This study is a comprehensive and quantitative combination of randomized controlled trials of the effects of probiotics in PD patients. We found that probiotics increased gastrointestinal motility, decreased serum levels of inflammatory markers, increased serum levels of antioxidants, reduced diabetes risk, improved motor, non-motor PD symptoms, and mental health. The improvement in gastrointestinal motility was greater when the probiotics were taken in capsule form than when consumed in fermented milk form. In addition, the longer the follow-up period, the better the gastrointestinal motility and mental health scores. These results suggest that probiotics can be considered as adjuvant treatment options based on the pathophysiology of “gut dysbiosis” in patients with PD.
PD is a multifactorial disease with both genetic and environmental risk factors, and the commonest cause of PD is idiopathic. Studies from 1957 and 1960 revealed a loss of neurons in substantia nigra and decreased dopamine in the striatum in patients with PD [4, 21]. Degeneration of dopaminergic neurons in the substantia nigra compacta and projection to the striatum induces PD. This denaturation appears as a toxic aggregation of alpha-synuclein (α-syn), a major component of Lewy bodies [8]. As a pathological marker of PD, α-syn accumulates in the central, peripheral, and enteric nervous systems and affects their function [24, 31].
The process by which “gut dysbiosis” leads to PD is explained by the accumulation of α-syn induced by changes in the gut microbiota. Short-chain fatty acids (SCFAs) are major metabolites produced by the microorganisms in the large intestine through anaerobic fermentation of undigested polysaccharides. SCFAs play an important role in maintaining the intestinal barrier integrity, preventing microbial migration, and preventing inflammation induction through regulation of expression of tight junction proteins [47]. An imbalance in the gut flora due to increased harmful bacteria creates endotoxins (e.g., lipopolysaccharides [LPS]) and damages the intestinal barrier, thus triggering the migration of microorganisms and bacterial metabolites and consequently inducing proinflammatory pathways. Previous studies have reported that bacteria that aid in SCFAs production include Butyricicoccus, Clostridium sensu stricto, Roseburia, and Faecalibacterium prausnitzii, whereas bacteria that decrease SCFAs and increase LPS include Akkermansia, Escherichia/Shigella, Flavonifractor, Intestinimonas, Phascolarctobacterium, and Sporobacter [15, 26, 29, 36, 40, 48, 50].
LPS interacts with immune cells to induce cytokines, such as tumor necrosis factor (TNF) and interleukins (ILs) to induce systemic inflammatory responses [18]. Reduced levels of SCFAs and increased levels of LPS destroy the blood-brain barrier as well as the intestinal barrier [1]. LPS also interacts with intestinal glial cells and brain microglia cells to activate inflammatory cytokines (Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and pro-inflammatory cytokine interleukin-1β (pro-IL-1ß)) via Cluster of differentiation 14+ (CD14+) and Toll-like receptor 4 (TLR4) receptors, which in turn produce neuroinflammatory α-syn aggregation in the vagus nerve and brain [13, 14, 23, 27, 38].
The vagus nerve directly innervates the myenteric plexus where the neurons run through the prevertebral ganglia within the spinal cord and finally to the brain. According to Braak’s hypothesis, pathogens enter the oral and nasal cavities and initiate the formation of Lewy bodies, thus resulting in sporadic PD [37]. Aggregation of α-syn initiates in the gut and olfactory sensory nerves, passes through the nasal olfactory lobe to the midbrain, and the vagus nerve propagates α-syn to the brainstem and cortex [7, 31]. In conclusion, although the exact mechanism is not yet known, the occurrence of Parkinson’s disease due to “gut dysbiosis” is explained by the accumulation of α-syn in the central nervous system, peripheral nervous system, and enteric nervous system due to neuroinflammation through the blood-brain barrier and the vagus nerve. The basic mechanism by which "gut dysbiosis" induces PD and the effects of probiotics are shown in Fig. 9.
The effectiveness of probiotics on gut dysbiosis has been confirmed in several papers. In the C. elegans model of synucleinopathy, it was confirmed that Bacillus subtilis was effective in eliminating α-syn aggregates and preventing their further aggregation [20]. In an in vitro model of the human colon microbiome, B. longum subsp. infantis reduced the levels of LPS [12]. Fermented milk that contains lactic acid bacteria reduced LPS-dependent neuroinflammation in a rat model [39]. In both in vitro and in vivo models of PD, probiotics reverse the “gut dysbiosis” by altering the composition of the gut microbiome, thus disrupting pathways associated with inflammation [9, 19].
Although there are few clinical trials in humans, our meta-analysis provides insights into the effects of probiotics in PD. Previous papers have reported that probiotics reduce inflammation and improve gastrointestinal symptoms in PD. However, studies to elucidate the precise mechanisms for the improvements of motor and nonmotor symptoms in PD are lacking. Therefore, additional studies are warranted.
Strengths and limitations
The strength of this meta-analysis was that we used quantitative statistical methods to determine the most comprehensive effects of probiotics in patients with PD. Additionally, we compared the effects of probiotics according to the type of administration and the duration of its use.
This meta-analysis had several limitations. First, the total number of studies and participants was small. We included only studies with participants who were diagnosed with idiopathic PD and excluded studies with patients with secondary Parkinsonism. Second, the study protocols were heterogeneous in terms of the probiotic strains, dosages, and duration of intervention. These differences should be considered while interpreting the results. Third, the duration of intervention in the included studies was short and insufficient to understand the long-term effects of probiotics. The duration of intervention in the studies ranged from 4 to 12 weeks. Fourth, some studies included in the meta-analysis might be from the same center, thus resulting in data overlap.
Future large-scale randomized controlled trials along with long-term follow-up are needed to provide more reliable evidence. Additionally, the study protocols should be subdivided according to the disease severity, type of probiotics, dose of probiotics, and the duration of intervention. Measures of motor function, cognitive function, and other symptoms of PD, and various predictors of inflammatory and metabolic diseases should also be included.