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

Evidence for	Evidence against
Epidemiological studies
Gastrointestinal symptoms usually precede the motor symptoms of PD [18].	CNS and PNS are simultaneously involved in PD, with peripheral symptoms appearing first owing to poorer compensatory mechanisms [19].
IBD increases the incidence of PD [20, 21, 22, 23, 24]. Effective treatment can reduce the risk of PD [23, 25].	A retrospective study did not confirm that IBD increases the risk for PD [26]. The results of a Mendelian randomization study did not support that treating IBD could prevent PD [27].
Vagotomy and appendectomy can lower the risk of PD [28, 29].	A long-term follow-up study did not confirm that vagotomy reduces the risk of PD [30]. In most studies, appendectomy is not correlated with PD; rather it even slightly increases the risk of PD in some studies [31, 32, 33].
Neuropathological studies
Pathological changes in PD may first occur in the ENS [34].	Results of several clinicopathological studies do not support the peripheral origin of PD. The studies showed that α-syn histopathology of the PNS rarely precedes the CNS [35, 36, 37].
Increased intestinal permeability and decreased level of the tight junction protein occludin in PD [38, 39, 40].
Clinical studies
Intestinal flora dysbiosis can occur in the prodromal phase of PD [41].
Gut microbes are associated with motor and nonmotor PD phenotypes [42].
Microbial therapy can improve the clinical manifestations of PD [43].
Animal studies
Changes in intestinal flora produce abnormal metabolites and structural proteins, which may trigger α-syn accumulation [44, 45].	The origin of PD may be multifocal [19].
α-Syn originates in the gut and spreads to the CNS through a transsynaptic intercellular approach [46].	PD pathologies, such as α-syn overexpression, can also propagate from the CNS to the intestine [47, 48, 49, 50, 51].
Fecal microbiome transplantation can exacerbate or improve PD-like symptoms in animal models [45].

Table 1 Evidence for and against the gut origin of PD

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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
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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