Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease
worldwide. It tends to occur in elderly patients aged
The most distinctive pathological feature of PD patients is
Bacteria, fungi, archaea, viruses and helminths in the gut comprise a
steady-state microbial environment numbering
The gut is not merely a simple digestive organ. In addition to the epithelial barrier, endocrine cells, muscle layer, enteric nervous system and immune cells, the gut also includes the dynamic microbial homeostatic system mentioned above. For this reason, the gut is sometimes called the second brain of the body . Indeed, a complex bidirectional communication pathway consisting of multiple mechanisms exists between the brain and the gastrointestinal system and is referred to as the microbiota-gut-brain axis. This system acts bidirectionally through the autonomic nervous system, the enteric nervous system (ENS), the hypothalamic-pituitary-adrenal axis (HPA) and the gut microbes, which is the key area of interaction between microorganisms and brain function . The brain can alter the gut homeostatic environment through the microbiota-gut-brain axis, including the permeability of the gut wall and the abundance of microbiota. Similarly, changes in the gut environment can affect brain activity through the same axis. The microbiota-gut-brain axis has been found to play an important role in the progression of several central nervous system diseases, such as Alzheimer’s disease, PD, epilepsy, ischemic cerebrovascular disease, schizophrenia and depression .
The gut microbiota affects brain function by regulating the neurotransmitters acetylcholine, serotonin, norepinephrine, dopamine, and glutamate. In addition to affecting the synthesis and metabolism of neurotransmitters in humans, microorganisms themselves can also produce neuroactive substances. These include Y-aminobutyric acid by Bifidobacterium and Lactobacillus, acetylcholine by Lactobacillus, and dopamine by Bacillus and Serratia . Because of the blood-brain barrier, neurotransmitters produced in the gut are unlikely to be transported to the brain but can affect the brain indirectly by acting on the ENS . Gut microbiota also produces enzymes that control the tryptophan metabolic pathway, resulting in the production of serotonin, kynurenine and indole derivatives. By affecting the serotonin precursor tryptophan, the microbiota can thus influence the serotonin content in the brain .
Compared to a sterile gut environment, a healthy gut microbiota can reduce the
permeability of the blood-brain barrier by upregulating the expression of tight
junction proteins, thereby reducing invasion by harmful substances . However,
pathological alterations in the gut microbiota lead to chronic gut inflammation
and increase gut permeability, thereby promoting the secretion of
pro-inflammatory cytokines, including interleukin 1
Although the clear mechanism behind the dysregulation of the gut microbiota in
PD patients has not been fully elucidated, extensive evidence now supports the
Braak theory. E. coli has been found to produce an amyloid protein
called “curli”, which has been shown to hybridize with human amyloid in
vitro to enhance
Microbes in the proximal small intestine of PD patients, especially Enterococcus and Lactobacillus, have been shown to produce more bacterial tyrosine decarboxylase than healthy individuals. This enzyme can decarboxylate levodopa to dopamine even in the presence of tyrosine, competitive substrates, and human decarboxylase inhibitors, thereby greatly reducing the therapeutic effect of levodopa in PD patients and increasing the amount needed to treat PD . However, elevated tyrosine decarboxylase is also accompanied by increased peripheral dopamine production, along with side-effects such as orthostatic hypotension and cardiac arrhythmias.
Gut microbes in the human body are always in a dynamic process of homeostasis. Compared to healthy individuals, gut microbial homeostasis is disrupted in PD patients. Common pathological changes have been detected in certain gut microbiota in many PD patients, suggesting that dysbiosis of gut microbiota is involved in the pathogenesis of PD. Table 1 (Ref. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39]) summarizes the relevant studies on the changes to gut microbial homeostasis reported recently in PD patients.
