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The microbiome–gut–brain axis in Parkinson disease — from basic research to the clinic

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.

Key points

  • Evidence is accumulating that the gut–brain axis has an important role in Parkinson disease (PD) risk and progression.

  • Key events include: ‘unhealthy’ alterations in gut microbiome structure and/or function; gut inflammation and hyperpermeability; and seeding and propagation of α-synuclein in the enteric nervous system. Ageing has an influence on all of these events.

  • Investigations into gut bacterial composition and activity have been greatly facilitated by ‘omics’ technologies; future progress will require greater collaboration to obtain large, longitudinal datasets and to develop harmonized research protocols.

  • Various gut disorders (including infections, dysbiosis, inflammation and dysmotility), gut interventions and dietary factors have been linked to PD development and progression, and have been shown to influence the response to PD medication.

  • Higher-resolution mechanistic studies are needed to understand the observed associations at the molecular, cellular and systems levels, and will aid the translation of microbiome science into new diagnostic, prognostic and therapeutic approaches.

  • Gut-related factors provide multiple potential targets for biomarker development and interventional strategies that should be explored in well-designed studies; microbiome-directed therapeutics to treat PD manifestations are already emerging.

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Fig. 1: Gastrointestinal function and levodopa pharmacokinetics in PD.
Fig. 2: Therapeutic modulation of the gut microbiome in Parkinson disease.
Fig. 3: Current gaps and future directions in PD microbiome research.

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Acknowledgements

The authors gratefully acknowledge support from the University of Malaya Parkinson’s Disease and Movement Disorders Research Program Fund (PV035-2017), and M. G. Rudakewich (Synapse Visuals) for providing professional medical illustration services for the figure in Box 2 (the original figure done by the artist was modified by the journal).

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Authors and Affiliations

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Contributions

A.H.T. and S.Y.L. developed the concept and structure of the manuscript, conducted the literature review and prepared the first draft of the manuscript. A.E.L. provided critical review of the manuscript. All authors contributed to the revision of the manuscript.

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Correspondence to Ai Huey Tan.

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The authors declare no competing interests.

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Nature Reviews Neurology thanks M. Cirstea, who co-reviewed with S. Appel-Cresswell; A. Keshavarzian; and R. Pfeiffer for their contribution to the peer review of this work.

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Review criteria

We searched PubMed for articles published in English from 1 January 2010 to 4 October 2021, using the following main search terms: “Parkinson’s disease” and “gut–brain axis”, “microbiome”, “dysbiosis”, “gut metabolites”, “constipation”, “inflammatory bowel disease”, “irritable bowel syndrome”, “vagotomy”, “appendectomy”, “Helicobacter pylori”, “small intestinal bacterial overgrowth”, “diet”, “gut motility”, “levodopa pharmacokinetics”, “prebiotics”, “probiotics”, “faecal microbiota transplantation”, “antimicrobials” and “postbiotics”. Where relevant, our literature search was expanded to include studies in healthy or older adults and related neurodegenerative diseases. We also used references cited in the publications retrieved. The final reference list was generated on the basis of relevance to the topics covered in this Review, with a focus on publications within the past 5 years. For the section “Gut dysbiosis in PD: evidence from clinical studies”, we systematically reviewed PubMed articles published in any language from 1 January 2000 to 31 May 2021, using the following search terms: “microbiome” or “microbiota” or “microflora” or “dysbiosis” and “Parkinson” or “parkinsonism”. The inclusion criteria were human case–control studies involving patients with PD, and microbial DNA extraction from stool samples. The results of this literature search are summarized in Supplementary Table 1.

Supplementary information

Glossary

Enteric nervous system

(ENS). An extensive neural network comprising neurons and glial cells embedded in the gut wall that coordinates the main functions of the gastrointestinal tract. Often referred to as the ‘second brain’, it is the largest of the three divisions of the autonomic nervous system, the other two being the sympathetic and the parasympathetic nervous system.

Dorsal motor nucleus of the vagus

(DMNV). The cluster of neuronal cell bodies in the medulla oblongata of the lower brainstem that supplies efferent fibres of the vagus nerve, which is the main contributor to the parasympathetic nervous system. DMNV fibres innervate the gastrointestinal tract from the distal third of the oesophagus to approximately the splenic flexure of the colon.

Microbiome

The collection of all the microorganisms (microbiota) living in a particular environment, including bacteria, fungi, protozoa and viruses. Sometimes, the term is used more specifically to denote the combined genetic material of these microorganisms.

Metabolome

The collection of all low-molecular-weight metabolites within a biological system (cell, biofluid, tissue or organism).

Lipopolysaccharide

An endotoxin and biologically active component of Gram-negative bacterial cell walls with potential immunostimulatory activity.

Defaecatory dyssynergia

A disorder of paradoxical anal sphincter contraction during attempted defaecation in patients with constipation.

Mendelian randomization

An observational research approach that uses variation in genes of known function as a proxy for an exposure (for example, to a drug), risk factor or phenotypic trait, so as to predict its causal effects on health outcomes. This method is less likely to be affected by confounding or reverse causation than are conventional observational studies.

Helicobacter pylori infection

A common, usually chronic, bacterial infection of the stomach and duodenal epithelium that is found worldwide. It is associated with perturbation of the upper gut microbiome and has been directly linked particularly to peptic ulcers and non-ulcer dyspepsia.

Small intestinal bacterial overgrowth

(SIBO). An acquired disorder defined by an excess of bacteria in the small intestine, often caused by colonization of coliform bacteria that usually reside in the colon.

Hypochlorhydria

A condition of reduced production of hydrochloric acid, one of the components of gastric acid. A common cause is atrophic gastritis induced by Helicobacter pylori infection.

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Tan, A.H., Lim, S.Y. & Lang, A.E. The microbiome–gut–brain axis in Parkinson disease — from basic research to the clinic. Nat Rev Neurol 18, 476–495 (2022). https://doi.org/10.1038/s41582-022-00681-2

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