Microbiome-based therapies for Parkinson's disease

Abstract

The human gut microbiome dysbiosis plays an important role in the pathogenesis of Parkinson's disease (PD). The bidirectional relationship between the enteric nervous system (ENS) and central nervous system (CNS) under the mediation of the gut-brain axis control the gastrointestinal functioning. This review article discusses key mechanisms by which modifications in the composition and function of the gut microbiota (GM) influence PD progression and motor control loss. Increased intestinal permeability, chronic inflammation, oxidative stress, α-synuclein aggregation, and neurotransmitter imbalances are some key factors that govern gastrointestinal pathology and PD progression. The bacterial taxa of the gut associated with PD development are discussed with emphasis on the enteric nervous system (ENS), as well as the impact of gut bacteria on dopamine production and levodopa metabolism. The pathophysiology and course of the disease are associated with several inflammatory markers, including TNF-α, IL-1β, and IL-6. Emerging therapeutic strategies targeting the gut microbiome include probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT). The article explored how dietary changes may affect the gut microbiota (GM) and the ways that can affect Parkinson's disease (PD), with a focus on nutrition-based, Mediterranean, and ketogenic diets. This comprehensive review synthesizes current evidence on the role of the gut microbiome in PD pathogenesis and explores its potential as a therapeutic target. Understanding these complex interactions may assist in the development of novel diagnostic tools and treatment options for this neurodegenerative disorder.

Keywords: FMT; Parkinson’s disease; enteric nervous system; gut dysbiosis; gut microbiota.

Figure 1

Gut microbiota alterations and their role in Parkinson’s disease (PD) progression. In PD, α-synuclein accumulates in enteric neurons before motor symptoms, with altered gut microbiota (GM) increasing oxidative stress and promoting α-synuclein aggregation. This aggregation may migrate to the brain via vagal and systemic pathways, leading to intestinal and systemic inflammation, blood–brain barrier (BBB) dysfunction, and microglial activation. Microbial species such as Bacteroides vulgatus, Parabacteroides distasonis, and Lactobacillus salivarius influence neuroinflammatory signaling. GM-induced CD4+ T cell activation triggers Th1/Th17 differentiation, cytokine release, and inflammation, promoting α-synuclein aggregation and its transference to the CNS. Elevated pro-inflammatory markers (TNF-α, IL-5, IFN-γ) are found in PD colonic biopsies.

Figure 2

Role of inflammatory cascades in Parkinson’s disease. The stool sample from the PD patient showed diminished population of anti-inflammatory microbiota such as Blautia, Coprococcus, and Roseburia. Furthermore, the sample from gastrointestinal mucosa also exhibited low population of anti-inflammatory bacteria such as Faecalibacterium. Studies suggest that these both conditions are linked to higher concentration of the inflammatory markers such as TNF-α, IL-5, and IFN-γ in PD patients. The inflammatory markers further triggers α-synuclein production which exacerbates the ailing condition.

Figure 3

Toll-like receptor (TLR) signaling in relation to Parkinson’s disease. Microbial components such as lipoproteins, peptidoglycans, and lipoteichoic acid, which serves as ligand for the receptor. After their binding, TLR receptors are overexpressed as observed in PD patients. The binding triggers formation of α-synuclein. Production of α-synuclein triggers TLR2/MyD88/NF-κB signaling cascade which in turn leads to expression on pro-inflammatory factors such as TNF-α, IL-5, and IFN-γ. These pro-inflammatory factors further aggregate the α-synuclein accumulation. The α-synuclein and pro-inflammatory factors via enteric nervous system reaches the brain and cause neuro-inflammation and microglia migration. Microbial migration is also one of the contributing factors to the neuroinflammation.