|Microbiota||Classification||Trend 1||Trend 2|
|Prevotellaceae||Bacteroidota; Bacteroidia; Bacteroidales|
|Faecalibacterium||Clostridia; Eubacteriales; Oscillospiraceae|
|Bifidobacterium||Actinomycetota; Actinomycetes; Bifidobacteriales; Bifidobacteriaceae|
|Akkermansia||Verrucomicrobiota; Verrucomicrobiae; Verrucomicrobiales; Akkermansiaceae|
|Aquabacterium||Pseudomonadota; Betaproteobacteria; Burkholderiales; Burkholderiales genera incertae sedis|
|Sphingomonas||Pseudomonadota; Alphaproteobacteria; Sphingomonadales; Sphingomonadaceae|
|Escherichia/Shigella||Pseudomonadota; Gammaproteobacteria; Enterobacterales; Enterobacteriaceae|
|Pasteurellaceae||Pseudomonadota; Gammaproteobacteria; Pasteurellales|
|Lachnospiraceae||Bacillota; Clostridia; Eubacteriales|
|Ruminococcaceae||Bacillota; Clostridia; Eubacteriales|
|Christensenellaceae||Bacillota; Clostridia; Eubacteriales|
|Roseburia||Bacillota; Clostridia; Eubacteriales; Lachnospiraceae|
|Coprococcus||Bacillota; Clostridia; Eubacteriales; Lachnospiraceae|
|Blautia||Bacillota; Clostridia; Eubacteriales; Lachnospiraceae|
|Clostridium XVIII||Bacillota; Clostridia; Eubacteriales; Clostridiaceae|
|Butyricicoccus||Bacillota; Clostridia; Eubacteriales; Clostridiaceae|
|Anaerotruncus||Bacillota; Clostridia; Eubacteriales; Oscillospiraceae|
|Lactobacillaceae||Bacillota; Bacilli; Lactobacillales|
|Holdemania||Bacillota; Erysipelotrichia; Erysipelotrichales; Erysipelotrichaceae|
Akkermansia is a Gram-negative bacterium that increases gut
permeability by degrading the gut mucus barrier, making the host more susceptible
to attack by harmful substances and triggering gut inflammation and systemic
inflammation . The protein secreted by Akkermansia was found to
increase the mitochondrial uptake of Ca
The reduction in several bacteria (Lachnospiraceae, Faecalibacterium and Coprococcus) that produce short chain fatty acids (SCFAs) can lead to an inflammatory state in the gut and may be associated with recurrent gastrointestinal symptoms in PD patients [31, 34]. The reduction in Lachnospiraceae and the increase in Lactobacillus, Christensenellaceae, Butyricicoccus and Clostridium XLVB have been associated with worse clinical characteristics, including cognitive impairment, gait abnormalities and postural instability [32, 35].
Reduced Prevotella may be associated with lower levels of mucin and
SCFAs, leading to increased risks of gut permeability and inflammation .
Reduced Prevotella is also associated with lower levels of
neuroprotective factors such as thiamin, folate and hydrogen sulfide. Growth
hormone-releasing peptides produced by Prevotella can also play a
protective role in the progression of degenerative diseases by altering the
intensity of mitochondrial respiration, maintaining ROS levels, inhibiting the
accumulation of pathological
It is generally accepted that Lactobacillus and Bifidobacterium strains are beneficial for the regulation of gut microbiome homeostasis and for maintaining gut barrier stability . Higher levels of Lactobacillus and Bifidobacterium strains are usually detected in PD patients. Contrary to popular perception, they do not appear to have the rightful role in PD for reasons that are not known. Some studies suggest that PD patients may have consumed more milk than the general population since milk increases the number of gut Lactobacillus and Bifidobacterium strains which could increase the risk of PD , although it does not always show an increase . Furthermore, the number of Lachnospiraceae, Bifidobacterium and Lactobacillus is positively correlated with levodopa dose. Long-term use of levodopa in PD patients can lead to an increased number of the aforementioned microbiome . To avoid interference from treatments such as levodopa in the study of gut microbial homeostasis, researchers have studied untreated subjects with newly diagnosed PD. In such patients, the composition of the gut microbiome in their fecal samples was similarly altered. The abundance of Lachnospiraceae, in particular, was reduced in PD patients. However, no increase was found in the number of Bifidobacteria or Lactobacillus .
