or aSyn aggregation remain unclear. Intestinal neuropeptides are key modulators of gut-brain communication, alter immune response to pathogens and environmental toxins, and may contribute to the function of the luminal gut barrier. Dysregulation of gut neuropeptide signaling, including vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide, ghrelin, cholecystokinin, glucagon-like peptide 1, and substance P, have been associated with pathologic effects of PD in animal models. Despite their potential role in pathogenesis and disease modulation, gut neuropeptide roles in PD are underexplored. This article reviews current knowledge surrounding microbial metabolite and immune influences on gut neuropeptide signaling, aSyn aggregation in the enteric nervous system, and downstream neuroimmune pathway alterations within the context of PD and its mouse models.
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Affiliation(s)
- Hayley N Templeton
- Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States
| | - Stuart A Tobet
- Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States
- School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado, United States
| | - Luke A Schwerdtfeger
- Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States
- Ann Romney Center for Neurological Disease, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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Oliver PJ, Civitelli L, Hu MT. The gut-brain axis in early Parkinson's disease: from prodrome to prevention. J Neurol 2025; 272:413. [PMID: 40394204 DOI: 10.1007/s00415-025-13138-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/22/2025]
Abstract
Parkinson's disease is the second most common neurodegenerative disorder and fastest growing neurological condition worldwide, yet its etiology and progression remain poorly understood. This disorder is characterized pathologically by the prion-like spread of misfolded neuronal alpha-synuclein proteins in specific brain regions leading to Lewy body formation, neurodegeneration, and progressive neurological impairment. It is unclear what triggers Parkinson's and where α-synuclein protein aggregation begins, although proposed induction sites include the olfactory bulb and dorsal motor nucleus of the vagus nerve. Within the last 20 years, there has been increasing evidence that Parkinson's could be triggered by early microbiome changes and α-synuclein accumulation in the gastrointestinal system. Gut microbiota dysbiosis that alters gastrointestinal motility, permeability, and inflammation could enable prion-like spread of α-synuclein from the gut-to-brain via the enteric nervous system. Individuals with isolated rapid eye movement sleep behavior disorder have a high likelihood of developing Parkinson's and might represent a prodromal 'gut-first' subtype of the condition. The gut-first model of Parkinson's offers novel gut-based therapeutic avenues, such as anti-, pre-, and pro-biotic preparations and fecal microbiota transplants. Crucially, gut-based interventions offer an avenue to treat Parkinson's at early prodromal stages with the aim of mitigating evolution to clinically recognizable Parkinson's disease characterized by motor impairment.
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Affiliation(s)
- Patrick James Oliver
- Clinical Medical School, University of Oxford, Oxford, UK
- Green Templeton College, University of Oxford, Oxford, UK
| | - Livia Civitelli
- Nuffield Department of Clinical Neurosciences, Oxford Parkinsons' Disease Center, University of Oxford, Oxford, UK
| | - Michele T Hu
- Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
- Department of Neurology, West Wing, Level 3, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK.
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Chakraborty AP, Mukherjee A, Sinharoy U, Chakrabarty M, Sengupta M, Chowdhury J, Biswas A. Motor and Non-motor Neurologic Symptoms of Wilson's Disease: Exploring the Associations. Ann Indian Acad Neurol 2025; 28:66-71. [PMID: 39915970 DOI: 10.4103/aian.aian_503_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 12/25/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Although the motor symptoms of Wilson's disease have received particular attention from researchers and medical professionals, non-motor symptoms might become increasingly prevalent with the advancement of the disease and can even appear before the onset of motor symptoms. However, clinicopathological correlations for most of these non-motor features are still poorly understood. The correlations between non-motor and motor symptoms have been examined in this study. METHODS Fifty patients with Wilson's disease participated in this study. Each subject was administered the Global Assessment Scale and the Non-Motor Symptom Questionnaire (NMS Quest) for the assessment of motor and non-motor symptoms, respectively. Cognitive functions were evaluated with Addenbrooke's Cognitive Examination III (Bengali version) and the Digit Span Test. Sleep-related problems were assessed with Pittsburgh Sleep Quality Index. RESULTS Of the patients who participated in this study, 82%, 56%, 90%, 18%, 82%, 8%, 60%, 56%, and 66% had digestive, urinary, apathy-attention-memory, hallucinations/delusions, depression/anxiety, sexual function, cardiovascular, sleep disorder, and miscellaneous (pain, weight, swelling, sweating, and diplopia) symptoms, respectively. NMS-Digestion ( P ≤ 0.001), NMS-Urinary ( P = 0.007), NMS-Miscellany ( P = 0.001), NMS-Memory (0.011), and NMS-Sleep Disorder ( P = 0.031) significantly predicted parkinsonism. NMS-Digestion was a significant predictor of dystonia ( P < 0.001). CONCLUSION Awareness regarding non-motor symptoms and their associations with motor symptoms might help physicians develop more efficient treatment regimens that can alleviate non-motor symptoms which can be equally troublesome and disabling for these patients. Management of non-motor symptoms is crucial for the overall well-being of these patients.
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Affiliation(s)
- Arka Prava Chakraborty
- Department of Neurology, Institute of Postgraduate Medical Education and Research and Bangur Institute of Neurosciences, Kolkata, West Bengal, India
| | - Adreesh Mukherjee
- Department of Neurology, Institute of Postgraduate Medical Education and Research and Bangur Institute of Neurosciences, Kolkata, West Bengal, India
| | - Uma Sinharoy
- Department of Neurology, Institute of Postgraduate Medical Education and Research and Bangur Institute of Neurosciences, Kolkata, West Bengal, India
| | - Madhushree Chakrabarty
- Department of Neurology, Institute of Postgraduate Medical Education and Research and Bangur Institute of Neurosciences, Kolkata, West Bengal, India
| | - Mainak Sengupta
- Department of Genetics, University of Calcutta, West Bengal, India
| | - Jasodhara Chowdhury
- Department of Neurology, Nil Ratan Sircar Medical College, Kolkata, West Bengal, India
| | - Atanu Biswas
- Department of Neurology, Institute of Postgraduate Medical Education and Research and Bangur Institute of Neurosciences, Kolkata, West Bengal, India
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Wang W, Gibson J, Horsman S, Mikkelsen D, Bertin F. Characterization and comparison of fecal microbiota in horses with pituitary pars intermedia dysfunction and age-matched controls. J Vet Intern Med 2025; 39:e17288. [PMID: 39853825 PMCID: PMC11758151 DOI: 10.1111/jvim.17288] [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: 06/18/2024] [Accepted: 12/04/2024] [Indexed: 01/26/2025] Open
Abstract
BACKGROUND Altered gut microbiota has been associated with dopaminergic degenerative diseases in people, but studies on horses with pituitary pars intermedia dysfunction (PPID) are lacking. HYPOTHESIS/OBJECTIVES Investigate the effect of PPID on fecal microbiota in horses. ANIMALS Nine horses with PPID and 13 age-matched control horses. METHODS Prospective control study. Fecal samples were collected bimonthly. Microbial analysis used 16S rRNA sequencing to determine the relative abundance at genus and phylum levels, assess alpha and beta diversity and identify core microbiota. RESULTS Horses with PPID had decreased relative abundances of Christensenellaceae R-7 group (median; 95% confidence interval [CI]: PPID, 2.04; 1.82-2.35 vs control, 2.54; 2.37-2.76; P = .02) and NK4A214 group (PPID, 2.21; 2.02-2.56 vs control, 2.62; 2.44-2.85; P = .05), and significant lower abundances of Romboutsia (log2FoldChange = -3.54; P = .04) and Peptococcaceae uncultured (log2FoldChange = -0.89; P = .04) by differential abundance analysis. However, the abundance of Fibrobacter (log2FoldChange = 0.74; P = .04) was significantly higher in the PPID group. A significant effect of PPID on beta diversity was observed (P = .004), whereas alpha diversity varied with months (P = .001). Seven unique genera were identified in horses with PPID and 12 in control horses. CONCLUSIONS AND CLINICAL IMPORTANCE The fecal microbial composition is altered in horses with PPID. These findings support the potential role of the microbiota-gut-brain axis in the pathogenesis of PPID.
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Affiliation(s)
- Wenqing Wang
- School of Veterinary ScienceThe University of QueenslandGattonQueenslandAustralia
| | - Justine Gibson
- School of Veterinary ScienceThe University of QueenslandGattonQueenslandAustralia
| | - Sara Horsman
- School of Veterinary ScienceThe University of QueenslandGattonQueenslandAustralia
| | - Deirdre Mikkelsen
- School of Agriculture and Food SciencesThe University of QueenslandSt LuciaQueenslandAustralia
| | - François‐René Bertin
- School of Veterinary ScienceThe University of QueenslandGattonQueenslandAustralia
- College of Veterinary MedicinePurdue UniversityWest LafayetteIndianaUSA
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Di Salvo C, D'Antongiovanni V, Benvenuti L, d'Amati A, Ippolito C, Segnani C, Pierucci C, Bellini G, Annese T, Virgintino D, Colucci R, Antonioli L, Fornai M, Errede M, Bernardini N, Pellegrini C. Lactiplantibacillus plantarum HEAL9 attenuates cognitive impairment and progression of Alzheimer's disease and related bowel symptoms in SAMP8 mice by modulating microbiota-gut-inflammasome-brain axis. Food Funct 2024; 15:10323-10338. [PMID: 39302233 DOI: 10.1039/d4fo02075h] [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: 09/22/2024]
Abstract
Background: Growing evidence highlights the relevance of the microbiota-gut-brain axis in Alzheimer's disease (AD). AD patients display gut dysbiosis, altered intestinal barrier and enteric inflammation that, besides bowel symptoms, can contribute to brain pathology. In this context, the modulation of gut microbiota is emerging as a therapeutical option to halt or slow down central pathology. Herein, we examined the effects of Lactiplantibacillus plantarum HEAL9 in a spontaneous mouse model of AD. Methods: Senescence-accelerated mouse prone 8 (SAMP8) mice and control SAMR1 mice were treated orally with HEAL9 1 × 109 CFU per mouse per day or placebo for two months to evaluate the effects of the probiotic during the earliest stages of AD, before the development of brain pathology. Cognitive impairment, in vivo and in vitro colonic motility, astrocyte and microglia reactive response, brain and colonic amyloid-β1-42 (Aβ1-42) levels, and inflammasome components activation (NLRP3, ASC, caspase-1 and interleukin-1β) were assessed. In addition, gut barrier alterations [circulating lipopolysaccharide-binding protein (LBP) levels] and acidic mucus were evaluated. Results: HEAL9 administration significantly attenuated cognitive impairment and counteracted colonic dysmotility in SAMP8 mice. Moreover, HEAL9 decreased astrogliosis and microgliosis, Aβ1-42 accumulation and inflammasome activation in colon and brain and normalized plasma LBP levels and colonic acidic mucus content. Conclusion: HEAL9 intake alleviated cognitive decline and normalized colonic motility in the prodromal phases of AD via the modulation of microbiota-gut-inflammasome-brain signalling. Thus, dietary supplementation with HEAL9 could be considered as a suitable therapeutical option for the treatment of AD and related intestinal symptoms in the early stages of the disease.
