Sage Journals: Discover world-class research

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss and α-synuclein (α-syn) aggregation. With the acceleration of population aging process, the incidence of PD is expected to increase, putting a heavy burden on the whole society. Recent studies have found the alterations of gut microbiota (GM) in PD patients and the clinical relevance of these changes, indicating the underlying relationship between GM and PD. Additionally, elevated inflammatory responses originating from the gut play a crucial role in the initiation and progression of PD, which is closely associated with GM. In this review, we will summarize recent studies on the correlation between GM and PD, and discuss the possible pathogenesis of PD mediated by GM and subsequent inflammatory cascades. We will also focus on the promising GM-based therapeutic strategies of PD, including antibiotics, probiotics and/or prebiotics, fecal microbiota transplantation, and dietary interventions, aiming to provide some new therapeutic insights for PD.

Keywords

Parkinson’s disease gut microbiota inflammation α-synuclein short chain fatty acids

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease, ranking only after Alzheimer’s disease (AD). With accelerated aging process of the population, the incidence of PD is expected to increase. In the most populous nations, it is estimated that nearly 9 million people may suffer from this progressive disorder of central nervous system (CNS) by 2030 (more than twice as many as the number in 2005).¹

Characterized by the loss of dopaminergic neurons and aberrant accumulation of α-synuclein (α-syn) in the substantia nigra and striatum,² PD presents with both motor and non-motor symptoms. Other than the commonly known motor symptoms (e.g., tremor, bradykinesia, and rigidity³), non-motor symptoms also severely affect the quality of life of PD patients. Moreover, some of those non-motor symptoms may precede the classical motor ones of PD by several years.⁴ Gastrointestinal (GI) symptoms of PD include constipation, abdominal pain, bloating, and defecation dysfunction,⁵ and they have been well recognized in PD patients, especially in the presymptomatic ones. Many (up to 80%) patients experienced constipation and delayed gastric empty several years before diagnosed with PD,⁶ and the occurrence of GI symptoms or gut microbial dysbiosis in healthy people is linked to an increased risk of PD.⁷

As a complex and multifactorial disease, the exact pathogenesis of PD remains unclear. However, some mechanisms have been identified to be related to PD, including α-syn aggregation, neuroinflammation, and mitochondrial dysfunction.⁸ Meanwhile, due to the limited knowledge of PD pathogenesis, there has been no comprehensive therapeutic strategy to cure or even prevent the progression of this disease. As the most commonly used drug for PD, levodopa can cross the blood–brain barrier (BBB) and be converted to dopamine in the CNS to alleviate some of the motor symptoms.⁹ However, it has no effect on both the non-motor symptoms and the dopaminergic neurodegeneration in PD.¹⁰ In addition, it has some possible side effects, such as orthostatic hypotension and dyskinesia.^11,12 In recent years, special attention has been paid to the role of GI tract and the inside gut microbiota (GM) as well as the inflammatory hypothesis which considers PD as a systemic disease. GM and its metabolites have been reported to be involved in the modulation of GI functions and the activity of enteric nervous system (ENS), thus affecting the CNS through the microbiota-gut-brain axis (MGBA) .¹³ Moreover, the peripheral inflammation including GM-induced intestinal inflammation may initiate the accumulation of α-syn and lead to systemic and CNS inflammation, finally contributing to the initiation and progression of PD.¹⁴ Therefore, GM-targeted treatment to attenuate intestinal inflammation may become a potential therapeutic strategy for PD.

In this review, we will summarize recent studies on the correlation between GM and PD, discuss the possible pathogenesis of PD mediated by GM and inflammation, and focus on the GM-targeted treatment of PD.

