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

• Published in: Nature reviews. Neurology Vol. 18; no. 8; pp. 476 - 495
• Main Authors: Tan, Ai Huey, Lim, Shen Yang, Lang, Anthony E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2022; Nature Publishing Group
• Subjects: 631/326; 692/617/375/1718; Biomarkers; Brain research; Clinical medicine; Gut-brain axis; Inflammation; Medicine; Medicine & Public Health; Microbiota; Nervous system; Neurology; Parkinson's disease; Pathogenesis; Permeability; Review Article; Tumor necrosis factor-TNF; Vagus nerve
• ISSN: 1759-4758; 1759-4766; 1759-4766
• DOI: 10.1038/s41582-022-00681-2

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. The prominence of gastrointestinal dysfunction among the non-motor features of Parkinson disease (PD) indicates a close bidirectional link between the brain and the gut. This Review discusses the proposed roles of gut-related factors in PD development, progression and treatment responses, and as therapeutic targets. 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.