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The Microbiota–Gut–Brain Axis in the Pathogenesis of Neurodegenerative Disorders
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The Microbiota–Gut–Brain Axis in the Pathogenesis of Neurodegenerative Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 24974

Special Issue Editors

Dr. Matteo Fornai

E-Mail Website
Guest Editor
Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Interests: gastrointestinal pharmacology; colonic motility; inflammatory bowel diseases; intestinal injury; obesity; neurodegenerative disorders; irritable bowel syndrome; nonsteroidal anti-inflamatory drugs
Dr. Annamaria Morelli

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
Interests: morphofunctional features and molecular basis of reproductive system dysfunctions; metabolic syndrome; inflammation; immunomodulatory actions of androgens; GnRH neurons; kisspeptin/KISS1R signaling; GPR30 estrogen receptor (GPER1); sex steroids and neuroprotection; neurogenesis; neurodegenerative disorders

Special Issue Information

Dear Colleagues,

Neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, are characterized by the occurrence of gastrointestinal alterations that can become manifest even several years before the onset of the typical clinical symptoms of the disease. In recent decades, an increasing body of evidence has supported the contention that the occurrence of intestinal microbiota alterations could play a significant role in the development of the digestive disturbances associated with neurodegenerative disorders, as well as to their initiation and spreading from the gut to the central nervous system. In particular, intestinal dysbiosis, characterized by changes in the production of bacterial metabolites (i.e., short chain fatty acids), essential for the maintenance of mucosal physiologic functions, can impair epithelial barrier integrity through alterations in tight junction protein expression. The resulting increase in intestinal permeability can favor the translocation of luminal antigens and subsequent activation of immune/inflammatory response, characterized by increase in pro-inflammatory cytokine levels, which could contribute to the development and maintenance of intestinal neuromuscular alterations. Moreover, such an inflammatory response could spread towards the central nervous system and contribute to the onset and progression of the neurodegenerative processes.

Based on the above considerations, the purpose of this Special Issue is to characterize the involvement of the microbiota–gut–brain axis in the pathophysiology of neurodegenerative diseases and related intestinal symptoms, with particular regard for the underlying molecular and cellular mechanisms. Understanding of these aspects could be useful for the characterization of novel pathophysiologic features and for providing further insights for the development of new therapeutic strategies.

Dr. Matteo Fornai
Guest Editor

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Keywords

  • neurodegenerative disorders
  • Parkinson’s disease
  • Alzheimer’s disease
  • microbiota
  • gut–brain axis
  • intestinal dysbiosis
  • intestinal dysmotility
  • neuroinflammation

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Published Papers (5 papers)