Gut microbiota alterations in PD

Gut microbiota

Gut microbiota (GM), predominated by bacteria, fungi, viruses, and protozoa,¹⁵ is the generic term for more than 100 trillion microbes existing in the human GI tract. Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia are the main phyla of human GM, in which Firmicutes and Bacteroidetes account for 90%.¹⁶ As a highly complex microbial community, GM has co-evolved with humans for millions of years, forming a mutually beneficial relationship.¹⁵ Physiologically, GM and its metabolites play a key role in the development of both the immune and nervous system.¹⁵ After the fetus is born, GM obtained from the mother as well as the environment start to colonize his or her GI tract. Through the bi-directional communication between GM and brain, termed as MGBA, GM will have an impact on the both the GI functions and CNS development.¹⁷ A balanced and stable GM is vital for the integrity of intestinal barrier, the mucosal immune function, and the motility of gut.¹⁸ Besides, GM and its metabolites can modulate the activity of ENS and the processes in CNS, such as the permeability of BBB and biochemical reactions in the brain.¹⁹ They can also influence humans’ behaviors, including emotional ones and the stress responsiveness.^20,21 However, healthy individuals only share one third of GM, leaving the remaining two thirds varying from person to person.²² The composition of GM can be affected by the delivery type as well as feeding mode of infants, lifestyle (especially the dietary habits), antibiotic treatment, and other factors which can alter either the internal or external environment.¹⁶

Alterations of gut microbiota in PD

Gut dysbiosis refers to the alteration of structure and/or function of GM, disrupting the gut homeostasis.²³ Like the shaping factors of normal composition of GM, gut dysbiosis can be caused by lifestyle changes (especially the dietary alterations), antibiotic exposure, inflammation, and other factors.¹⁶ Recent study by Wallen et al.²⁴ suggested the potential role of genetics on GM. They found that alterations of the host genotype at α-syn locus may influence the abundance of some opportunistic pathogens in PD gut, further indicating that PD-related genetic variants may increase susceptibility of PD via GM alterations. As an essential part of the MGBA, gut dysbiosis is correlated to several diseases, including GI diseases, autoimmune diseases, metabolic disorders, and CNS-related diseases.²⁵ Hager et al.²⁶ studied GM in patients with Crohn’s disease, finding that their levels of Candida tropicalis, E. coli, and Serratia marcescens were higher as compared to healthy controls. These microbes work in symbiosis to form biofilms, leading to the gut inflammatory responses. Studies have also shown the potential role of gut dysbiosis in CNS-related conditions, such as AD,²⁷ depression,²⁰ schizophrenia,²⁸ multiple sclerosis,²⁹ and autism.³⁰ Similarly, recent studies have highlighted the correlation of gut dysbiosis and PD,^31-33 while some results seem inconsistent, possibly due to the differences in methodology (i.e., sampling parts and methods), geographical regions, and patients’ dietary habits.^2,34,35

Numerous studies have shown the alterations of GM in PD patients. Recent studies on the major alterations of gut microbiota at family levels in PD patients are summarized in Table 1. There are some differences in the alterations of Lachnospiraceae and Lactobacillaceae, in which most studies have shown an increase in Lactobacillaceae and a decrease in Lachnospiraceae as compared to healthy controls.^33,36-45 Contradictions may be attributed to the differences in methodology, dietary, and geographical factors. Consistent increases in PD patients were principally showed in the family Verrucomicrobiaceae, genus Akkermansia, and species Akkermansia muciniphila.^36,37 Taking the mucin as a source of energy, Akkermansia will degrade the gut mucous layer when the fibers taken in are limited. Then function of intestinal epithelial barrier will decrease and the permeability of it may increase, facilitating the possible stimuli to enter the blood circulation, exposing the ENS system to a toxic or pro-inflammatory environment, thus enhancing the infectious and inflammatory risk.⁴⁶ All these above contribute to the initiation and development of PD through the MGBA. However, possibility for more substances in the gut to cross the intestinal barrier may also serve as a potential target for microbial intervention to relieve the symptoms of related diseases. Ou et al.⁴⁷ found that A. muciniphila may improve the dysfunction of intestinal barrier and dyslipidemia, delaying the pathological changes in the CNS through the MGBA.

Table 1.

Alterations of gut microbiota at the family level in Parkinson’s disease(PD) patients and animal models.