Currently, symptomatic treatment is mainly used to improve the clinical manifestations and enhance the quality of life of PD patients. The most common approach is the use of levodopa, which supplements the deficiency in physiological brain dopamine and stimulates brain dopamine receptors. This approach has its drawbacks, however, since patients are inclined to develop tolerance to the drug in the late stages of treatment, and increased dosage tends to trigger a series of abnormalities in motor function. Moreover, the administration of levodopa does not stop disease progression. Levodopa is mainly used to improve the motor symptoms of PD patients, and many non-motor symptoms may not respond to dopaminergic therapy . In addition, gut dysfunction in PD patients also weakens the absorption of levodopa. Therefore, there is an urgent need for new therapeutic methods to treat the clinicopathological manifestations of PD patients, including non-motor symptoms. The close correlation between gut microbiota and PD suggests it is important to trial the use of gut microbes to reduce mortality and morbidity after neurological injury in patients. Here, we focus on recent advances in the treatment of PD from the perspective of the microbiota-gut-brain axis.
One intervention is the use of probiotics or specific bacterial strains that may
be beneficial to the host in PD patients. Using a synuclein disease model of
Caenorhabditis elegans, Goya et al.  found the probiotic
Bacillus subtilis strain had an inhibitory effect on
Tamtaji et al.  conducted a randomized, double-blind, placebo-controlled clinical trial of several probiotics (Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus royi and Lactobacillus fermentum) in 60 PD patients for 12 weeks. Compared to placebo, probiotic supplementation was found to reduce the levels of high-sensitivity C-reactive protein and malondialdehyde and to have a positive effect on parameters such as motor function, insulin metabolism and oxidative stress in PD patients.
The most direct way to alter the gut microbial homeostatic environment is through fecal microbiota transplantation (FMT), in which feces from healthy organisms are transplanted into subjects with a disturbed gut microbiota system. This technique has been used successfully for the treatment of recurrent or refractory Clostridium difficile infections. Moreover, it is currently being trialed for the treatment of several conditions, including ulcerative colitis, infant gut microbial repair, and neurological lesions .
FMT has been reported to reduce gut microbial dysbiosis, increase striatal
dopamine and 5-hydroxytryptamine levels, decrease the expression of pathological
A prospective, single-study in PD patients found that FMT restored the overgrowth of gut microbiota, with an increased abundance of Blautia and Prevotella and a marked decrease in the abundance of Bacteroidetes . Moreover, scores for the Parkinson’s Disease Rating Scale (UPDRS) and the non-motor symptoms questionnaire (NMSs) declined significantly in PD patients. Guangzhou First People’s Hospital in China will carry out a study on PD patients involving a 6-month treatment with FMT for analysis of gut microbiota diversity and evaluation of the efficacy and safety of FMT for constipation symptoms in patients receiving levodopa treatment (ClinicalTrials.gov Identifier: NCT04837313). A randomized, double-blind, placebo-controlled clinical trial on PD patients conducted by Ghent University in Belgium will examine the effects of FMT on serum marker levels, gut and central nervous system barrier function, and microbiota changes associated with motor and non-motor symptoms (ClinicalTrials.gov Identifier: NCT03808389). A 6-month phase 2/3 clinical trial conducted by the Soroka University Medical Center in Israel will study the effect of using FMT to introduce or restore a stable, “healthy” gut microbial community on motor symptoms and constipation levels in PD patients (ClinicalTrials.gov Identifier: NCT03876327). A phase 1/2 clinical trial conducted by the Warsaw Medical University in Poland will evaluate the effect of FMT on tremor, slow movement and balance problems in PD patients within the first year of treatment, as well as on the frequency of constipation (ClinicalTrials.gov Identifier: NCT05204641).
In addition to the therapeutic strategy of using dopamine to stimulate dopamine receptors in the brain of PD patients, researchers have also explored the design of relevant drug regimens from a microbiota-gut-brain axis perspective.
Minocycline can attenuate the rotenone-induced progressive loss of tyrosine hydroxylase-immunoreactive neurons in rats . Its antioxidant and anti-inflammatory properties may also provide protection against dopaminergic neurology in the Drosophila DJ-1A model of PD . To evaluate the effect of minocycline on the progression of PD, a randomized, double-blind phase 2 trial involving 42 trial centres and 195 PD patients was carried out in the United States and Canada (ClinicalTrials.gov Identifier: NCT00063193). Unfortunately, minocycline showed no significant benefit for patients .
