Translational Neurodegeneration

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Parkinson’s disease and gut microbiota: from clinical to mechanistic and therapeutic studies

Xuxiang Zhang, Beisha Tang, Jifeng Guo

Translational Neurodegeneration, 2023, 12(0): 59. DOI: 10.1186/s40035-023-00392-8

Ref.	Sample size	Type	Treatment duration	Main results
Probiotics
[263]	Probiotics treatment: 25 Placebo: 25	Lactobacillus acidophilus, Bifidobacterium bifidum, L. reuteri, and L. fermentum	12 weeks	Downregulated the gene expression of IL-1, IL-8, and TNF-α and upregulated TGF-β and PPAR-γ in PBMC
[264]	Probiotics treatment: 30 Placebo: 30	L. acidophilus, B. bifidum, L. reuteri, and L. fermentum	12 weeks	Decreased MDS-UPDRS, hs-CRP, and malondialdehyde, enhanced glutathione, and improved insulin sensitivity
[265]	Probiotics treatment: 34 Placebo: 38	L. acidophilus, L. reuteri, L. gasseri, L. rhamnosus, B. bifidum, B. longum, Enterococcus faecalis, E. faecium	4 weeks	Improved constipation symptoms
[266]	Probiotics treatment: 23 Placebo: 23	Bacillus licheniformis, L. acidophilus, B. longum, E. faecalis	12 weeks	Improved constipation symptoms and positively affected gut microbiota
Prebiotics
[267]	PD: 19	A diet rich in insoluble fiber	2 months	Improved constipation symptoms and increased plasma levodopa bioavailability and motor function
[268]	Resistant starch: 32 PD, 30 control Solely dietary instructions: 25 PD	Resistant starch	8 weeks	Improved nonmotor symptom scores, increased fecal butyrate, and decreased fecal calprotectin levels
[191]	Newly diagnosed, non-medicated PD: 10 Treated PD: 10	Prebiotic fiber	10 days	Prebiotic intervention was well tolerated and safe, associated with beneficial biological changes in microbiota, SCFA, inflammation, and neurofilament light chain, and may improve clinical symptoms (i.e., gastrointestinal symptoms and UPDRS)
Synbiotics
[269]	Multiple probiotic strains and prebiotic fiber: 80 Placebo: 40	Multiple probiotic strains: Streptococcus salivarius subsp. thermophilus, E. faecium, L. rhamnosus GG, L. acidophilus, L. plantarum, L. paracasei, L. delbrueckii subsp. bulgaricus, and Bifidobacterium Prebiotic fiber: fructo-oligosaccharides	4 weeks	Improved constipation symptoms
[270]	Multi-strain probiotic (Hexbio®): 22 Placebo: 26	Multi-strain probiotic (Lactobacillus sp. and Bifidobacterium sp.) with fructo-oligosaccaride	8 weeks	Improved bowel opening frequency and whole gut transit time
Fecal microbiota transplantation
[271]	PD: 15	Purified fecal microbiota suspension	Once	Relieved motor and nonmotor symptoms with acceptable safety
[272]	PD: 6	Fecal suspension	Once	Relieved motor and nonmotor symptoms, including constipation
[273]	PD: 11	Frozen fecal microbiota	Once	Reconstructed gut microbiota and improved motor and nonmotor symptoms
[274]	PD: 12	FMT capsules (n = 8) placebo (n = 4)	Twice weekly for 12 weeks	Improved subjective motor and non-motor complaints, intestinal microbiota diversity, gut transit, and motility

Table 5 Microbial therapies for PD

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Table 1 Evidence for and against the gut origin of PD
Table 2 Microbiome alterations in clinical cohorts of PD
Fig. 1 The most commonly reported 11 families and 12 genera of gut microbiota that are different between the PD and the NC groups. Orange bars represent the number of studies in which PD had a higher abundance than NC. Cyan bars represent the number of studies in which PD had a lower abundance than NC. PD, Parkinson’s disease, NC, normal control
Fig. 2 Alterations in intestinal flora in White and Asian populations with PD. The figure illustrates the number of times the intestinal flora at the family and genus levels have been cumulatively reported in the literature
Fig. 3 The microbiota-gut-brain axis in Parkinson’s disease (PD). Disordered gut microbes, through the microbiota-gut-brain axis, play a role in the pathogenesis of PD via the immune, endocrine, and nervous systems. a Alterations in intestinal microbes and their metabolites can leave the gut in an inflammatory state. These substances can cross the damaged intestinal barrier, activate mucosal immune cells, induce the release of pro-inflammatory cytokines, and promote misfolding and aggregation of α-syn. b Increased intestinal permeability allows release of signaling molecules by intestinal microbes and activated immune cells as well as through metabolic secretion to enter the circulation and cause systemic inflammation. c Misfolded α-syn in the gut can be transferred to the brain through intercellular transmission via the vagus nerve, and this transmission may be bidirectional. d The damaged blood-brain barrier and vagal pathways allow pathological products and α-syn to enter the brain, promoting the activation of immune cells in the brain, including microglia and astrocytes, causing neuroinflammation, and ultimately leading to the loss of dopaminergic neurons and the development of PD
Table 3 Altered gut microbial metabolites in patients with PD
Table 4 Mechanistic studies of microbiota in animal models of PD
Fig. 4 Effect of intestinal microbes on the metabolic pathway of levodopa. After oral administration, L-dopa enters the circulation through active transport in the intestine and crosses the blood-brain barrier into the brain, where it exerts anti-Parkinson’s disease effects by restoring striatal dopaminergic neurotransmission. However, only a small fraction of the drug eventually reaches the brain due to interference by various factors. Studies have revealed that tyrDC from Enterococcus faecalis can convert L-dopa to dopamine in the intestine and affect its absorption. a Elevated E. feacalis and tyrDC levels enable more L-dopa to be metabolized to dopamine in the intestine, resulting in impaired L-dopa absorption. b Conversely, a decrease in tyrDC allows more L-dopa to be absorbed and utilized. In addition, the small molecule inhibitor (S)-α-fluoromethyltyrosine (AFMT) can suppress tyrDC, thereby increasing the bioavailability of L-dopa
Fig. 5 Microbial therapies for Parkinson’s disease. a Probiotics, prebiotics, synbiotics, and fecal microbiota transplantation are the most commonly used microbial therapies for PD. These therapies can be administered through oral, nasogastric, rectal, or colonoscopic route. b Microbial therapies have neuroprotective effects on the brain by reducing the blood-brain barrier damage, decreasing microglial and astrocytic activation, suppressing neuroinflammation, and inhibiting α-syn aggregation, thereby preventing the death of dopaminergic neurons. c In the gut, microbial therapies can regulate gut microbes, improve intestinal metabolism, modulate the intestinal mucosal immune system, inhibit gut inflammation, and restore gut barrier damage, resulting in improved intestinal symptoms. d In conclusion, microbial therapies relieve nonmotor symptoms of PD, particularly constipation, as well as the motor symptoms through multiple pathways

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