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Research

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11 pages, 1518 KiB  
Article
The Ketogenic Diet Improves Gut–Brain Axis in a Rat Model of Irritable Bowel Syndrome: Impact on 5-HT and BDNF Systems
by Antonella Orlando, Guglielmina Chimienti, Maria Notarnicola and Francesco Russo
Int. J. Mol. Sci. 2022, 23(3), 1098; https://doi.org/10.3390/ijms23031098 - 20 Jan 2022
Cited by 7 | Viewed by 3804
Abstract
Altered gut–brain communication can contribute to intestinal dysfunctions in the intestinal bowel syndrome. The neuroprotective high-fat, adequate-protein, low-carbohydrate ketogenic diet (KD) modulates the levels of different neurotransmitters and neurotrophins. The aim was to evaluate the effects of KD on levels of 5-HT, the [...] Read more.
Altered gut–brain communication can contribute to intestinal dysfunctions in the intestinal bowel syndrome. The neuroprotective high-fat, adequate-protein, low-carbohydrate ketogenic diet (KD) modulates the levels of different neurotransmitters and neurotrophins. The aim was to evaluate the effects of KD on levels of 5-HT, the receptors 5-HT3B and 5-HT4, the 5-HT transporter SERT, the neurotrophin BDNF, and its receptor TrkB in the colon and brain of a rat model of irritable bowel syndrome (IBS). Samples from Wistar rats exposed to maternal deprivation as newborns and then fed with a standard diet (IBS-Std) or KD (IBS-KD) for ten weeks were analyzed. As controls, unexposed rats (Ctrl-Std and Ctrl-KD) were studied. IBS-Std rats had a disordered enteric serotoninergic signaling shown by increased mucosal 5-HT content and reduced SERT, 5-HT3B, and 5-HT4 levels compared to controls. In the brain, these animals showed up-regulation of the BDNF receptor TrkB as a counteracting response to the stress-induced reduction of the neurotrophin. KD showed a dual effect in improving the altered 5-HT and BDNF systems. It down-regulated the increased mucosal 5-HT without affecting transporter and receptor levels. KD improved brain BDNF levels and established negative feedback, leading to a compensatory downregulation of TrkB to maintain a physiological steady state. Full article
(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis in the Pathogenesis of Neurodegenerative Disorders)
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16 pages, 7551 KiB  
Article
Influence of a High-Impact Multidimensional Rehabilitation Program on the Gut Microbiota of Patients with Multiple Sclerosis
by Monica Barone, Laura Mendozzi, Federica D’Amico, Marina Saresella, Simone Rampelli, Federica Piancone, Francesca La Rosa, Ivana Marventano, Mario Clerici, Alessia d’Arma, Luigi Pugnetti, Valentina Rossi, Marco Candela, Patrizia Brigidi and Silvia Turroni
Int. J. Mol. Sci. 2021, 22(13), 7173; https://doi.org/10.3390/ijms22137173 - 2 Jul 2021
Cited by 21 | Viewed by 4000
Abstract
Multiple sclerosis (MS) is a neurodegenerative inflammatory condition mediated by autoreactive immune processes. Due to its potential to influence host immunity and gut-brain communication, the gut microbiota has been suggested to be involved in the onset and progression of MS. To date, there [...] Read more.
Multiple sclerosis (MS) is a neurodegenerative inflammatory condition mediated by autoreactive immune processes. Due to its potential to influence host immunity and gut-brain communication, the gut microbiota has been suggested to be involved in the onset and progression of MS. To date, there is no definitive cure for MS, and rehabilitation programs are of the utmost importance, especially in the later stages. However, only a few people generally participate due to poor support, knowledge, and motivation, and no information is available on gut microbiota changes. Herein we evaluated the potential of a brief high-impact multidimensional rehabilitation program (B-HIPE) in a leisure environment to affect the gut microbiota, mitigate MS symptoms and improve quality of life. B-HIPE resulted in modulation of the MS-typical dysbiosis, with reduced levels of pathobionts and the replenishment of beneficial short-chain fatty acid producers. This partial recovery of a eubiotic profile could help counteract the inflammatory tone typically observed in MS, as supported by reduced circulating lipopolysaccharide levels and decreased populations of pro-inflammatory lymphocytes. Improved physical performance and fatigue relief were also found. Our findings pave the way for integrating clinical practice with holistic approaches to mitigate MS symptoms and improve patients’ quality of life. Full article
(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis in the Pathogenesis of Neurodegenerative Disorders)
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28 pages, 4660 KiB  
Article
Prodromal Intestinal Events in Alzheimer’s Disease (AD): Colonic Dysmotility and Inflammation Are Associated with Enteric AD-Related Protein Deposition
by Carolina Pellegrini, Simona Daniele, Luca Antonioli, Laura Benvenuti, Vanessa D’Antongiovanni, Rebecca Piccarducci, Deborah Pietrobono, Valentina Citi, Eugenia Piragine, Lorenzo Flori, Chiara Ippolito, Cristina Segnani, Pablo Palazon-Riquelme, Gloria Lopez-Castejon, Alma Martelli, Rocchina Colucci, Nunzia Bernardini, Maria Letizia Trincavelli, Vincenzo Calderone, Claudia Martini, Corrado Blandizzi and Matteo Fornaiadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2020, 21(10), 3523; https://doi.org/10.3390/ijms21103523 - 15 May 2020
Cited by 29 | Viewed by 4122
Abstract
Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer’s disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. [...] Read more.
Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer’s disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aβ, tau proteins, α-synuclein and IL-1β were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aβ on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1β, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aβ promoted IL-1β release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aβ decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD. Full article
(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis in the Pathogenesis of Neurodegenerative Disorders)
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Review

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16 pages, 2679 KiB  
Review
Enteric Glia at the Crossroads between Intestinal Immune System and Epithelial Barrier: Implications for Parkinson Disease
by Laura Benvenuti, Vanessa D'Antongiovanni, Carolina Pellegrini, Luca Antonioli, Nunzia Bernardini, Corrado Blandizzi and Matteo Fornai
Int. J. Mol. Sci. 2020, 21(23), 9199; https://doi.org/10.3390/ijms21239199 - 2 Dec 2020
Cited by 40 | Viewed by 4706
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis in the Pathogenesis of Neurodegenerative Disorders)
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20 pages, 890 KiB  
Review
Gut–Brain Axis and Neurodegeneration: State-of-the-Art of Meta-Omics Sciences for Microbiota Characterization
by Bruno Tilocca, Luisa Pieroni, Alessio Soggiu, Domenico Britti, Luigi Bonizzi, Paola Roncada and Viviana Greco
Int. J. Mol. Sci. 2020, 21(11), 4045; https://doi.org/10.3390/ijms21114045 - 5 Jun 2020
Cited by 49 | Viewed by 7676
Abstract
Recent advances in the field of meta-omics sciences and related bioinformatics tools have allowed a comprehensive investigation of human-associated microbiota and its contribution to achieving and maintaining the homeostatic balance. Bioactive compounds from the microbial community harboring the human gut are involved in [...] Read more.
Recent advances in the field of meta-omics sciences and related bioinformatics tools have allowed a comprehensive investigation of human-associated microbiota and its contribution to achieving and maintaining the homeostatic balance. Bioactive compounds from the microbial community harboring the human gut are involved in a finely tuned network of interconnections with the host, orchestrating a wide variety of physiological processes. These includes the bi-directional crosstalk between the central nervous system, the enteric nervous system, and the gastrointestinal tract (i.e., gut–brain axis). The increasing accumulation of evidence suggest a pivotal role of the composition and activity of the gut microbiota in neurodegeneration. In the present review we aim to provide an overview of the state-of-the-art of meta-omics sciences including metagenomics for the study of microbial genomes and taxa strains, metatranscriptomics for gene expression, metaproteomics and metabolomics to identify and/or quantify microbial proteins and metabolites, respectively. The potential and limitations of each discipline were highlighted, as well as the advantages of an integrated approach (multi-omics) to predict microbial functions and molecular mechanisms related to human diseases. Particular emphasis is given to the latest results obtained with these approaches in an attempt to elucidate the link between the gut microbiota and the most common neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Full article
(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis in the Pathogenesis of Neurodegenerative Disorders)
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