Doxycycline can block 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in mice
by inhibiting microglia and astrocyte expression . In addition, it can
inhibit LPS-induced dopaminergic neuronal degeneration by downregulating
microglial histocompatibility complex II (MHC II) expression . Doxycycline can also effectively eliminate
cognitive and daily activity deficits in A53T mice by reducing the structural
stability of pathologic
Ceftriaxone can downregulate the levels of glial fibrillary acidic protein (GFAP) and ionize calcium binding adaptor molecule 1 (Iba1), which are markers of astrocytes and microglia, respectively. It can also decrease the abundance of gut Aspergillus and increase probiotic abundance while also increasing the production of tight junction proteins in the colon of a PD mouse model . Ceftriaxone also increases the expression of the glutamate transporter protein glutamate transporter 1 (GLT1) in the brain, delays the loss of neuronal and muscle strength, and increases survival in a mouse model of PD . Of note, ceftriaxone may also enhance systemic inflammation in mice . An exacerbated inflammatory response is associated with deterioration of the colonic structure and dysregulation of gut microbiota homeostasis. Researchers plan to conduct a randomized, double-blind, placebo-controlled, phase 2 clinical trial involving 106 participants to determine the potential efficacy and safety of ceftriaxone in patients with Parkinson’s dementia (ClinicalTrials.gov Identifier: NCT03413384).
Researchers have also investigated other drugs besides antibiotics for the
treatment of PD from the perspective of the microbiota-gut-brain axis, but most
are still in the animal testing phase. de la Cuesta-Zuluaga et al. 
reported that diabetic participants taking metformin had a higher relative
abundance of the probiotics Butyrivibrio, Bifidobacterium bifidum, Megasphaera and Prevotella than non-diabetic
participants. Diabetic participants not taking metformin also had a higher
relative abundance of the harmful microbe Clostridiaceae02d06 and a
lower abundance of the probiotic Enterococcus casseliflavus compared to
non-diabetics. Hou et al.  found a dose-response correlation between
metformin and the incidence of PD in type 2 diabetic patients. Diabetic patients
treated with low doses of metformin were less likely to develop PD, while higher
doses of metformin treatment were not neuroprotective. Another study evaluated
squalamine the synthetic squalamine salt (ENT-01) for the treatment of PD symptoms. Experiments have shown that
squalamine improved normal peristaltic behaviour in a mouse model of PD by
As mentioned previously, gut microbes can use tyrosine decarboxylase to
decarboxylate levodopa and thus reduce its efficacy. Researchers, therefore,
designed a tyrosine mimic, (s)-
A Western diet (WD) high in fat and sugar can increase the abundance of microorganisms that produce harmful substances such as lipopolysaccharides, thereby inducing dysbiosis of the gut microbiota and increasing gut permeability. A WD can also induce damage to the blood-brain barrier and cause neuroinflammation associated with toxic amyloid aggregation, both of which are closely related to the development of PD . In contrast, the Mediterranean diet (MeDiet), rich in foods such as tea, vegetables, nuts, olive oil and coffee, can exert neuroprotective effects and reduce the daily required dose of levodopa. MeDiet promotes beneficial microbiome metabolism, induces gut gluconeogenesis and the production of brain-derived neurotrophic factor (BDNF), and reduces the production of harmful substances such as trimethylamine N-oxide (TMAO) , thereby improving symptoms such as depression, constipation and daytime sleepiness in PD patients [71, 72]. In addition, branched-chain amino acids (BCAAs) such as leucine, isoleucine and valine are commonly used as dietary supplements and essential amino acids to modulate brain function. A diet high in BCAAs can increase intestinal probiotics and attenuate inflammation levels. Experiments with a mouse model of PD have shown that BCAAs can even reverse motor and non-motor dysfunction, as well as reduce dopaminergic neuronal damage .
Using a mouse model of PD, Jang et al.  found that acupuncture can increase the number of dopaminergic fibers and neurons in the striatum and substantia nigra, block inflammatory responses and apoptosis, and improve the relative abundance of gut microbes. The effects of acupuncture on enhancing motor function and protecting dopaminergic neurons may be related to its regulation of gut microbial homeostasis. Zhang et al.  designed an optogenetically-engineered probiotic that released Exendin-4 in response to red light. This drug was fused to the antineoplastic Fc receptor and could be transported to the brain via the microbiota-gut-brain axis to modulate brain function.