Research	Altered gut microbiota at family level
Research	Akkermansiaceae	Bifidobactellaceae	Christensenellaceae	Enterobacteriaceae	Enterococcaceae	Erysipelotrichaceae	Lachnospiraceae	Lactobacillaceae	Pasteurellaceae	Porphyromonadaceae	Prevotellaceae	Rikenellaceae	Ruminococcaceae	Verrucomicrobiaceae
Bedarf et al.³⁴	↑	—	—	—	—	↓	↓	—	—	—	↓	—	—	↑
Hill-burns et al.³⁵	↑	↑	↑	—	—	—	↓	↑	↓	↑	—	—	—	↑
Hopfner et al.³⁶	—	—	—	—	↑	—	—	↑	—	—	—	—	—	—
Li W et al.¹²⁹	—	—	—	↑	↑	—	—	—	—	—	—	—	—	—
Heintz-buschart et al.⁵¹	↑	—	—	—	—	—	—	—	—	—	—	—	—	↑
Qian et al.³¹	—	—	—	—	—	↑	—	↓	—	—	—	↑	—	—
Lin a et al.³⁷	—	↑	—	—	—	—	↓	—	↓	—	—	—	—	—
Aho et al.³³	—	—	—	—	—	—	—	—	—	—	↓	—	—	—
Barichella et al.³²	—	↑	↑	↑	—	—	↓	↑	—	—	—	—	—	↑
Li C et al.³⁰	—	—	—	—	—	—	—	↓	—	—	—	—	—	↑
Li F et al.⁶⁶	↑	—	—	—	—	—	↑	—	↓	↑	↓	—	—	↑
Lin CH et al.³⁸	↑	—	—	—	↑	↑	—	↑	—	↑	↓	↑	—	↑
Pietrucci et al.³⁹	—	—	—	↑	—	—	↓	↑	—	—	—	—	—	—
Wallen et al.⁴²	—	—	—	—	—	—	↓	—	—	—	—	—	↓	—
Nishiwaki et al.⁴⁶	↑	—	—	—	—	—	—	—	—	—	—	—	—	—
Cristea et al.⁴⁰	—	—	↑	—	—	—	↓	—	—	—	—	—	—	—
Vascellari et al.⁴¹	—	↑	—	↑	—	—	↓	—	—	—	—	—	—	↑
Aho et al.¹³⁰	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Rosario et al.⁴³	↑	—	—	—	—	—	↓	—	↓	—	—	—	—	—

Notes: ↑: significantly increase in PD patients or animal models; ↓: significantly decrease in PD patients or animal models.

Alterations of GM composition are closely related to the metabolism and function of these microbes. Roseburia and Faecalibaterium were reported to decrease in PD patients.⁴⁸ Known as the health-promoting genera, Roseburia and Faecalibaterium can produce butyrate, a kind of short chain fatty acids (SCFAs). SCFAs can induce the expression of anti-inflammatory cytokines genes, exerting anti-inflammatory and neuroprotective effect through the MGBA.⁴⁹ Therefore, a decrease of Roseburia and Faecalibaterium in PD patients will create an inflammatory environment, contributing to the aggregation of α-syn and the cascading neuroinflammation.⁵⁰ Similarly, both Wallen et al.⁴⁴ and Cristea et al.⁴² have reported lower abundance of SCFA-producing bacteria in PD patients, while they also have their own points. Wallen et al.⁴⁴ revealed that there was a significant increase in Lactobacillus and Bifidobacterium, two carbohydrate-metabolizing bacteria. Cristea et al.⁴² also found an increase in Bifidobacterium, and they pointed that GM in PD patients demonstrated a lower capacity of carbohydrate fermentation and butyrate synthesis, with the process of proteolytic fermentation enhanced and production of deleterious amino acid metabolites increased.

