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	Control factors	Method	Microbiota alterations	Alpha diversity	Beta diversity
[86]	PD: 72 non-PD: 72	Onset age > 50 years; age- and sex-matched; no endocrine diseases	16S rRNA V1-3	Family increased: Lactobacillaceae, Verrucomicrobiaceae, Bradyrhizobiaceae, Clostridiales Incertae Sedis IV, Ruminococcaceae; family decreased: Prevotellaceae	nd	sd
[87]	PD: 31 non-PD: 28	Early, L-DOPA-naïve PD; only male; age-matched; diet and smoking habits considered	shotgun metagenomic	Family/genus increased: Verrucomicrobiaceae (genus Akkermansia); family/genus decreased: Prevotellaceae (genus Prevotella), Erysipelotrichaceae (genus Eubacterium); species increased: Akkermansia muciniphila, Alistipes shahii; species decreased: Prevotella copri, Eubacterium bioforme, Clostridium saccharolyticum	nd	sd
[88]	PD: 24 healthy: 14	Age-, sex-, BMI-matched; no diabetes, infectious diseases or special diets	16S rRNA V3-5	Family increased: Enterobacteriaceae, Veillonellaceae, Erysipelotrichaceae, Coriobacteriaceae, Streptococcaceae, Moraxellaceae, Enterococcaceae; genus increased: Acidaminococcus, Acinetobacter, Enterococcus, Escherichia-Shigella, Megamonas, Megasphaera, Proteus, Streptococcus; genus decreased: Blautia, Faecalibacterium, Ruminococcus	nd	sd
[89]	PD: 76 RBD: 21 healthy: 78	Comorbidities and comedication were documented	16S/18S rRNA V4	Family increased: Verrucomicrobiaceae; genus increased: Akkermansia	nd	sd
[90]	PD: 45 healthy: 45	Spouses as control; no serious chronic illnesses (e.g., diabetes); IBS excluded	16S rRNA V3-4	Genus increased: Clostridium IV, Holdemania, Clostridium XVIII, Butyricicoccus, Anaerotruncus, Aquabacterium, Sphingomonas	sd ( >)	sd
[91]	PD: 64 Control: 64	Age- and sex-matched; dietary habits and medications assessed	16S rRNA V3-4	Family decreased: Prevotellaceae; genus increased: Bifidobacterium; genus decreased: Roseburia	nd	sd
[92]	PD: 193 PSP: 22 MSA: 22 non-PD: 113	39 drug-naïve PD; age-, BMI-, region-matched; spouses as control; dietary habits assessed; autoimmune disease and advanced-stage PD excluded	16S rRNA V3-4	Family increased: Verrucomicrobiaceae, Enterobacteriaceae, Christensenellaceae, Lactobacillaceae, Coriobacteriaceae, Bifidobacteriaceae; family decreased: Lachnospiraceae; genus increased: Akkermansia, Parabacteroides; genus decreased: Roseburia	sd ( >)	sd
[93]	PD: 197 healthy: 103	Age 40-85 years, onset age 40-80 years, disease duration ≤ 12 years; age-matched; medications, diet, and demographics collected	16S rRNA V4	Family increased: Christensenellaceae, Desulfovibrionaceae; family decreased: Lachnospiraceae; genus increased: Bilophila, Akkermansia; genus decreased: Roseburia, Faecalibacterium	nd	sd
[94]	Training set PD: 40 healthy: 40 Validation set PD: 78 healthy: 75 MSA: 40 AD: 25	Spouses as partial control; no serious illness (e.g. heart failure); no chronic disease (e.g., diabetes); lifestyle factors and medications considered	shotgun metagenomic	Family increased: Carnobacteriaceae, Lactobacillaceae, Rikenellaceae, Streptococcaceae, Synergistaceae Genus increased: Alistipes, Enterobacter, Gordonibacter, Granulicatella, Holdemania, Lactobacillus, Streptococcus Species increased: Clostridium_asparagiforme, Clostridium_leptum, Enterobacter_cloacae, Gordonibacter_pamelaeae, Granulicatella_unclassified, Holdemania_filiformis, Lachnospiraceae_bacterium 1_1_57FAA, Lachnospiraceae_bacterium 3_1_57FAA_CT1, Lactobacillus_salivarius, Paraprevotella_clara, Streptococcus_anginosus, Streptococcus_salivarius, Streptococcus_thermophilus	sd ( >)	sd
[95]	PD: 26 Control: 25	Early, L-DOPA-naïve PD; only male; 11 healthy controls, 14 diseased controls had cardiovascular risk factors	shotgun metagenomic	Species increased: Akkermansia muciniphila, Alistipes shahii, Alistipes obesi, Alistipes ihumii; species decreased: Prevotella copri, Clostridium saccharolyticum, Desulfibrio piger	na	na
[96]	PD: 104 non-PD: 96	91 spouses, 5 siblings as control; diet, lifestyle and housing condition considered	16S rRNA V3-4	Family increased: Christensenellaceae, Verrucomicrobiaceae, Synergistaceae, Catabacteriaceae, Lactobacillaceae; genus increased: Cloacibacillus, Catabacter, Christensenella, Butyrivibrio, Bifidobacterium, Megasphaera; species increased: Bacteroides fragilis, Lactobacillus acidophilus	nd	na
[97]	PD: 490 healthy: 234	Region-matched; 55% controls were spouses	shotgun metagenomic	Genus: 23 ↑, 11 ↓; species: 55 ↑, 29 ↓	na	sd
[98]	PD: 96 non-PD: 74	Newly diagnosed PD; environmental factors considered; no immunocompromised	16S rRNA V4	Phylum increased: Proteobacteria, Verrucomicrobiota, Actinobacteria; genus increased: Akkermansia, Enterococcus, Hungatella	sd ( <)	sd

Table 2 Microbiome alterations in clinical cohorts of PD

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Table 1 Evidence for and against the gut origin 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
Table 5 Microbial therapies for PD
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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