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Affiliation(s)
- C Di Salvo
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - V D'Antongiovanni
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - L Benvenuti
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - A d'Amati
- Human Anatomy and Histology Unit, Department of Basic Medical Sciences, Neuroscience, and Sensory Organs, University of Bari School of Medicine, Bari, Italy.
| | - C Ippolito
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - C Segnani
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - C Pierucci
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - G Bellini
- Unit of Neurology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - T Annese
- Human Anatomy and Histology Unit, Department of Basic Medical Sciences, Neuroscience, and Sensory Organs, University of Bari School of Medicine, Bari, Italy.
- Department of Medicine and Surgery, University LUM Giuseppe Degennaro, Casamassima, Bari, Italy
| | - D Virgintino
- Human Anatomy and Histology Unit, Department of Basic Medical Sciences, Neuroscience, and Sensory Organs, University of Bari School of Medicine, Bari, Italy.
| | - R Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - L Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - M Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - M Errede
- Human Anatomy and Histology Unit, Department of Basic Medical Sciences, Neuroscience, and Sensory Organs, University of Bari School of Medicine, Bari, Italy.
| | - N Bernardini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - C Pellegrini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
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Lucarini E, Benvenuti L, Di Salvo C, D’Antongiovanni V, Pellegrini C, Valdiserra G, Ciampi C, Antonioli L, Lambiase C, Cancelli L, Grosso A, Di Cesare Mannelli L, Bellini M, Ghelardini C, Fornai M. Evaluation of the beneficial effects of a GABA-based product containing Melissa officinalis on post-inflammatory irritable bowel syndrome: a preclinical study. Front Pharmacol 2024; 15:1466824. [PMID: 39372212 PMCID: PMC11449869 DOI: 10.3389/fphar.2024.1466824] [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: 07/18/2024] [Accepted: 09/02/2024] [Indexed: 10/08/2024] Open
Abstract
Introduction Visceral pain represents the most common digestive issue, frequently resulting from long-term inflammation, such as inflammatory bowel diseases. The lack of effective drugs prompted search of new therapeutic approaches. In this regard, gamma-aminobutyric acid (GABA) and Melissa officinalis (Mo) appear as excellent candidates as they were recognized to have several positive effects on the digestive system. The aim of this research was to evaluate the effects of a compound containing GABA and Mo (GABA-Mo 5:1) in inflammation-induced intestinal damage and visceral pain. Methods Colitis was induced in rats by intrarectal 2,4-dinitrobenzenesulfonic acid (DNBS) administration. DNBS-treated animals received GABA-Mo (80 mg/kg BID), starting 3 days before DNBS administration, until 14 days after colitis induction (preventive protocol), or starting 7 days after DNBS until day 21 (curative protocol). Visceral pain was assessed by measuring the viscero-motor response (VMR) and the abdominal withdrawal reflex (AWR) to colorectal distension on day 7, 14 (both protocols) and 21 (curative protocol) after DNBS administration. Results In the preventive protocol, GABA-Mo reduced AWR at day 14 but had no effect on VMR. In the spinal cord, treatment with GABA-Mo significantly prevented microglia reactivity (Iba-1 positive cells). In the colon, the supplement significantly decreased malondialdehyde (MDA, index of oxidative stress) and IL-1β levels and counteracted the decreased expression of claudin-1. Moreover, GABA-Mo normalized the increased levels of plasma lipopolysaccharide binding protein (LBP, index of altered intestinal permeability). In the curative protocol, GABA-Mo significantly counteracted visceral hypersensitivity persistence in DNBS-treated animals (day 14 and 21). In the spinal cord, GABA-Mo significantly reduced GFAP positive cell density (astrocytes). Histological evaluations highlighted a mild but significant effect of GABA-Mo in promoting healing from DNBS-induced colon damage. Colonic MDA and myeloperoxidase (index of leukocyte infiltration) levels were reduced, while the decreased colonic claudin-1 expression was normalized. In addition, the increased levels of plasma LBP were normalized by GABA-Mo administration. Discussion In conclusion GABA-Mo, particularly in the curative protocol, was able to reduce visceral pain and intestinal inflammation, likely through a reinforcement of intestinal barrier integrity, thus representing a suitable approach for the management of abdominal pain, especially in the remission stages of colitis.
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Affiliation(s)
- Elena Lucarini
- Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, University of Florence, Florence, Italy
| | - Laura Benvenuti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Clelia Di Salvo
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Carolina Pellegrini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giulia Valdiserra
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Clara Ciampi
- Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, University of Florence, Florence, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Christian Lambiase
- Department of Translational Research, New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Lorenzo Cancelli
- Department of Translational Research, New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Antonio Grosso
- Department of Translational Research, New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Lorenzo Di Cesare Mannelli
- Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, University of Florence, Florence, Italy
| | - Massimo Bellini
- Department of Translational Research, New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Carla Ghelardini
- Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, University of Florence, Florence, Italy
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Koutsokostas C, Merkouris E, Goulas A, Aidinopoulou K, Sini N, Dimaras T, Tsiptsios D, Mueller C, Nystazaki M, Tsamakis K. Gut Microbes Associated with Neurodegenerative Disorders: A Comprehensive Review of the Literature. Microorganisms 2024; 12:1735. [PMID: 39203576 PMCID: PMC11357424 DOI: 10.3390/microorganisms12081735] [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: 07/25/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/03/2024] Open
Abstract
Evidence shows that neurodegenerative and neuropsychiatric disorders are influenced by alterations in the gut microbiome. Various diseases have been linked to microbiome dysbiosis, yet there are inconclusive data regarding which microorganisms are associated with each disorder. The aim of our study is to systematically review the recent literature of the past decade to clarify whether the gut microbiome contributes to the understanding of pathogenesis and progression of neurodegenerative disorders. Most included studies showed a strong correlation between the relative abundance of certain microorganisms, mainly species of the phyla Firmicutes and Bacteroidetes, and disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). It is speculated that the microorganisms and their byproducts have a significant role in brain protein accumulation, neuro-inflammation, and gut permeability. The estimation of microbial populations could potentially improve clinical outcomes and hinder the progression of the disease. However, further research is needed to include more diseases and larger patient samples and identify specific species and subspecies associated with these disorders.
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Affiliation(s)
- Christos Koutsokostas
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupoli, Greece; (C.K.); (E.M.); (A.G.); (K.A.); (N.S.); (T.D.)
| | - Ermis Merkouris
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupoli, Greece; (C.K.); (E.M.); (A.G.); (K.A.); (N.S.); (T.D.)
| | - Apostolos Goulas
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupoli, Greece; (C.K.); (E.M.); (A.G.); (K.A.); (N.S.); (T.D.)
| | - Konstantina Aidinopoulou
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupoli, Greece; (C.K.); (E.M.); (A.G.); (K.A.); (N.S.); (T.D.)
| | - Niki Sini
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupoli, Greece; (C.K.); (E.M.); (A.G.); (K.A.); (N.S.); (T.D.)
| | - Theofanis Dimaras
- Neurology Department, Democritus University of Thrace, 68100 Alexandroupoli, Greece; (C.K.); (E.M.); (A.G.); (K.A.); (N.S.); (T.D.)
| | | | - Christoph Mueller
- Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London SE5 8AB, UK;
- Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London SE5 8AF, UK
| | - Maria Nystazaki
- 2nd Department of Psychiatry, University General Hospital ‘Attikon’, 12462 Athens, Greece;
| | - Konstantinos Tsamakis
- Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London SE5 8AB, UK;
- Institute of Medical and Biomedical Education, St George’s, University of London, London SW17 0RE, UK
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Homolak J, Joja M, Grabaric G, Schiatti E, Virag D, Babic Perhoc A, Knezovic A, Osmanovic Barilar J, Salkovic-Petrisic M. The Absence of Gastrointestinal Redox Dyshomeostasis in the Brain-First Rat Model of Parkinson's Disease Induced by Bilateral Intrastriatal 6-Hydroxydopamine. Mol Neurobiol 2024; 61:5481-5493. [PMID: 38200352 PMCID: PMC11249596 DOI: 10.1007/s12035-023-03906-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024]
Abstract
The gut-brain axis plays an important role in Parkinson's disease (PD) by acting as a route for vagal propagation of aggregated α-synuclein in the gut-first endophenotype and as a mediator of gastrointestinal dyshomeostasis via the nigro-vagal pathway in the brain-first endophenotype of the disease. One important mechanism by which the gut-brain axis may promote PD is by regulating gastrointestinal redox homeostasis as overwhelming evidence suggests that oxidative stress plays a key role in the etiopathogenesis and progression of PD and the gastrointestinal tract maintains redox homeostasis of the organism by acting as a critical barrier to environmental and microbiological electrophilic challenges. The present aim was to utilize the bilateral intrastriatal 6-hydroxydopamine (6-OHDA) brain-first PD model to study the effects of isolated central pathology on redox homeostasis of the gastrointestinal tract. Three-month-old male Wistar rats were either not treated (intact controls; CTR) or treated bilaterally intrastriatally with vehicle (CIS) or 6-OHDA (6-OHDA). Motor deficits were assessed with the rotarod performance test, and the duodenum, ileum, and colon were dissected for biochemical analyses 12 weeks after the treatment. Lipid peroxidation, total antioxidant capacity, low-molecular-weight thiols, and protein sulfhydryls, the activity of total and Mn/Fe superoxide dismutases, and total and azide-insensitive catalase/peroxidase were measured. Both univariate and multivariate models analyzing redox biomarkers indicate that significant disturbances in gastrointestinal redox balance are not present. The findings demonstrate that motor impairment observed in the brain-first 6-OHDA model of PD can occur without concurrent redox imbalances in the gastrointestinal system.
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Affiliation(s)
- Jan Homolak
- Department of Pharmacology & Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia.
- Interfaculty Institute of Microbiology and Infection Medicine & Cluster of Excellence "Controlling Microbes to Fight Infections,", University of Tübingen, Tübingen, Germany.
| | - Mihovil Joja
- Department of Pharmacology & Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Gracia Grabaric
- Department of Pharmacology & Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia
| | - Emiliano Schiatti
- Faculty of Medicine and Surgery, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Davor Virag
- Department of Pharmacology & Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia
| | - Ana Babic Perhoc
- Department of Pharmacology & Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia
| | - Ana Knezovic
- Department of Pharmacology & Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia
| | - Jelena Osmanovic Barilar
- Department of Pharmacology & Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia
| | - Melita Salkovic-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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Bhardwaj K, Singh AA, Kumar H. Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration-Gut Connection in Parkinson's Disease. ACS Chem Neurosci 2024; 15:2454-2469. [PMID: 38896463 DOI: 10.1021/acschemneuro.4c00293] [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] [Indexed: 06/21/2024] Open
Abstract
Parkinson's disease, a classical motor disorder affecting the dopaminergic system of the brain, has been as a disease of the brain, but this classical notion has now been viewed differently as the pathology begins in the gut and then gradually moves up to the brain regions. The microorganisms in the gut play a critical role in maintaining the physiology of the gut from maintaining barrier integrity to secretion of microbial products that maintain a healthy gut state. The pathology subsequently alters the normal composition of gut microbes and causes deleterious effects that ultimately trigger strong neuroinflammation and nonmotor symptoms along with characteristic synucleopathy, a pathological hallmark of the disease. Understanding the complex pathomechanisms in distinct and established preclinical models is the primary goal of researchers to decipher how exactly gut pathology has a central effect; the quest has led to many answered and some open-ended questions for researchers. We summarize the popular opinions and some contrasting views, concise footsteps in the treatment strategies targeting the gastrointestinal system.