The results of studies on PD animal models are similar to most of those on PD patients. Sun et al.⁵¹ reported an increase in phylum Proteobacteria in fecal samples of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, which is consistent with the findings in humans. Likewise, Lai et al.⁵² found the decreased family Lachnospiraceae in a MPTP-induced mouse model, just like the results in PD patients. However, there are some inconsistencies at both families and genera levels, which may be ascribed to the differences between humans and mice, especially the dietary habits of PD patients and healthy controls.

In a word, GM in PD patients and animal models are significantly altered, which can possibly be regarded as biomarkers for early diagnosis or targets for PD treatment. However, due to the differences in the design of studies as well as the selection of subjects, the exact rules of alterations including the altered types and timepoints remain unclear.

Clinical correlations between alterations of gut microbiota and PD

Emerging studies have shown the correlations between GM alterations and the phenotypes of PD, which are summarized in Table 2. Prior to other prominent symptoms, the non-motor symptoms have sparked increasing attention. For example, Heintz-Buschart et al. ⁵³ found that GM of genera Anaerotruncus and Akkermansia were significantly related to non-motor symptoms of PD according to MDS-UPDRS part I. Of numerous non-motor symptoms of PD, GI symptoms are the most prevalent ones. For instance, the taxonomic shifts and elevated proteolytic metabolites, which were caused by the alterations of GM composition, are relevant to the stool consistency (a proxy for colonic transit time) and severity of constipation.⁴² Since constipation precedes the motor symptoms for years and last throughout the whole course, it is promising to target the alterations of GM as a biomarker for early diagnosis and to improve the quality of life for PD patients.⁴² Other PD-related non-motor symptoms include depression, anxiety and cognitive decline, which are known as the neuropsychiatric symptoms. Studies have found association between these non-motor symptoms and GM alterations in PD patients. For example, an altered abundance of Anaerotruncus spp. was linked to depression by Heintz-Buschart et al.,⁵³ which is consistent with results from other human cohorts^54,55 and animal models.^56,57 Alifrova et al.⁵⁸ found that PD patients with moderate depression had a higher abundance of Christensenella minuta, Clostridium disporicum, and Oscillibacter valericigenes as compared to those without depression or with mild depression, and PD patients with clinically significant anxiety had higher abundance of Clostridium clariflavum compared to the anxiety-free ones. As for cognitive impairment, Ren et al.⁵⁹ found that decreased abundance of genus Blautia and Ruminococcus was negatively correlated with cognitive ability of sporadic PD patients. Ishii et al.⁶⁰ confirmed that oral administration of probiotic Bifidobacteriumbreve improves the cognition of an MPTP-induced PD mouse model.

Table 2.

Clinical correlations between gut microbiota or its metabolites and Parkinson’s disease(PD).

Clinical phenotypes of PD		Alterations of gut microbiota and its metabolites	References
Motor symptoms	Motor complications (MDS-UPDRS total/Part III scores)	Anaerotruncus sp., Clostridium XIVa, lachnospiracae ↑	⁵¹
		Prevotellaceae ↓	⁵³
		Lactobacillaceae ↑	³²
		Bifdobacterium, Atopobium↓	¹³¹
		Aquabacterium, Peptococcus, Sphingomonas↑	³¹
	Disease severity and motor impairment	Enterobacteriaceae ↑ Lachnospiraceae ↓	³⁹
	Postural instability and gait difficulty	Enterobacteriaceae↑	⁵³
		Lachnospiraceae ↓	¹³²
		Butyrate levels↓	³²
Non-motor symptoms	MDS-UPDRS part I scores	Christensenellaceae ↑	³²
	MDS-UPDRS part I scores	Anaerotruncus, Akkermansia↑	⁵¹
	Constipation	Taxonomic shifts, proteolytic metabolites of GM↑	⁴⁰
	Constipation	NMPCs of xanthine, D-alanine, L-lactic acid, D-ribose, pantothenic acid↑	¹³³
	Depression	Bifidobacterium ↓	³¹
		Anaerotruncus spp. ↑	⁵¹
		Christensenella minuta, Clostridium disporicum, Oscillibacter valericigenes↑	⁵²
	Anxiety	Clostridium clarifavum↑	⁵²
	Cognitive decline	Butyricicoccus, Clostridium XlVb ↑	³¹
	Cognitive decline	SCFAs↓	¹³²
	Hallucinations and delusions	Bifdobacterium↓	¹³¹
Others	Early onset	Pasteurellaceae ↑	³⁷
	Disease duration	Lachnospiraceae ↓	¹³⁴
	Disease duration	Escherichia/Shigella↑	³¹
	iRBD	Anaerotruncus↑ Prevotellaceae↓	⁵¹

