Gut-oriented disease modifying therapy for Parkinson’s disease
In recent years, a potential relationship has been identified between the commensal (healthy) bacteria in the gut and the brain, which is hypothesized to be capable of influencing neurodevelopment, brain function, and health (Klann et al., 2022). This communication is frequently termed the gut-brain axis, and serves to link emotional and cognitive centers of the brain with peripheral intestinal functions (Carabotti et al., 2015).
Figure 1. Routes across the gut-brain axis. (Lin et al., 2013)
As remarked by figure 1, there are many pathways in which microbiota can influence neurological function, including direct absorption through the gut-blood/lymphatic-brain pathways, local signaling to immune cells, and vagal retrograde signaling pathways (Lin et al., 2023). The imbalance of gut microbiota may be involved in the promotion of PD neuropathology and neurodegeneration through these pathways, resulting in impaired brain function and behavior (Dinan & Cryan, 2017). Many studies remark the reduced presence of various anti-inflammatory and short-chain fatty acid (SCFA)-producing bacteria in PD patients when compared to controls (Cirstea et al., 2021). These changes in microbiota also correlate with the progression of PD, as a decrease in SCFA-producing microbiota and increase in pro-inflammatory bacteria correlate with motor and cognitive severity in patients (Lin et al., 2023).
This mounting evidence has highlighted the importance of bacteria in the regulation of PD pathogenesis, and has led to the development of various interventions to target this axis, with the hopes of modifying the course of disease (Lin et al., 2023). These interventions include:
While still requiring further investigation, there is evidence that certain probiotics can modify the gut microbiota in a way that prevents the bacterial imbalance (dysbiosis) that causes the neurodegeneration associated with PD (Lin et al., 2023). Specifically, certain probiotics have been shown to reduce inflammation involved in neuroinflammation which is one of the causal factors of neurodegeneration (Lin et al., 2023). Most notably, various probiotics can reduce the loss of dopaminergic neurons which is the main hallmark of PD (Tan et al., 2020).
Prebiotics are specific ingredients in food that specifically trigger the growth of selective types of bacteria in the gut (Lin et al., 2023). In regards to the reduction in SCFA-producing bacteria seen in PD patients, it was actually found that certain prebiotic fibers could rectify this loss.
The combination of a probiotic with a prebiotic is called a synbiotic. Synbiotics work by favoring the growth of certain probiotic microorganisms. A specific example is the combination of polymannuronic acid, a prebiotic, and Lacticaseibacillus ramnosus GG, a probiotic, which has been shown to alleviate dopaminergic neuronal loss and improve locomotor function in PD mice (Lin et al., 2023).
4. Fecal microbiota transplantation
Despite currently limited data from human PD patients, pre-clinical animal studies on fecal microbiota transplantation (FMT) has shown some exciting outcomes in relation to PD. During FMT, fecal material from healthy donors is delivered into recipients of gut dysbiosis-related disorders. In one of these animal studies, FMT from healthy mice rescued motor function, reduced dysbiosis and increased dopamine levels in certain brain regions, amongst other beneficial effects observed (Lin et al., 2023).
5. Live biotherapeutic products
Live biotherapeutic products (LBPs) are a new class of drugs that contain live organisms including bacteria, which can be used for preventing, treating, or curing disease (Ağagündüz et al., 2022). Some organisms of LBPs can be genetically engineered to have a certain gene added or removed from it to elicit a desired effect (Lin et al., 2023). Some of these engineered LBPs showed an ability to diminish motor dysfunction and neuroinflammation (Lin et al., 2023)
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