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Affiliation(s)
- Kritika Bhardwaj
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Opposite Air force station, Palaj, Gandhinagar, 382355 Gujarat, India
| | - Aditya A Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Opposite Air force station, Palaj, Gandhinagar, 382355 Gujarat, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A), Opposite Air force station, Palaj, Gandhinagar, 382355 Gujarat, India
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10
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Benvenuti L, Di Salvo C, Bellini G, Seguella L, Rettura F, Esposito G, Antonioli L, Ceravolo R, Bernardini N, Pellegrini C, Fornai M. Gut-directed therapy in Parkinson's disease. Front Pharmacol 2024; 15:1407925. [PMID: 38974034 PMCID: PMC11224490 DOI: 10.3389/fphar.2024.1407925] [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: 03/27/2024] [Accepted: 05/17/2024] [Indexed: 07/09/2024] Open
Abstract
Parkinson's disease (PD) is a common and slow-progressing neurodegenerative disorder characterized by motor and non-motor symptoms, including gastrointestinal (GI) dysfunctions. Over the last years, the microbiota-gut-brain (MGB) axis is emerging as a bacterial-neuro-immune ascending pathway that contributes to the progression of PD. Indeed, PD patients are characterized by changes in gut microbiota composition, alterations of intestinal epithelial barrier (IEB) and enteric neurogenic/inflammatory responses that, besides determining intestinal disturbances, contribute to brain pathology. In this context, despite the causal relationship between gut dysbiosis, impaired MGB axis and PD remains to be elucidated, emerging evidence shows that MGB axis modulation can represent a suitable therapeutical strategy for the treatment of PD. This review provides an overview of the available knowledge about the beneficial effects of gut-directed therapies, including dietary interventions, prebiotics, probiotics, synbiotics and fecal microbiota transplantation (FMT), in both PD patients and animal models. In this context, particular attention has been devoted to the mechanisms by which the modulation of MGB axis could halt or slow down PD pathology and, most importantly, how these approaches can be included in the clinical practice.
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Affiliation(s)
- Laura Benvenuti
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Clelia Di Salvo
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gabriele Bellini
- Unit of Neurology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luisa Seguella
- Department of Physiology and Pharmacology “V.Erspamer”, Sapienza University of Rome, Rome, Italy
| | - Francesco Rettura
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Giuseppe Esposito
- Department of Physiology and Pharmacology “V.Erspamer”, Sapienza University of Rome, Rome, Italy
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Roberto Ceravolo
- Unit of Neurology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nunzia Bernardini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Carolina Pellegrini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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11
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Pellegrini C, Travagli RA. Gastrointestinal dysmotility in rodent models of Parkinson's disease. Am J Physiol Gastrointest Liver Physiol 2024; 326:G345-G359. [PMID: 38261717 PMCID: PMC11212145 DOI: 10.1152/ajpgi.00225.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/09/2024] [Accepted: 01/22/2024] [Indexed: 01/25/2024]
Abstract
Multiple studies describe prodromal, nonmotor dysfunctions that affect the quality of life of patients who subsequently develop Parkinson's disease (PD). These prodromal dysfunctions comprise a wide array of autonomic issues, including severe gastrointestinal (GI) motility disorders such as dysphagia, delayed gastric emptying, and chronic constipation. Indeed, strong evidence from studies in humans and animal models suggests that the GI tract and its neural, mainly vagal, connection to the central nervous system (CNS) could have a major role in the etiology of PD. In fact, misfolded α-synuclein aggregates that form Lewy bodies and neurites, i.e., the histological hallmarks of PD, are detected in the enteric nervous system (ENS) before clinical diagnosis of PD. The aim of the present review is to provide novel insights into the pathogenesis of GI dysmotility in PD, focusing our attention on functional, neurochemical, and molecular alterations in animal models.
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Affiliation(s)
- Carolina Pellegrini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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12
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Thomasi B, Valdetaro L, Gulbransen B, Tavares-Gomes AL. Neuroimmune Connectomes in the Gut and Their Implications in Parkinson's Disease. Mol Neurobiol 2024; 61:2081-2098. [PMID: 37840070 PMCID: PMC11151216 DOI: 10.1007/s12035-023-03679-z] [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: 08/26/2022] [Accepted: 09/28/2023] [Indexed: 10/17/2023]
Abstract
The gastrointestinal tract is the largest immune organ and it receives dense innervation from intrinsic (enteric) and extrinsic (sympathetic, parasympathetic, and somatosensory) neurons. The immune and neural systems of the gut communicate with each other and their interactions shape gut defensive mechanisms and neural-controlled gut functions such as motility and secretion. Changes in neuroimmune interactions play central roles in the pathogenesis of diseases such as Parkinson's disease (PD), which is a multicentric disorder that is heterogeneous in its manifestation and pathogenesis. Non-motor and premotor symptoms of PD are common in the gastrointestinal tract and the gut is considered a potential initiation site for PD in some cases. How the enteric nervous system and neuroimmune signaling contribute to PD disease progression is an emerging area of interest. This review focuses on intestinal neuroimmune loops such as the neuroepithelial unit, enteric glial cells and their immunomodulatory effects, anti-inflammatory cholinergic signaling and the relationship between myenteric neurons and muscularis macrophages, and the role of α-synuclein in gut immunity. Special consideration is given to the discussion of intestinal neuroimmune connectomes during PD and their possible implications for various aspects of the disease.
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Affiliation(s)
- Beatriz Thomasi
- Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building - Gulbransen lab, 567, Wilson Rd, Room 3199, East Lansing, MI, USA.
| | - Luisa Valdetaro
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, USA
| | - Brian Gulbransen
- Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building - Gulbransen lab, 567, Wilson Rd, Room 3199, East Lansing, MI, USA
| | - Ana Lúcia Tavares-Gomes
- Programa de Pós-Graduação Em Neurociências, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
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13
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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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14
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Zhang XL, Sun Q, Quan ZS, Wu L, Liu ZM, Xia YQ, Wang QY, Zhang Y, Zhu JX. Dopamine regulates colonic glial cell-derived neurotrophic factor secretion through cholinergic dependent and independent pathways. Br J Pharmacol 2024; 181:413-428. [PMID: 37614042 DOI: 10.1111/bph.16226] [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: 10/10/2022] [Revised: 06/02/2023] [Accepted: 08/03/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND AND PURPOSE Glial cell-derived neurotrophic factor (GDNF) maintains gut homeostasis. Dopamine promotes GDNF release in astrocytes. We investigated the regulation by dopamine of colonic GDNF secretion. EXPERIMENTAL APPROACH D1 receptor knockout (D1 R-/- ) mice, adeno-associated viral 9-short hairpin RNA carrying D2 receptor (AAV9-shD2 R)-treated mice, 6-hydroxydopamine treated (6-OHDA) rats and primary enteric glial cells (EGCs) culture were used. Incubation fluid from colonic submucosal plexus and longitudinal muscle myenteric plexus were collected for GDNF and ACh measurements. KEY RESULTS D2 receptor-immunoreactivity (IR), but not D1 receptor-IR, was observed on EGCs. Both D1 receptor-IR and D2 receptor-IR were co-localized on cholinergic neurons. Low concentrations of dopamine induced colonic GDNF secretion in a concentration-dependent manner, which was mimicked by the D1 receptor agonist SKF38393, inhibited by TTX and atropine and eliminated in D1 R-/- mice. SKF38393-induced colonic ACh release was absent in D1 R-/- mice. High concentrations of dopamine suppressed colonic GDNF secretion, which was mimicked by the D2 receptor agonist quinpirole, and absent in AAV-shD2 R-treated mice. Quinpirole decreased GDNF secretion by reducing intracellular Ca2+ levels in primary cultured EGCs. Carbachol ( ACh analogue) promoted the release of GDNF. Quinpirole inhibited colonic ACh release, which was eliminated in the AAV9-shD2 R-treated mice. 6-OHDA treated rats with low ACh and high dopamine content showed decreased GDNF content and increased mucosal permeability in the colon. CONCLUSION AND IMPLICATIONS Low concentrations of dopamine promote colonic GDNF secretion via D1 receptors on cholinergic neurons, whereas high concentrations of dopamine inhibit GDNF secretion via D2 receptors on EGCs and/or cholinergic neurons.
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Affiliation(s)
- Xiao-Li Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Qi Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zhu-Sheng Quan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Liang Wu
- Endoscopy Center, Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zi-Ming Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yan-Qi Xia
- Grade 2020 Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Qian-Yi Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yue Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jin-Xia Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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15
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Yuan XY, Chen YS, Liu Z. Relationship among Parkinson's disease, constipation, microbes, and microbiological therapy. World J Gastroenterol 2024; 30:225-237. [PMID: 38314132 PMCID: PMC10835526 DOI: 10.3748/wjg.v30.i3.225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/16/2023] [Accepted: 12/26/2023] [Indexed: 01/18/2024] Open
Abstract
This comprehensive review elucidates the complex interplay between gut microbiota and constipation in Parkinson's disease (PD), a prevalent non-motor symptom contributing significantly to patients' morbidity. A marked alteration in the gut microbiota, predominantly an increase in the abundance of Proteobacteria and Bacteroidetes, is observed in PD-related constipation. Conventional treatments, although safe, have failed to effectively alleviate symptoms, thereby necessitating the development of novel therapeutic strategies. Microbiological interventions such as prebiotics, probiotics, and fecal microbiota transplantation (FMT) hold therapeutic potential. While prebiotics improve bowel movements, probiotics are effective in enhancing stool consistency and alleviating abdominal discomfort. FMT shows potential for significantly alleviating constipation symptoms by restoring gut microbiota balance in patients with PD. Despite promising developments, the causal relationship between changes in gut microbiota and PD-related constipation remains elusive, highlighting the need for further research in this expanding field.
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Affiliation(s)
- Xin-Yang Yuan
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
- Institute of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Zhanjiang 524000, Guangdong Province, China
| | - Yu-Sen Chen
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
- Institute of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Zhanjiang 524000, Guangdong Province, China
| | - Zhou Liu
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
- Institute of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Zhanjiang 524000, Guangdong Province, China
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16
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Montalbán-Rodríguez A, Abalo R, López-Gómez L. From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson's Disease. Int J Mol Sci 2024; 25:1294. [PMID: 38279293 PMCID: PMC10816228 DOI: 10.3390/ijms25021294] [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: 11/30/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 01/28/2024] Open
Abstract
The brain-gut axis has been identified as an important contributor to the physiopathology of Parkinson's disease. In this pathology, inflammation is thought to be driven by the damage caused by aggregation of α-synuclein in the brain. Interestingly, the Braak's theory proposes that α-synuclein misfolding may originate in the gut and spread in a "prion-like" manner through the vagus nerve into the central nervous system. In the enteric nervous system, enteric glial cells are the most abundant cellular component. Several studies have evaluated their role in Parkinson's disease. Using samples obtained from patients, cell cultures, or animal models, the studies with specific antibodies to label enteric glial cells (GFAP, Sox-10, and S100β) seem to indicate that activation and reactive gliosis are associated to the neurodegeneration produced by Parkinson's disease in the enteric nervous system. Of interest, Toll-like receptors, which are expressed on enteric glial cells, participate in the triggering of immune/inflammatory responses, in the maintenance of intestinal barrier integrity and in the configuration of gut microbiota; thus, these receptors might contribute to Parkinson's disease. External factors like stress also seem to be relevant in its pathogenesis. Some authors have studied ways to reverse changes in EGCs with interventions such as administration of Tryptophan-2,3-dioxygenase inhibitors, nutraceuticals, or physical exercise. Some researchers point out that beyond being activated during the disease, enteric glial cells may contribute to the development of synucleinopathies. Thus, it is still necessary to further study these cells and their role in Parkinson's disease.