Notes: ↑: a positive correlation between the microbiota and symptoms; ↓: a negative correlation between the microbiota and symptoms.

Abbreviations: MDS-UPDRS: Movement Disorder Society-Unified Parkinson Disease Rating Scale; NMPCs: net maximal production capabilities; iRBD: idiopathic rapid-eye-movement sleep behavior disorder; SCFAs: short chain fatty acids.

Recently, clinical correlations between GM and PD have been extended to other aspects, including the motor symptoms, staging and duration as well as the onset time of PD.^34,39,61 For example, Tan et al. found that increased Enterobacteriaceae and decreased Lachnospiracae was associated with motor impairment.^41,62 However, abundant Lachnospiracae was related to motor symptoms by Heintz-Buschart et al.,⁵³ which might be attributed to different selection of cohorts. Studies by Zhang et al.⁶³ revealed that 15 genera are related to the Hoehn and Yahr stage while 11 genera are linked to the duration of PD. Furthermore, 8 inflammation-associated genera are positively associated with the Hoehn and Yahr stage or the disease duration, indicating the potential role of inflammation in PD pathogenesis.

Other than correlated with the clinical phenotype and severity of PD, alterations of GM can also serve as a marker for the initiation and progression of PD. For example, idiopathic rapid-eye-movement sleep behavior disorder (iRBD) is known to predispose to neurodegenerative diseases including PD.⁶⁴ Nishiwaki et al.⁵⁰ found that there was an increase in Akkermancia but not a decrease in SCFA-producing bacteria in iRBD. Thus, a decrease in a SCFA-producing genus Faecalibacterium might be a hallmark for the transition from iRBD to PD, indicating GM as a potential therapeutic target to retard the progression of PD. However, due to the difficulties in identifying non-motor symptoms of PD in clinical practice, the number of clinical studies among newly diagnosed or pre-motor patients are limited. Yan et al.⁶⁵ found elevated Sybergistetes, Akkermansia, and Eggerthella lenta and decreased Prevotella in A53T transgenic monkey models with early stages of PD. Based on existing data of 423 newly diagnosed PD patients, Jones et al.⁶⁶ concluded that gastrointestinal symptoms, which is associated with GM dysbiosis, may predict cognitive function in de novo PD. Further clinical studies focusing on pre-motor stages of PD are warranted.

In general, alterations in GM are clinically correlated with the symptoms and development of PD. However, mechanisms behind the correlations have not been clarified, and evidence of the relationship between the specific changes of GM and the development of PD is limited. Therefore, we expect more cohort studies with data supporting the association between GM alterations and the progression of PD as well as the specific alterations of GM composition.

Possible GM-inflammation-PD pathogenesis

Emerging studies have revealed that the initiation and progression of PD can be attributed to the inflammation originating from the gut. For instance, inflammatory bowel diseases (IBD) share some risk genes such as LRRK2⁶⁷ and CARD15⁶⁸ with PD, indicating the potential role of genetic risk factors in gut inflammation through MGBA. Besides, PD patients were reported to have increased bowel inflammation.⁶⁹ Devos et al.⁷⁰ found an increase in some pro-inflammatory cytokines (IL-1β, IL-6, IFN-γ, TNF-α) and glial markers (GFAP, Sox-10) in colonic biopsies of PD patients. Stool immune profiles of PD patients also revealed an elevated expression of several pro-inflammatory cytokines and chemokines such as IL-1α, IL-1β, and IL-8.⁶⁹ In this part, we will discuss the possible pathogenesis of PD represented by GM dysbiosis, intestinal barrier, gut inflammation, and neuroinflammation, highlighting the two mediators: α-syn and pro-inflammatory substances produced by GM.