A large body of research evidence links the microbiota-gut-brain axis to the
development of human neurological disorders such as epilepsy, stroke, depression,
Alzheimer’s disease and PD. Gut microbiota and their metabolites can influence
immune activation, neurotransmitter production and endocrine function in the
body. Additional findings now support the Braak theory, which suggests that gut
microbiota regulate brain nervous system function by regulating the production
and transmission of pathological
In the present work, we describe the microbiota-gut-brain axis and focus on the impact of gut microbiota on PD. We analyse the distinctive changes in the microbiota of PD patients, relate these changes to the disease, and evaluate various approaches to the treatment of PD from the perspective of the microbiota-gut-brain axis. Elucidation of the exact mechanism by which gut microbiota and their products affect PD progression is currently the most urgent issue with regard to therapeutic approaches involving the microbiota-gut-brain axis.
Additional gut microbes have now been identified following the development of microbial identification technologies such as metagenomics and 16S rRNA gene amplicons. Although some common alterations have been detected in the gut microbiota of PD patients, many patients do not show highly consistent changes. This is probably because gut microbes are also influenced by diet, lifestyle habits, treatment status (drug/non-drug), personal constitution and geographical location. These variables increase the uncertainty around the impact of gut microbiota on the progress of PD. Accurate identification of microbes that exert a protective or pathogenic effect for PD is highly challenging due to the enormous diversity of the gut microbiome and the complex relationships between microbial members.
The primary means of treating the motor and non-motor symptoms of PD from the
perspective of the microbiota-gut-brain axis include but are not limited to,
probiotics, FMT, dietary interventions, and related pharmacological treatments.
Probiotic therapy appears to be more in line with the concept of
microbiota-targeted therapy than FMT, which requires an understanding of the
temporal and causal relationship between a specific probiotic and the development
of PD. The applicability of the probiotic as a biomarker of PD needs to be
assessed and the dose and course determined, as well as other medication details
for the treatment of PD. FMT appears to be a “once only” solution for the repair
of recipient gut microbial damage by transplanting donor feces directly into the
recipient. In practice, however, there are many uncertainties associated with
this technique. Firstly, the transplanted feces contain not only the target
microbiota but also viruses, fungi, harmful metabolites, and so on that can
increase the risk of infection when transplanted, especially in immune-restricted
populations. More studies are needed that include purification of the
microorganisms in donor feces. Secondly, FMT, that contains multiple
microorganisms makes it very difficult to identify therapeutic mechanisms at the
molecular level and to develop targeted microbiota therapeutic approaches.
Finally, more clinical trials are needed to determine whether the transplanted
fecal microorganisms will be rejected by the recipient and whether the
transplanted fecal microorganisms will deliver long-term and stable effects.
Furthermore, both the use of probiotics and FMT need to be considered in terms of
their impact on the uptake and absorption of levodopa medication taken by PD
patients. Provided that a balanced diet is maintained, a low-fat, low-sugar diet
with characteristics of the MeDiet can alleviate gastrointestinal symptoms in PD
patients and attenuate neuroinflammation. Antibiotics can inhibit or destroy
certain microorganisms present at low concentrations, as well as promote the
growth of other gut microbiota or the emergence of new microbial species. Thus,
antibiotics may exert anti-inflammatory and neuroprotective effects, as well as
anti-pathological effects on
At present, large clinical studies for the treatment of PD based on the microbiota-gut-brain axis theory are still lacking. Previous small but well-designed studies can be meta-analysed to provide new insights into the mechanisms involved in disease treatment. In addition, more animal or human trials on the treatment of PD are needed from the perspective of the microbiota-gut-brain axis. These studies should help to reveal the exact mechanisms of microbial-induced gut and systemic inflammation, especially at the molecular level. The biological signals produced by the gut microbiota are transmitted along the gut-brain axis to the central nervous system, where they act to regulate cells, signaling pathways, and target tissues and organs. Further studies should aim to identify new biomarkers for early diagnosis and monitoring of disease progression and to develop more effective and personalized treatment strategies for disease management.
WZ and XL mainly conceptualized the notion of this review manuscript. YLY and JYS revised the manuscript and contributed to literature review. TS, TTX, LHX, XFQ and QJZ contributed to the literature review. All authors contributed to the editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have contributed sufficiently to the work and agree to be accountable for all aspects of the work.
Thanks to all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.
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