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Affiliation(s)
- Alba Montalbán-Rodríguez
- Department of Basic Health Sciences, Faculty of Health Sciences, University Rey Juan Carlos (URJC), 28922 Alcorcon, Spain; (A.M.-R.); (L.L.-G.)
- High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), University Rey Juan Carlos (URJC), 28922 Alcorcón, Spain
| | - Raquel Abalo
- Department of Basic Health Sciences, Faculty of Health Sciences, University Rey Juan Carlos (URJC), 28922 Alcorcon, Spain; (A.M.-R.); (L.L.-G.)
- High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), University Rey Juan Carlos (URJC), 28922 Alcorcón, Spain
- Associated R+D+i Unit to the Institute of Medicinal Chemistry (IQM), Scientific Research Superior Council (CSIC), 28006 Madrid, Spain
- Working Group of Basic Sciences on Pain and Analgesia, Spanish Pain Society, 28046 Madrid, Spain
- Working Group of Basic Sciences on Cannabinoids, Spanish Pain Society, 28046 Madrid, Spain
| | - Laura López-Gómez
- Department of Basic Health Sciences, Faculty of Health Sciences, University Rey Juan Carlos (URJC), 28922 Alcorcon, Spain; (A.M.-R.); (L.L.-G.)
- High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), University Rey Juan Carlos (URJC), 28922 Alcorcón, Spain
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17
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Zhang X, Tang B, Guo J. Parkinson's disease and gut microbiota: from clinical to mechanistic and therapeutic studies. Transl Neurodegener 2023; 12:59. [PMID: 38098067 PMCID: PMC10722742 DOI: 10.1186/s40035-023-00392-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 11/27/2023] [Indexed: 12/17/2023] Open
Abstract
Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases. The typical symptomatology of PD includes motor symptoms; however, a range of nonmotor symptoms, such as intestinal issues, usually occur before the motor symptoms. Various microorganisms inhabiting the gastrointestinal tract can profoundly influence the physiopathology of the central nervous system through neurological, endocrine, and immune system pathways involved in the microbiota-gut-brain axis. In addition, extensive evidence suggests that the gut microbiota is strongly associated with PD. This review summarizes the latest findings on microbial changes in PD and their clinical relevance, describes the underlying mechanisms through which intestinal bacteria may mediate PD, and discusses the correlations between gut microbes and anti-PD drugs. In addition, this review outlines the status of research on microbial therapies for PD and the future directions of PD-gut microbiota research.
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Affiliation(s)
- Xuxiang Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Beisha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008, China
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, 410008, China
- Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, China
- Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jifeng Guo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008, China.
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, 410008, China.
- Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, China.
- Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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18
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Qamar MA, Tall P, van Wamelen D, Wan YM, Rukavina K, Fieldwalker A, Matthew D, Leta V, Bannister K, Chaudhuri KR. Setting the clinical context to non-motor symptoms reflected by Park-pain, Park-sleep, and Park-autonomic subtypes of Parkinson's disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 174:1-58. [PMID: 38341227 DOI: 10.1016/bs.irn.2023.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2024]
Abstract
Non-motor symptoms (NMS) of Parkinson's disease (PD) are well described in both clinical practice and the literature, enabling their management and enhancing our understanding of PD. NMS can dominate the clinical pictures and NMS subtypes have recently been proposed, initially based on clinical observations, and later confirmed in data driven analyses of large datasets and in biomarker-based studies. In this chapter, we provide an update on what is known about three common subtypes of NMS in PD. The pain (Park-pain), sleep dysfunction (Park-sleep), and autonomic dysfunction (Park-autonomic), providing an overview of their individual classification, clinical manifestation, pathophysiology, diagnosis, and potential treatments.
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Affiliation(s)
- Mubasher A Qamar
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence and Department of Neurology and Neurosciences, King's College Hospital NHS Trust, London, United Kingdom.
| | - Phoebe Tall
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence and Department of Neurology and Neurosciences, King's College Hospital NHS Trust, London, United Kingdom
| | - Daniel van Wamelen
- Parkinson's Foundation Centre of Excellence and Department of Neurology and Neurosciences, King's College Hospital NHS Trust, London, United Kingdom; Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Centre of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
| | - Yi Min Wan
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence and Department of Neurology and Neurosciences, King's College Hospital NHS Trust, London, United Kingdom; Department of Psychiatry, Ng Teng Fong General Hospital, Singapore, Singapore
| | - Katarina Rukavina
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence and Department of Neurology and Neurosciences, King's College Hospital NHS Trust, London, United Kingdom
| | - Anna Fieldwalker
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Central Modulation of Pain Lab, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Donna Matthew
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence and Department of Neurology and Neurosciences, King's College Hospital NHS Trust, London, United Kingdom
| | - Valentina Leta
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence and Department of Neurology and Neurosciences, King's College Hospital NHS Trust, London, United Kingdom; Department of Clinical Neurosciences, Parkinson, and Movement Disorders Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Kirsty Bannister
- Central Modulation of Pain Lab, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - K Ray Chaudhuri
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence and Department of Neurology and Neurosciences, King's College Hospital NHS Trust, London, United Kingdom
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19
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Thomasi B, Valdetaro L, Ricciardi MC, Gonçalves de Carvalho M, Fialho Tavares I, Tavares-Gomes AL. Enteric glia as a player of gut-brain interactions during Parkinson's disease. Front Neurosci 2023; 17:1281710. [PMID: 38027511 PMCID: PMC10644407 DOI: 10.3389/fnins.2023.1281710] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/10/2023] [Indexed: 12/01/2023] Open
Abstract
The enteric glia has been shown as a potential component of neuroimmune interactions that signal in the gut-brain axis during Parkinson's disease (PD). Enteric glia are a peripheral glial type found in the enteric nervous system (ENS) that, associated with enteric neurons, command various gastrointestinal (GI) functions. They are a unique cell type, with distinct phenotypes and distribution in the gut layers, which establish relevant neuroimmune modulation and regulate neuronal function. Comprehension of enteric glial roles during prodromal and symptomatic phases of PD should be a priority in neurogastroenterology research, as the reactive enteric glial profile, gastrointestinal dysfunction, and colonic inflammation have been verified during the prodromal phase of PD-a moment that may be interesting for interventions. In this review, we explore the mechanisms that should govern enteric glial signaling through the gut-brain axis to understand pathological events and verify the possible windows and pathways for therapeutic intervention. Enteric glia directly modulate several functional aspects of the intestine, such as motility, visceral sensory signaling, and immune polarization, key GI processes found deregulated in patients with PD. The search for glial biomarkers, the investigation of temporal-spatial events involving glial reactivity/signaling, and the proposal of enteric glia-based therapies are clearly demanded for innovative and intestine-related management of PD.
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Affiliation(s)
- Beatriz Thomasi
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Luisa Valdetaro
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, United States
| | - Maria Carolina Ricciardi
- Neuroglial Interaction Lab, Neuroscience Program, Universidade Federal Fluminense, Niterói, Brazil
| | | | - Isabela Fialho Tavares
- Neuroglial Interaction Lab, Neurobiology Department, Universidade Federal Fluminense, Niterói, Brazil
| | - Ana Lucia Tavares-Gomes
- Neuroglial Interaction Lab, Neuroscience Program, Universidade Federal Fluminense, Niterói, Brazil
- Neuroglial Interaction Lab, Neurobiology Department, Universidade Federal Fluminense, Niterói, Brazil
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20
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Nie S, Ge Y. The link between the gut microbiome, inflammation, and Parkinson's disease. Appl Microbiol Biotechnol 2023; 107:6737-6749. [PMID: 37736791 DOI: 10.1007/s00253-023-12789-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 09/04/2023] [Accepted: 09/11/2023] [Indexed: 09/23/2023]
Abstract
As our society ages, the growing number of people with Parkinson's disease (PD) puts tremendous pressure on our society. Currently, there is no effective treatment for PD, so there is an urgent need to find new treatment options. In recent years, increasing studies have shown a strong link between gut microbes and PD. In this review, recent advances in research on gut microbes in PD patients were summarized. Increased potential pro-inflammatory microbes and decreased potential anti-inflammatory microbes are prominent features of gut microbiota in PD patients. These changes may lead to an increase in pro-inflammatory substances (such as lipopolysaccharide and H2S) and a decrease in anti-inflammatory substances (such as short-chain fatty acids) to promote inflammation in the gut. This gut microbiota-mediated inflammation will lead to pathological α-synuclein accumulation in the gut, and the inflammation and α-synuclein can spread to the brain via the microbiota-gut-brain axis, thereby promoting neuroinflammation, apoptosis of dopaminergic neurons, and ultimately the development of PD. This review also showed that therapies based on gut microbiota may have a bright future for PD. However, more research and new approaches are still needed to clarify the causal relationship between gut microbes and PD and to determine whether therapies based on gut microbiota are effective in PD patients. KEY POINTS: • There is a strong association between gut microbes and PD. • Inflammation mediated by gut microbes may promote the development of PD. • Therapies based on the gut microbiome provide a promising strategy for PD prevention.
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Affiliation(s)
- Shiqing Nie
- State Key Laboratory of Urban and Regional Ecology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing, 100085, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuan Ge
- State Key Laboratory of Urban and Regional Ecology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing, 100085, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Craig CF, Finkelstein DI, McQuade RM, Diwakarla S. Understanding the potential causes of gastrointestinal dysfunctions in multiple system atrophy. Neurobiol Dis 2023; 187:106296. [PMID: 37714308 DOI: 10.1016/j.nbd.2023.106296] [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: 08/03/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/17/2023] Open
Abstract
Multiple system atrophy (MSA) is a rare, progressive neurodegenerative disorder characterised by autonomic, pyramidal, parkinsonian and/or cerebellar dysfunction. Autonomic symptoms of MSA include deficits associated with the gastrointestinal (GI) system, such as difficulty swallowing, abdominal pain and bloating, nausea, delayed gastric emptying, and constipation. To date, studies assessing GI dysfunctions in MSA have primarily focused on alterations of the gut microbiome, however growing evidence indicates other structural components of the GI tract, such as the enteric nervous system, the intestinal barrier, GI hormones, and the GI-driven immune response may contribute to MSA-related GI symptoms. Here, we provide an in-depth exploration of the physiological, structural, and immunological changes theorised to underpin GI dysfunction in MSA patients and highlight areas for future research in order to identify more suitable pharmaceutical treatments for GI symptoms in patients with MSA.
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Affiliation(s)
- Colin F Craig
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - David I Finkelstein
- Parkinson's Disease Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
| | - Rachel M McQuade
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC 3021, Australia
| | - Shanti Diwakarla
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC 3021, Australia.