Gut microbiota, intestinal barrier, and gut inflammation

There is a mutual relationship between GM, intestinal barrier, and gut inflammation (Figure 1). As an organic complex, GM can synthesize various metabolites to adapt to their living environment, some of which are linked to gut inflammation, such as pro-inflammatory or anti-inflammatory cytokines, LPS, neurotransmitters and neuromodulators.⁷¹ They can also produce neurotoxic metabolites including D-lactic acid and ammonia,⁷² which will affect the CNS through a direct neural communication by stimulating the afferent neurons in the ENS.⁷³ Studies have revealed anti-inflammatory role of SCFAs. A decrease in SCFA-producing GM will lead to a reduced synthesis of mucin and increased permeability of intestinal barrier, exposing the internal environment to the bacterial antigens as well as the endotoxins in the gut and contributing to the overexpression and misfolding of α-syn.⁴⁹ In addition, the clearance of α-syn will also be downregulated due to the SCFA-dependent modulation.⁷⁴ All these mechanisms can result in the gut inflammation, which is supported by the colonic biopsies of PD patients.⁷⁵ By metabolizing the dietary tryptophan, GM can also produce kynurenic acid, exerting neuroprotective effect in the gut due to its anti-inflammatory properties.⁷⁶

Figure 1.

The link between gut microbiota dysbiosis, intestinal barrier and gut inflammation. There is a mutual relationship between gut microbiota dysbiosis, intestinal barrier and gut inflammation. Alterations of gut microbiota may increase the permeability of intestinal epithelial barrier, exposing the enteric nervous system and the immune system to the bacteria and their metabolites and thus contributing to the gut inflammation. The inflammatory environment will aggravate the dysfunction of intestinal barrier and the dysbiosis of gut microbiota.

GM dysbiosis in PD are shown to be associated with the destructed intestinal barrier. Involved in the mucin synthesis and the production of SCFA, Prevotellaceae were reported to decrease in PD patients,⁷⁷ suggesting the possible role of increasing intestinal permeability in PD pathogenesis. Due to the gastroparesis and impaired GI motility in PD, small intestinal bacterial overgrowth (SIBO) is common in PD patients,⁷⁸ which will disrupt the integrity of the small intestinal barrier, resulting in the immune stimulation and/or alterations in L-dopa absorption. This was supported by the observation that motor fluctuations were improved after treating PD patients with rifaximin.⁷⁹

Increased permeability of intestinal barrier is closely associated with gut inflammation, which has been proved in both PD patients⁸⁰ and animal models.⁸¹ The intestinal epithelial barrier prevents the invading pathogenic microbes and other environmental factors from altering gut homeostasis, thus alleviating gut inflammation. The possible mediators between the impaired intestinal barrier and gut inflammation include the ENS and the immune system. As the first level of the neural network of the GI system,⁸² ENS is represented by neurons of the myenteric (Auerbach’s) plexi, submucosal (Meissner’s) plexi, and enteric glial cells (EGCs).⁸³ The neurons are responsible for the local reflexes such as the relaxation and contraction of the smooth muscle, while EGCs are essential for the development and differentiation of the neurons.⁸⁴ Additionally, EGCs are involved in the modulation of the intestinal barrier and gut inflammation.⁷⁰ Glial-derived neurotrophic factors (GDNFs) were shown to be fundamental in maintaining the integrity of the intestinal epithelial barrier,⁸⁴ and some pro-inflammatory cytokines and glial markers were increased in colonic biopsies of PD patients, which is link with the disease duration.⁷⁰ Pro-inflammatory cytokines secreted by GM activate the EGCs, contributing to the subsequent inflammation in the ENS and even the CNS. Besides, the neurotoxic metabolites of GM can stimulate the afferent neurons of ENS, thus resulting in the neurological dysfunction through direct neural communication⁷³ and affecting the function of the intestinal barrier as well as gut inflammation.