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22
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Cui H, Elford JD, Alitalo O, Perez-Pardo P, Tampio J, Huttunen KM, Kraneveld A, Forsberg MM, Myöhänen TT, Jalkanen AJ. Nigrostriatal 6-hydroxydopamine lesions increase alpha-synuclein levels and permeability in rat colon. Neurobiol Aging 2023; 129:62-71. [PMID: 37271045 DOI: 10.1016/j.neurobiolaging.2023.05.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/25/2023] [Accepted: 05/03/2023] [Indexed: 06/06/2023]
Abstract
Increasing evidence suggests that the gut-brain axis plays a crucial role in Parkinson's disease (PD). The abnormal accumulation of aggregated alpha-synuclein (aSyn) in the brain is a key pathological feature of PD. Intracerebral 6-hydroxydopamine (6-OHDA) is a widely used dopaminergic lesion model of PD. It exerts no aSyn pathology in the brain, but changes in the gut have not been assessed. Here, 6-OHDA was administered unilaterally either to the rat medial forebrain bundle (MFB) or striatum. Increased levels of glial fibrillary acidic protein in the ileum and colon were detected at 5 weeks postlesion. 6-OHDA decreased the Zonula occludens protein 1 barrier integrity score, suggesting increased colonic permeability. The total aSyn and Ser129 phosphorylated aSyn levels were elevated in the colon after the MFB lesion. Both lesions generally increased the total aSyn, pS129 aSyn, and ionized calcium-binding adapter molecule 1 (Iba1) levels in the lesioned striatum. In conclusion, 6-OHDA-induced nigrostriatal dopaminergic damage leads to increased aSyn levels and glial cell activation particularly in the colon, suggesting that the gut-brain axis interactions in PD are bidirectional and the detrimental process may start in the brain.
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Affiliation(s)
- Hengjing Cui
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Joshua D Elford
- Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Helsinki, the Netherlands
| | - Okko Alitalo
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Paula Perez-Pardo
- Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Helsinki, the Netherlands
| | - Janne Tampio
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | | | - Aletta Kraneveld
- Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Helsinki, the Netherlands
| | | | - Timo T Myöhänen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Aaro J Jalkanen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
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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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6-OHDA-Induced Changes in Colonic Segment Contractility in the Rat Model of Parkinson's Disease. Gastroenterol Res Pract 2023; 2023:9090524. [PMID: 36743531 PMCID: PMC9897937 DOI: 10.1155/2023/9090524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 12/20/2022] [Accepted: 01/04/2023] [Indexed: 01/29/2023] Open
Abstract
Background Gastrointestinal dysfunction is one of the most common non-motor symptoms in Parkinson's disease (PD). The exact mechanisms behind these symptoms are not clearly understood. Studies in the well-established 6-hydroxydopamine (6-OHDA) lesioned rats of PD have shown altered contractility in isolated circular and longitudinal smooth muscle strips of distal colon. Contractile changes in proximal colon and distal ileum are nevertheless poorly studied. Moreover, segments may serve as better tissue preparations to understand the interplay between circular and longitudinal smooth muscle. This study aimed to compare changes in contractility between isolated full-thickness distal colon muscle strips and segments, and extend the investigation to proximal colon and distal ileum in the 6-OHDA rat model. Methods Spontaneous contractions and contractions induced by electrical field stimulation (EFS) and by the non-selective muscarinic agonist methacholine were investigated in strip and/or segment preparations of smooth muscle tissue from distal and proximal colon and distal ileum in an in vitro organ bath comparing 6-OHDA-lesioned rats with Sham-operated animals. Key Results. Our data showed increased contractility evoked by EFS and methacholine in segments, but not in circular and longitudinal tissue strips of distal colon after central 6-OHDA-induced dopamine denervation. Changes in proximal colon segments were also displayed in high K+ Krebs-induced contractility and spontaneous contractions. Conclusions This study further confirms changes in smooth muscle contractility in distal colon and to some extent in proximal colon, but not in distal ileum in the 6-OHDA rat model of PD. However, the changes depended on tissue preparation.
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Guo Y, Song L, Huang Y, Li X, Xiao Y, Wang Z, Ren Z. Latilactobacillus sakei Furu2019 and stachyose as probiotics, prebiotics, and synbiotics alleviate constipation in mice. Front Nutr 2023; 9:1039403. [PMID: 36687730 PMCID: PMC9849682 DOI: 10.3389/fnut.2022.1039403] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 11/17/2022] [Indexed: 01/06/2023] Open
Abstract
Introduction Slow transit constipation (STC) is a common disorder in the digestive system. This study aimed to evaluate the effects of stachyose (ST) and Latilactobacillus sakei Furu 2019 (L. sakei) alone or combined on diphenoxylate-induced constipation and explore the underlying mechanisms using a mouse model. Methods ICR mice were randomly divided into five groups. The normal and constipation model groups were intragastrically administrated with PBS. The ST, L. sakei, and synbiotic groups were intragastrically administrated with ST (1.5 g/kg body weight), alive L. sakei (3 × 109 CFU/mouse), or ST + L. sakei (1.5 g/kg plus 3 × 109 CFU/mouse), respectively. After 21 days of intervention, all mice except the normal mice were intragastrically administrated with diphenoxylate (10 mg/kg body weight). Defecation indexes, constipation-related intestinal factors, serum neurotransmitters, hormone levels, short-chain fatty acids (SCFAs), and intestinal microbiota were measured. Results Our results showed that three interventions with ST, L. sakei, and synbiotic combination (ST + L. sakei) all alleviated constipation, and synbiotic intervention was superior to ST or L. sakei alone in some defecation indicators. The RT-PCR and immunohistochemical experiment showed that all three interventions relieved constipation by affecting aquaporins (AQP4 and AQP8), interstitial cells of Cajal (SCF and c-Kit), glial cell-derived neurotrophic factor (GDNF), and Nitric Oxide Synthase (NOS). The three interventions exhibited a different ability to increase the serum excitatory neurotransmitters and hormones (5-hydroxytryptamine, substance P, motilin), and reduce the serum inhibitory neurotransmitters (vasoactive intestinal peptide, endothelin). The result of 16S rDNA sequencing of feces showed that synbiotic intervention significantly increased the relative abundance of beneficial bacteria such as Akkermansia, and regulated the gut microbes of STC mice. In conclusion, oral administration of ST or L. sakei alone or combined are all effective to relieve constipation and the symbiotic use may have a promising preventive effect on STC.
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Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ. Dopamine, Immunity, and Disease. Pharmacol Rev 2023; 75:62-158. [PMID: 36757901 PMCID: PMC9832385 DOI: 10.1124/pharmrev.122.000618] [Citation(s) in RCA: 103] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022] Open
Abstract
The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson's disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. SIGNIFICANCE STATEMENT: Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.
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Affiliation(s)
- Breana Channer
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Stephanie M Matt
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Emily A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Vasiliki Pappa
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Yash Agarwal
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Jason Wickman
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Peter J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
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Salim S, Ahmad F, Banu A, Mohammad F. Gut microbiome and Parkinson's disease: Perspective on pathogenesis and treatment. J Adv Res 2022:S2090-1232(22)00242-9. [PMID: 36332796 PMCID: PMC10403695 DOI: 10.1016/j.jare.2022.10.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/26/2022] [Accepted: 10/26/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain. AIM of Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved inneuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further exploredin humans through clinical trials. Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.
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Silva DF, Empadinhas N, Cardoso SM, Esteves AR. Neurodegenerative Microbially-Shaped Diseases: Oxidative Stress Meets Neuroinflammation. Antioxidants (Basel) 2022; 11:2141. [PMID: 36358513 PMCID: PMC9686748 DOI: 10.3390/antiox11112141] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/25/2022] [Accepted: 10/27/2022] [Indexed: 04/18/2025] Open
Abstract
Inflammation and oxidative stress characterize a number of chronic conditions including neurodegenerative diseases and aging. Inflammation is a key component of the innate immune response in Alzheimer's disease and Parkinson's disease of which oxidative stress is an important hallmark. Immune dysregulation and mitochondrial dysfunction with concomitant reactive oxygen species accumulation have also been implicated in both diseases, both systemically and within the Central Nervous System. Mitochondria are a centrally positioned signalling hub for inflammatory responses and inflammatory cells can release reactive species at the site of inflammation often leading to exaggerated oxidative stress. A growing body of evidence suggests that disruption of normal gut microbiota composition may induce increased permeability of the gut barrier leading to chronic systemic inflammation, which may, in turn, impair the blood-brain barrier function and promote neuroinflammation and neurodegeneration. The gastrointestinal tract is constantly exposed to myriad exogenous substances and microbial pathogens, which are abundant sources of reactive oxygen species, oxidative damage and pro-inflammatory events. Several studies have demonstrated that microbial infections may also affect the balance in gut microbiota composition (involving oxidant and inflammatory processes by the host and indigenous microbiota) and influence downstream Alzheimer's disease and Parkinson's disease pathogenesis, in which blood-brain barrier damage ultimately occurs. Therefore, the oxidant/inflammatory insults triggered by a disrupted gut microbiota and chronic dysbiosis often lead to compromised gut barrier function, allowing inflammation to "escape" as well as uncontrolled immune responses that may ultimately disrupt mitochondrial function upwards the brain. Future therapeutic strategies should be designed to "restrain" gut inflammation, a goal that could ideally be attained by microbiota modulation strategies, in alternative to classic anti-inflammatory agents with unpredictable effects on the microbiota architecture itself.
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Affiliation(s)
- Diana Filipa Silva
- CNC—Center for Neuroscience and Cell Biology and CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Nuno Empadinhas
- CNC—Center for Neuroscience and Cell Biology and CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Sandra Morais Cardoso
- CNC—Center for Neuroscience and Cell Biology and CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Ana Raquel Esteves
- CNC—Center for Neuroscience and Cell Biology and CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
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Cui G, Li S, Ye H, Yang Y, Huang Q, Chu Y, Shi Z, Zhang X. Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study. Front Immunol 2022; 13:956005. [PMID: 36159838 PMCID: PMC9493012 DOI: 10.3389/fimmu.2022.956005] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundSeveral studies have shown that neurodegenerative diseases (e.g., Parkinson’s disease [PD] and Alzheimer’s disease [AD]) are associated with inflammatory bowel disease (IBD), but the causality and direction of their associations remain unclear. Mendelian randomization (MR) studies have explored the causal effects of IBD on PD and AD. However, only a few studies examined this reverse association. Thus, this study aimed to explore whether there are causal associations of genetically predicted PD and AD with IBD, using a two-sample MR study.MethodsSummary statistics for IBD, ulcerative colitis (UC), and Crohn’s disease (CD) were derived from a genome-wide association study (GWAS) meta-analysis, which included the International IBD Genetics Consortium and the UK IBD Genetics Consortium (n=59,957). Genetic variants associated with the largest meta-analysis of GWAS of PD (n=1,474,097) and AD (n=455,258) were used as instrumental variables. We used multiple methods, including inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, weighted mode, and Robust Adjusted Profile Score (RAPS) methods, to estimate the effects of genetically predicted PD and AD on IBD. To confirm the validity of the analysis, we also evaluated the pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis that drive causal associations.ResultsThe results of the IVW method, WM, and RAPS showed that genetically predicted PD was significantly associated with an increased risk of UC (odds ratio [OR]IVW=1.068, ORWM=1.107, ORRAPS=1.069, all P<0.05). Additionally, we found that there were significant associations of genetically predicted PD with CD (ORIVW=1.064, ORRAPS=1.065, all P<0.05) and IBD (ORIVW=1.062, ORRAPS=1.063, all P<0.05) using the IVW method and RAPS. However, there was no significant causal evidence of genetically predicted AD in IBD, UC, or CD among all MR methods. In all MR analyses, there were no horizontal pleiotropy (all P>0.05), or statistical heterogeneity. The sensitivity analysis results of the leave-one-out sensitivity analysis showed that the causal effect estimations of genetically predicted PD and AD on IBD were robust.ConclusionsOur MR study corroborated a causal association between genetically predicted PD and IBD but did not support a causal effect of genetically predicted AD on IBD. More animal experiments or population-based observational studies are required to clarify the underlying mechanisms of PD and IBD.
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Affiliation(s)
- Guanghui Cui
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital; Institute of Integrated Traditional Chinese and Western Medicine, Peking University, Beijing, China
| | - Shaojie Li
- School of Public Health, Peking University, Beijing, China
| | - Hui Ye
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital; Institute of Integrated Traditional Chinese and Western Medicine, Peking University, Beijing, China
| | - Yao Yang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital; Institute of Integrated Traditional Chinese and Western Medicine, Peking University, Beijing, China
| | - Qiuyue Huang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital; Institute of Integrated Traditional Chinese and Western Medicine, Peking University, Beijing, China
| | - Yingming Chu
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital; Institute of Integrated Traditional Chinese and Western Medicine, Peking University, Beijing, China
| | - Zongming Shi
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital; Institute of Integrated Traditional Chinese and Western Medicine, Peking University, Beijing, China
| | - Xuezhi Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital; Institute of Integrated Traditional Chinese and Western Medicine, Peking University, Beijing, China
- *Correspondence: Xuezhi Zhang,
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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: 172] [Impact Index Per Article: 57.3] [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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The Gut Microbiome-Brain Crosstalk in Neurodegenerative Diseases. Biomedicines 2022; 10:biomedicines10071486. [PMID: 35884791 PMCID: PMC9312830 DOI: 10.3390/biomedicines10071486] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 02/06/2023] Open
Abstract
The gut–brain axis (GBA) is a complex interactive network linking the gut to the brain. It involves the bidirectional communication between the gastrointestinal and the central nervous system, mediated by endocrinological, immunological, and neural signals. Perturbations of the GBA have been reported in many neurodegenerative diseases, suggesting a possible role in disease pathogenesis, making it a potential therapeutic target. The gut microbiome is a pivotal component of the GBA, and alterations in its composition have been linked to GBA dysfunction and CNS inflammation and degeneration. The gut microbiome might influence the homeostasis of the central nervous system homeostasis through the modulation of the immune system and, more directly, the production of molecules and metabolites. Small clinical and preclinical trials, in which microbial composition was manipulated using dietary changes, fecal microbiome transplantation, and probiotic supplements, have provided promising outcomes. However, results are not always consistent, and large-scale randomized control trials are lacking. Here, we give an overview of how the gut microbiome influences the GBA and could contribute to disease pathogenesis in neurodegenerative diseases.
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Thomasi BBDM, Valdetaro L, Ricciardi MCG, Hayashide L, Fernandes ACMN, Mussauer A, da Silva ML, da Cunha Faria-Melibeu A, Ribeiro MGL, de Mattos Coelho-Aguiar J, Campello-Costa P, Moura-Neto V, Tavares-Gomes AL. Enteric glial cell reactivity in colonic layers and mucosal modulation in a mouse model of Parkinson’s disease induced by 6-hydroxydopamine. Brain Res Bull 2022; 187:111-121. [DOI: 10.1016/j.brainresbull.2022.06.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 05/20/2022] [Accepted: 06/25/2022] [Indexed: 11/02/2022]
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Cerantola S, Faggin S, Caputi V, Bosi A, Banfi D, Rambaldo A, Porzionato A, Di Liddo R, De Caro R, Savarino EV, Giaroni C, Giron MC. Small intestine neuromuscular dysfunction in a mouse model of dextran sulfate sodium-induced ileitis: Involvement of dopaminergic neurotransmission. Life Sci 2022; 301:120562. [PMID: 35487304 DOI: 10.1016/j.lfs.2022.120562] [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: 02/09/2022] [Revised: 04/06/2022] [Accepted: 04/13/2022] [Indexed: 11/28/2022]
Abstract
AIMS Anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and preclinical models of IBD. Thus, we aimed to evaluate the impact of dextran sodium sulfate (DSS)-induced ileitis on enteric dopaminergic pathways. MATERIALS AND METHODS Male C57/Bl6 mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and were then switched to regular drinking water for 3 days. To measure ileitis severity inflammatory cytokines (IL-1β, TNFα, IL-6) levels were assessed. Changes in ileal muscle tension were isometrically recorded following: 1) cumulative addition of dopamine on basal tone (0.1-1000 μM); ii) 4-Hz electric field stimulation (EFS) in the presence of 30 μM dopamine with/without 10 μM SCH-23390 (dopamine D1 receptor (D1R) antagonist) or 10 μM sulpiride (D2R antagonist). Immunofluorescence distribution of the neuronal HuC/D protein, glial S100β marker, D1R, and dopamine transporter (DAT) were determined in longitudinal-muscle-myenteric plexus whole-mounts (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR. KEY FINDINGS DSS caused an inflammatory process in the small intestine associated to dysmotility and altered barrier permeability, as suggested by decreased fecal output and enhanced stool water content. DSS treatment caused a significant increase of DAT and D1R myenteric immunoreactivity as well as of D1R and D2R mRNA levels, accompanied by a significant reduction of dopamine-mediated relaxation, involving primarily D1-like receptors. SIGNIFICANCE Mouse ileitis affects enteric dopaminergic neurotransmission mainly involving D1R-mediated responses. These findings provide novel information on the participation of dopaminergic pathways in IBD-mediated neuromuscular dysfunction.
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Affiliation(s)
- Silvia Cerantola
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Sofia Faggin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Valentina Caputi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy; Department of Poultry Science, University of Arkansas, Fayetteville, AR 72704, USA
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Anna Rambaldo
- Department of Neuroscience, University of Padova, Padova, Italy
| | | | - Rosa Di Liddo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | | | - Edoardo V Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy; IRCCS San Camillo Hospital, 30126 Venice, Italy.
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Van Den Berge N, Ulusoy A. Animal models of brain-first and body-first Parkinson's disease. Neurobiol Dis 2022; 163:105599. [DOI: 10.1016/j.nbd.2021.105599] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/14/2021] [Accepted: 12/20/2021] [Indexed: 12/15/2022] Open
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Kurnik-Łucka M, Pasieka P, Łączak P, Wojnarski M, Jurczyk M, Gil K. Gastrointestinal Dopamine in Inflammatory Bowel Diseases: A Systematic Review. Int J Mol Sci 2021; 22:12932. [PMID: 34884737 PMCID: PMC8657776 DOI: 10.3390/ijms222312932] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND an increased prevalence of gastro-duodenal ulceration was described almost sixty years ago as prodromal to idiopathic Parkinson's disease, while duodenal ulcers have been rarely diagnosed in patients with schizophrenia. The cytoprotective role of dopamine in animal models of gastrointestinal ulcerations has also been described. Interestingly, Parkinson's disease (PD) might share common pathophysiological links with inflammatory bowel disease (IBD) as epidemiological and genetic links already suggest. Thus, the aim of our study was to review the existing literature on the role of the gastrointestinal dopaminergic system in IBD pathogenesis and progression. METHODS a systematic search was conducted according to the PRISMA methodology. RESULTS twenty-four studies satisfied the predetermined criteria and were included in our qualitative analysis. Due to different observations (cross-sectional studies) as well as experimental setups and applied methodologies (in vivo and in vitro studies) a meta-analysis could not be performed. No ongoing clinical trials with dopaminergic compounds in IBD patients were found. CONCLUSIONS the impairment of the dopaminergic system seems to be a significant, yet underestimated, feature of IBD, and more in-depth observational studies are needed to further support the existing preclinical data.
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Affiliation(s)
- Magdalena Kurnik-Łucka
- Department of Pathophysiology, Faculty of Medicine, Jagiellonian University Medical College, 31-121 Krakow, Poland; (P.P.); (P.Ł.); (M.W.); (M.J.); (K.G.)
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Pellegrini C, D'Antongiovanni V, Ippolito C, Segnani C, Antonioli L, Fornai M, Bernardini N. From the intestinal mucosal barrier to the enteric neuromuscular compartment: an integrated overview on the morphological changes in Parkinson's disease. Eur J Histochem 2021; 65. [PMID: 34802221 PMCID: PMC8636839 DOI: 10.4081/ejh.2021.3278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 10/20/2021] [Indexed: 11/22/2022] Open
Abstract
Gastrointestinal dysfunctions represent the most common non-motor symptoms in Parkinson’s disease (PD). Of note, changes in gut microbiota, impairments of intestinal epithelial barrier (IEB), bowel inflammation and neuroplastic rearrangements of the enteric nervous system (ENS) could be involved in the pathophysiology of the intestinal disturbances in PD. In this context, although several review articles have pooled together evidence on the alterations of enteric bacteria-neuro-immune network in PD, a revision of the literature on the specific morphological changes occurring in the intestinal mucosal barrier, the ENS and enteric muscular layers in PD, is lacking. The present review provides a complete appraisal of the available knowledge on the morphological alterations of intestinal mucosal barrier, with particular focus on IEB, ENS and enteric muscular layers in PD. In particular, our intent was to critically discuss whether, based on evidence from translational studies and preclinical models, morphological changes in the intestinal barrier and enteric neuromuscular compartment contribute to the pathophysiology of intestinal dysfunctions occurring in PD.
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Affiliation(s)
- Carolina Pellegrini
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa.
| | - Vanessa D'Antongiovanni
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa.
| | - Chiara Ippolito
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa.
| | - Cristina Segnani
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa.
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa.
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa.
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, Unit of Histology; Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa.
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D'Antongiovanni V, Pellegrini C, Antonioli L, Benvenuti L, Di Salvo C, Flori L, Piccarducci R, Daniele S, Martelli A, Calderone V, Martini C, Fornai M. Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer's Disease. Front Pharmacol 2021; 12:748021. [PMID: 34658885 PMCID: PMC8511319 DOI: 10.3389/fphar.2021.748021] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/20/2021] [Indexed: 12/20/2022] Open
Abstract
Palmitoylethanolamide (PEA), an endogenous lipid mediator, is emerging as a promising pharmacological agent in multiple neurodegenerative disorders for its anti-inflammatory and neuroprotective properties. However, its effects on enteric inflammation and colonic dysmotility associated with Alzheimer’s disease (AD) are lacking. This study was designed to investigate the beneficial effect of PEA administration in counteracting the enteric inflammation and relieving the bowel motor dysfunctions in an AD mouse model, SAMP8 mice. In addition, the ability of PEA in modulating the activation of enteric glial cells (EGCs), pivotally involved in the pathophysiology of bowel dysfunctions associated with inflammatory conditions, has also been examined. SAMP8 mice at 4 months of age were treated orally with PEA (5 mg/kg/day) for 2 months. SAMR1 animals were employed as controls. At the end of treatment, parameters dealing with colonic motility, inflammation, barrier integrity and AD protein accumulation were evaluated. The effect of PEA on EGCs was tested in cultured cells treated with lipopolysaccharide (LPS) plus β-amyloid 1–42 (Aβ). SAMP8 treated with PEA displayed: 1) an improvement of in vitro colonic motor activity, citrate synthase activity and intestinal epithelial barrier integrity and 2) a decrease in colonic Aβ and α-synuclein (α-syn) accumulation, S100-β expression as well as enteric IL-1β and circulating LPS levels, as compared with untreated SAMP8 mice. In EGCs, treatment with PEA counteracted the increment of S100-β, TLR-4, NF-κB p65 and IL-1β release induced by LPS and Aβ. These results suggest that PEA, under a condition of cognitive decline, prevents the enteric glial hyperactivation, reduces AD protein accumulation and counteracts the onset and progression of colonic inflammatory condition, as well as relieves intestinal motor dysfunctions and improves the intestinal epithelial barrier integrity. Therefore, PEA represents a viable approach for the management of the enteric inflammation and motor contractile abnormalities associated with AD.
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Affiliation(s)
| | - Carolina Pellegrini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Laura Benvenuti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Clelia Di Salvo
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Lorenzo Flori
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | | | | | - Alma Martelli
- Department of Pharmacy, University of Pisa, Pisa, Italy.,Interdepartmental Research Center "Nutrafood: Nutraceutica e Alimentazione per la Salute", University of Pisa, Pisa, Italy.,Interdepartmental Research Center "Biology and Pathology of Ageing", University of Pisa, Pisa, Italy
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Pisa, Italy.,Interdepartmental Research Center "Nutrafood: Nutraceutica e Alimentazione per la Salute", University of Pisa, Pisa, Italy.,Interdepartmental Research Center "Biology and Pathology of Ageing", University of Pisa, Pisa, Italy
| | | | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Tirassa P, Schirinzi T, Raspa M, Ralli M, Greco A, Polimeni A, Possenti R, Mercuri NB, Severini C. What substance P might tell us about the prognosis and mechanism of Parkinson's disease? Neurosci Biobehav Rev 2021; 131:899-911. [PMID: 34653503 DOI: 10.1016/j.neubiorev.2021.10.008] [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: 06/22/2021] [Accepted: 10/05/2021] [Indexed: 10/20/2022]
Abstract
The neuropeptide substance P (SP) plays an important role in neurodegenerative disorders, among which Parkinson's disease (PD). In the present work we have reviewed the involvement of SP and its preferred receptor (NK1-R) in motor and non-motor PD symptoms, in both PD animal models and patients. Despite PD is primarily a motor disorder, non-motor abnormalities, including olfactory deficits and gastrointestinal dysfunctions, can represent diagnostic PD predictors, according to the hypothesis that the olfactory and the enteric nervous system represent starting points of neurodegeneration, ascending to the brain via the sympathetic fibers and the vagus nerve. In PD patients, the α-synuclein aggregates in the olfactory bulb and the gastrointestinal tract, as well as in the dorsal motor nucleus of the vagus nerve often co-localize with SP, indicating SP-positive neurons as highly vulnerable sites of degeneration. Considering the involvement of the SP/NK1-R in both the periphery and specific brain areas, this system might represent a neuronal substrate for the symptom and disease progression, as well as a therapeutic target for PD.
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Affiliation(s)
- Paola Tirassa
- Institute of Biochemistry and Cell Biology, National Research Council, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy.
| | - Tommaso Schirinzi
- Department of Systems Medicine, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy
| | - Marcello Raspa
- Institute of Biochemistry and Cell Biology, National Research Council, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Massimo Ralli
- Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Antonio Greco
- Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Antonella Polimeni
- Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Roberta Possenti
- Department of Systems Medicine, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy
| | - Nicola Biagio Mercuri
- Department of Systems Medicine, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy
| | - Cinzia Severini
- Institute of Biochemistry and Cell Biology, National Research Council, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy.
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Drobny A, Ngo PA, Neurath MF, Zunke F, López-Posadas R. Molecular Communication Between Neuronal Networks and Intestinal Epithelial Cells in Gut Inflammation and Parkinson's Disease. Front Med (Lausanne) 2021; 8:655123. [PMID: 34368179 PMCID: PMC8339315 DOI: 10.3389/fmed.2021.655123] [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: 01/18/2021] [Accepted: 06/14/2021] [Indexed: 12/18/2022] Open
Abstract
Intestinal symptoms, such as nausea, vomiting, and constipation, are common in Parkinson's disease patients. These clinical signs normally appear years before the diagnosis of the neurodegenerative disease, preceding the occurrence of motor manifestations. Moreover, it is postulated that Parkinson's disease might originate in the gut, due to a response against the intestinal microbiota leading to alterations in alpha-synuclein in the intestinal autonomic nervous system. Transmission of this protein to the central nervous system is mediated potentially via the vagus nerve. Thus, deposition of aggregated alpha-synuclein in the gastrointestinal tract has been suggested as a potential prodromal diagnostic marker for Parkinson's disease. Interestingly, hallmarks of chronic intestinal inflammation in inflammatory bowel disease, such as dysbiosis and increased intestinal permeability, are also observed in Parkinson's disease patients. Additionally, alpha-synuclein accumulations were detected in the gut of Crohn's disease patients. Despite a solid association between neurodegenerative diseases and gut inflammation, it is not clear whether intestinal alterations represent cause or consequence of neuroinflammation in the central nervous system. In this review, we summarize the bidirectional communication between the brain and the gut in the context of Parkinson's disease and intestinal dysfunction/inflammation as present in inflammatory bowel disease. Further, we focus on the contribution of intestinal epithelium, the communication between intestinal epithelial cells, microbiota, immune and neuronal cells, as well as mechanisms causing alterations of epithelial integrity.
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Affiliation(s)
- Alice Drobny
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Phuong A Ngo
- Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Markus F Neurath
- Medicine 1, University Hospital Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Friederike Zunke
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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Pellegrini C, Fornai M, Benvenuti L, Colucci R, Caputi V, Palazon-Riquelme P, Giron MC, Nericcio A, Garelli F, D'Antongiovanni V, Segnani C, Ippolito C, Nannipieri M, Lopez-Castejon G, Pelegrin P, Haskó G, Bernardini N, Blandizzi C, Antonioli L. NLRP3 at the crossroads between immune/inflammatory responses and enteric neuroplastic remodelling in a mouse model of diet-induced obesity. Br J Pharmacol 2021; 178:3924-3942. [PMID: 34000757 DOI: 10.1111/bph.15532] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Enteric neurogenic/inflammation contributes to bowel dysmotility in obesity. We examined the role of NLRP3 in colonic neuromuscular dysfunctions in mice with high-fat diet (HFD)-induced obesity. EXPERIMENTAL APPROACH Wild-type C57BL/6J and NLRP3-KO (Nlrp3-/- ) mice were fed with HFD or standard diet for 8 weeks. The activation of inflammasome pathways in colonic tissues from obese mice was assessed. The role of NLRP3 in in vivo colonic transit and in vitro tachykininergic contractions and substance P distribution was evaluated. The effect of substance P on NLRP3 signalling was tested in cultured cells. KEY RESULTS HFD mice displayed increased body and epididymal fat weight, cholesterol levels, plasma resistin levels and plasma and colonic IL-1β levels, colonic inflammasome adaptor protein apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) and caspase-1 mRNA expression and ASC immunopositivity in macrophages. Colonic tachykininergic contractions were enhanced in HFD mice. HFD NLRP3-/- mice developed lower increase in body and epididymal fat weight, cholesterol levels, systemic and bowel inflammation. In HFD Nlrp3-/- mice, the functional alterations of tachykinergic pathways and faecal output were normalized. In THP-1 cells, substance P promoted IL-1β release. This effect was inhibited upon incubation with caspase-1 inhibitor or NK1 antagonist and not observed in ASC-/- cells. CONCLUSION AND IMPLICATIONS In obesity, NLRP3 regulates an interplay between the shaping of enteric immune/inflammatory responses and the activation of substance P/NK1 pathways underlying the onset of colonic dysmotility. Identifying NLRP3 as a therapeutic target for the treatment of bowel symptoms related to obesity.
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Affiliation(s)
- Carolina Pellegrini
- Department of Pharmacy, University of Pisa, Pisa, Italy.,Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Laura Benvenuti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
| | - Valentina Caputi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy.,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Pablo Palazon-Riquelme
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
| | - Anna Nericcio
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
| | - Francesca Garelli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy
| | | | - Cristina Segnani
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Ippolito
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Monica Nannipieri
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gloria Lopez-Castejon
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Pablo Pelegrin
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, New York, USA
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Cerantola S, Caputi V, Contarini G, Mereu M, Bertazzo A, Bosi A, Banfi D, Mantini D, Giaroni C, Giron MC. Dopamine Transporter Genetic Reduction Induces Morpho-Functional Changes in the Enteric Nervous System. Biomedicines 2021; 9:biomedicines9050465. [PMID: 33923250 PMCID: PMC8146213 DOI: 10.3390/biomedicines9050465] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 12/23/2022] Open
Abstract
Antidopaminergic gastrointestinal prokinetics are indeed commonly used to treat gastrointestinal motility disorders, although the precise role of dopaminergic transmission in the gut is still unclear. Since dopamine transporter (DAT) is involved in several brain disorders by modulating extracellular dopamine in the central nervous system, this study evaluated the impact of DAT genetic reduction on the morpho-functional integrity of mouse small intestine enteric nervous system (ENS). In DAT heterozygous (DAT+/-) and wild-type (DAT+/+) mice (14 ± 2 weeks) alterations in small intestinal contractility were evaluated by isometrical assessment of neuromuscular responses to receptor and non-receptor-mediated stimuli. Changes in ENS integrity were studied by real-time PCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations (). DAT genetic reduction resulted in a significant increase in dopamine-mediated effects, primarily via D1 receptor activation, as well as in reduced cholinergic response, sustained by tachykininergic and glutamatergic neurotransmission via NMDA receptors. These functional anomalies were associated to architectural changes in the neurochemical coding and S100β immunoreactivity in small intestine myenteric plexus. Our study provides evidence that genetic-driven DAT defective activity determines anomalies in ENS architecture and neurochemical coding together with ileal dysmotility, highlighting the involvement of dopaminergic system in gut disorders, often associated to neurological conditions.
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Affiliation(s)
- Silvia Cerantola
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
| | - Valentina Caputi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
- Department of Poultry Science, University of Arkansas, Fayetteville, AR 72704, USA
| | - Gabriella Contarini
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95131 Catania, Italy;
| | - Maddalena Mereu
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
| | - Antonella Bertazzo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (C.G.)
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (C.G.)
| | - Dante Mantini
- IRCCS San Camillo Hospital, 30126 Venice, Italy; or
- Motor Control and Neuroplasticity Research Group, KU Leuven, 3000 Leuven, Belgium
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (A.B.); (D.B.); (C.G.)
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (S.C.); (V.C.); (M.M.); (A.B.)
- IRCCS San Camillo Hospital, 30126 Venice, Italy; or
- Correspondence: ; Tel.: +39-049-827-5091; Fax: +39-049-827-5093
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Gastrointestinal dysfunction in Parkinson's disease: molecular pathology and implications of gut microbiome, probiotics, and fecal microbiota transplantation. J Neurol 2021; 269:1154-1163. [PMID: 33881598 DOI: 10.1007/s00415-021-10567-w] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 12/23/2022]
Abstract
Gastrointestinal symptoms and gut dysbiosis may occur before the onset of motor symptoms in Parkinson's disease (PD). Prediagnostic and prodromal features, such as constipation and α-synuclein pathology, can be detected several years before the clinical diagnosis of PD and have the potential to develop as early PD biomarkers. Environmental toxins and gut dysbiosis may trigger oxidative stress and mucosal inflammation, and initiate α-synuclein accumulation in the enteric nervous system, early in PD. Chronic gut inflammation can lead to a leaky gut and systemic inflammation, neuro inflammation, and neuro degeneration via gut-vagus-brain signaling or through blood-brain barrier permeability. Concepts regarding the gut-brain signaling in PD pathogenesis are changing rapidly and more investigation is required. The gut microbiota interacts with the human body by modulating the enteric and central nervous systems, and immune activity. Understanding the immune responses between gut microbiota and human body might help in elucidating the PD pathogenesis. As changes in gut microbiota composition might be associated with different clinical phenotypes of PD, gut microbiota-modulating interventions, such as probiotics and fecal microbiota transplantation (FMT), have the potential to restore the gut dysbiosis, reduce inflammation, and possibly modulate the clinical PD phenotype.
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44
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Wang Q, Luo Y, Chaudhuri KR, Reynolds R, Tan EK, Pettersson S. The role of gut dysbiosis in Parkinson's disease: mechanistic insights andtherapeutic options. Brain 2021; 144:2571-2593. [PMID: 33856024 DOI: 10.1093/brain/awab156] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/23/2021] [Accepted: 03/23/2021] [Indexed: 12/02/2022] Open
Abstract
Parkinson's disease is a common neurodegenerative disease in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alteration in gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the central nervous system, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries and alterations of the gut microbiota in Parkinson's disease, and highlight current mechanistic insights on the microbiota-gut-brain axis in disease pathophysiology. We discuss the interactions between production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we also draw attention to diet modification, use of probiotics and prebiotics and fecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease.
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Affiliation(s)
- Qing Wang
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - Yuqi Luo
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - K Ray Chaudhuri
- Parkinson Foundation International Centre of Excellence at King's College Hospital, and Kings College, Denmark Hill, London, SE5 9RS, UK
| | - Richard Reynolds
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK.,Centre for Molecular Neuropathology, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232
| | - Eng-King Tan
- Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore.,Duke-NUS Medical School, Singapore
| | - Sven Pettersson
- Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore.,Duke-NUS Medical School, Singapore.,LKC School of Medicine, NTU, Singapore.,Sunway University, Department of Medical Sciences, Kuala Lumpur, Malaysia
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Kakoty V, K C S, Dubey SK, Yang CH, Kesharwani P, Taliyan R. The gut-brain connection in the pathogenicity of Parkinson disease: Putative role of autophagy. Neurosci Lett 2021; 753:135865. [PMID: 33812929 DOI: 10.1016/j.neulet.2021.135865] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/13/2021] [Accepted: 03/25/2021] [Indexed: 01/09/2023]
Abstract
Parkinson disease (PD) is a progressive movement functionality disorder resulting in tremor and inability to execute voluntary functions combined with the preponderant non-motor disturbances encompassing constipation and gastrointestinal irritation. Despite continued research, the pathogenesis of PD is not yet clear. The available class of drugs for effective symptomatic management of PD includes a combination of levodopa and carbidopa. In recent past, the link between gut with PD has been explored. According to recent preclinical evidence, pathogens such as virus or bacterium may initiate entry into the gut via the nasal cavity that may aggravate lewy pathology in the gut that eventually propagates and progresses towards the brain via the vagus nerve resulting in the prodromal non-motor symptoms. Additionally, experimental evidence also suggests that alpha-synuclein misfolding commences at a very early stage in the gut and is transported via the vagus nerve prior to seeding PD pathology in the brain. However, this progression and resultant deterioration of the neurones can effectively be altered by an autophagy inducer, Trehalose, although the mechanism behind it is still enigmatic. Hence, this review will mainly focus on analysing the basic components of the gut that might be responsible for aggravating lewy pathology, the mediator(s) responsible for transmission of PD pathology from gut to brain and the important role of trehalose in ameliorating gut dysbiosis related PD complications that would eventually pave the way for therapeutic management of PD.
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Affiliation(s)
- Violina Kakoty
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India
| | - Sarathlal K C
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India
| | - Sunil Kumar Dubey
- R&D Healthcare Division, Emami Ltd, Kolkatta, India; Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, 333031, India
| | - Chih Hao Yang
- Department of Pharmacology, Taipei Medical University, Taiwan
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Rajeev Taliyan
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, India.
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Lee HS, Lobbestael E, Vermeire S, Sabino J, Cleynen I. Inflammatory bowel disease and Parkinson's disease: common pathophysiological links. Gut 2021; 70:408-417. [PMID: 33067333 DOI: 10.1136/gutjnl-2020-322429] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/19/2020] [Accepted: 08/28/2020] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease and Parkinson's disease are chronic progressive disorders that mainly affect different organs: the gut and brain, respectively. Accumulating evidence has suggested a bidirectional link between gastrointestinal inflammation and neurodegeneration, in accordance with the concept of the 'gut-brain axis'. Moreover, recent population-based studies have shown that inflammatory bowel disease might increase the risk of Parkinson's disease. Although the precise mechanisms underlying gut-brain interactions remain elusive, some of the latest findings have begun to explain the link. Several genetic loci are shared between both disorders with a similar direction of effect on the risk of both diseases. The most interesting example is LRRK2 (leucine-rich repeat kinase 2), initially identified as a causal gene in Parkinson's disease, and recently also implicated in Crohn's disease. In this review, we highlight recent findings on the link between these seemingly unrelated diseases with shared genetic susceptibility. We discuss supporting and conflicting data obtained from epidemiological and genetic studies along with remaining questions and concerns. In addition, we discuss possible biological links including the gut-brain axis, microbiota, autoimmunity, mitochondrial function and autophagy.
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Affiliation(s)
- Ho-Su Lee
- Department of Human Genetics, KU Leuven, Leuven, Belgium.,Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Evy Lobbestael
- Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Chronic diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - João Sabino
- Department of Chronic diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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Feng XY, Xue H, Guo ZH, Yan JT, Liu S, Zhu JX. Dopamine and Gastrointestinal Mucosa Function. DOPAMINE IN THE GUT 2021:87-131. [DOI: 10.1007/978-981-33-6586-5_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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48
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Enteric Glia at the Crossroads between Intestinal Immune System and Epithelial Barrier: Implications for Parkinson Disease. Int J Mol Sci 2020; 21:ijms21239199. [PMID: 33276665 PMCID: PMC7730281 DOI: 10.3390/ijms21239199] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 11/30/2020] [Accepted: 11/30/2020] [Indexed: 12/15/2022] Open
Abstract
Over recent years, several investigations have suggested that Parkinson’s disease (PD) can be regarded as the consequence of a bowel disorder. Indeed, gastrointestinal symptoms can occur at all stages of this neurodegenerative disease and in up to a third of cases, their onset can precede the involvement of the central nervous system. Recent data suggest that enteric glial cells (EGCs) may play a major role in PD-related gastrointestinal disturbances, as well as in the development and progression of the central disease. In addition to their trophic and structural functions, EGCs are crucial for the homeostatic control of a wide range of gastrointestinal activities. The main purpose of this review was to provide a detailed overview of the role of EGCs in intestinal PD-associated alterations, with particular regard for their participation in digestive and central inflammation as well as the dynamic interactions between glial cells and intestinal epithelial barrier. Accumulating evidence suggests that several pathological intestinal conditions, associated with an impairment of barrier permeability, may trigger dysfunctions of EGCs and their shift towards a proinflammatory phenotype. The reactive gliosis is likely responsible for PD-related neuroinflammation and the associated pathological changes in the ENS. Thus, ameliorating the efficiency of mucosal barrier, as well as avoiding IEB disruption and the related reactive gliosis, might theoretically prevent the onset of PD or, at least, counteract its progression.
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Murillo MDP, Aronsson P, Winder M, Carlsson T. Desipramine, commonly used as a noradrenergic neuroprotectant in 6-OHDA-lesions, leads to local functional changes in the urinary bladder and gastrointestinal tract in healthy rats. Heliyon 2020; 6:e05472. [PMID: 33251357 PMCID: PMC7679251 DOI: 10.1016/j.heliyon.2020.e05472] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/29/2020] [Accepted: 11/05/2020] [Indexed: 11/16/2022] Open
Abstract
The 6-hydroxydopamine (6-OHDA) rat model is one of the most common animal models of Parkinson's disease. When experimentally inducing dopaminergic neurodegeneration in the nigrostriatal pathway using 6-OHDA, the noradrenergic reuptake inhibitor desipramine is often systemically injected in order to protect against damages to the noradrenergic system in the brain. An increasing number of studies are focusing on understanding the pathophysiological changes underlying autonomic non-motor symptoms, in particular urinary bladder and gastrointestinal dysfunctions, of the disease. Several of these studies have investigated the contractile properties and the activation of smooth muscle in the 6-OHDA rat model. Since the injection of desipramine is commonly placed in close proximity to the urinary bladder and gastrointestinal tract, in the current study we wanted to understand if the drug alone has an effect. For this, we have injected a single dose (25 mg/kg) of desipramine either intraperitonially or subcutaneously and investigated smooth muscle contractility in vitro in the urinary bladder, proximal colon and distal ileum four weeks post injection. Our data show that desipramine significantly alters smooth muscle contractility of the urinary bladder and proximal colon in healthy rats. Conclusively, we suggest, based on our data, that desipramine should be omitted when using the 6-OHDA rat model to investigate smooth muscle function in Parkinson's disease research.
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Affiliation(s)
- Maria Del Pilar Murillo
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Box 431, SE-40530 Gothenburg, Sweden
| | - Patrik Aronsson
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Box 431, SE-40530 Gothenburg, Sweden
| | - Michael Winder
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Box 431, SE-40530 Gothenburg, Sweden
| | - Thomas Carlsson
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Box 431, SE-40530 Gothenburg, Sweden
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50
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Parkinson disease and the gut: new insights into pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol 2020; 17:673-685. [PMID: 32737460 DOI: 10.1038/s41575-020-0339-z] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/23/2020] [Indexed: 12/12/2022]
Abstract
The classic view portrays Parkinson disease (PD) as a motor disorder resulting from loss of substantia nigra pars compacta dopaminergic neurons. Multiple studies, however, describe prodromal, non-motor dysfunctions that affect the quality of life of patients who subsequently develop PD. These prodromal dysfunctions comprise a wide array of gastrointestinal motility disorders including dysphagia, delayed gastric emptying and chronic constipation. The histological hallmark of PD - misfolded α-synuclein aggregates that form Lewy bodies and neurites - is detected in the enteric nervous system prior to clinical diagnosis, suggesting that the gastrointestinal tract and its neural (vagal) connection to the central nervous system could have a major role in disease aetiology. This Review provides novel insights on the pathogenesis of PD, including gut-to-brain trafficking of α-synuclein as well as the newly discovered nigro-vagal pathway, and highlights how vagal connections from the gut could be the conduit by which ingested environmental pathogens enter the central nervous system and ultimately induce, or accelerate, PD progression. The pathogenic potential of various environmental neurotoxicants and the suitability and translational potential of experimental animal models of PD will be highlighted and appraised. Finally, the clinical manifestations of gastrointestinal involvement in PD and medications will be discussed briefly.
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