Studies have also revealed both the innate and the adaptive immune system are dysregulated in neurodegenerative diseases including PD.⁸⁵ As an essential part of the innate immunity, toll-like receptors (TLRs) are closely related to the early recognition of infection defensing against the invading microbes.⁸⁶ Evidence has shown that the disruption of TLR signaling may be involved in PD. For instance, expressed in the ENS and the gut smooth muscle, TLR2 can regulate not only the integrity of the intestinal barrier but also the activation of the ENS, even the microglial cells in the CNS.⁸⁷ Moderate activation of TLR2 was reported to restore the neurogenesis in the gut and increase the number of nitrergic neurons in GF mice,⁸⁸ while excessive activation of TLR2 can overstimulate the microglial cells, leading to the subsequent neuroinflammation and PD development.⁸⁷ TLR4 also plays a crucial role in the process of inflammation. Increased permeability of intestinal barrier contributes to the translocation of some GM metabolites including LPS to the internal environment, thus activating the TLR4-mediated inflammatory cascades. The cascades then induce the systematic inflammation and/or the neuroinflammation, aggravating the neurodegeneration in PD.⁸⁹ Another supporting study found that the knockdown of TLR4 substantially alleviated the dysfunction of intestinal barrier, decreased the activation of microglia and the loss of dopaminergic cells in the CNS, explaining the relief of some motor symptoms in rotenone-induced PD mice.⁹⁰ Alternatively, elevated gut inflammation will destruct the intestinal barrier, contributing to a more severe leakage of bacteria and their metabolites to the blood circulation.⁹¹ The dysfunction of intestinal barrier and the inflammatory environment can also disrupt the homeostasis of GM, affecting the diversity and function of these microbes.⁹²

CNS inflammation

Neuroinflammation presented by the activation of microglia and the dysfunction of BBB can be essential in PD pathology.^{93, 94} As the most substantial immunocytes in the CNS, microglia are at the first line of defensing against the pathogenic infection in the brain, initiating the downstream immune responses.⁹⁵ Moderate microglial activation was proved to be beneficial,⁹⁶ while overactivation of microglia will lead to the excessive production of pro-inflammatory cytokines (including IL-1β, IL-6, IFN-γ, and TNF), exerting negative effect on the dopaminergic neurons.⁹⁷ Consisting of endothelial cells, the basal membrane, tight junction and the end feet of astroglia, BBB is essential for the homeostasis of brain. Disruption of the integrity of BBB was proved to be related to several neurodegenerative diseases including PD.⁹⁸ Permeability of BBB in germ-free (GF) mice was increased due to the decreased expression of tight junction proteins such as claudin-5 and occludin, while administration of butyrate can strengthen the tight junctions and preserve BBB permeability in GF mice.⁹⁹ Likewise, sodium butyrate alleviated BBB lesion in MPTP-induced PD mice by upregulating the expression of occluding and ZO-1,¹⁰⁰ indicating the impact of GM and their metabolites on BBB integrity, neuroinflammation, and consequent neurodegeneration. Other metabolites like quinolinic acids can also serve as modulators of BBB, influencing the pathology of neurodegenerative diseases like PD.¹⁰¹ BBB dysfunction has also been assessed in the midbrain and striatum of PD patients.^102-104 Kortekaas et al.¹⁰² found PD patients have reduced P-glycoprotein function in the BBB of midbrain, facilitating the translocation of pro-inflammatory substances. Striatal BBB permeability also increased in PD patients, allowing for the potential therapeutic usage.¹⁰³

Potential mediators: α-syn and pro-inflammatory substances

There has been substantial evidence on the association between gut inflammation and PD.^68,70,74,75 However, the specific mechanism remains unclear. The most promising mediators contain α-syn and GM-originating pro-inflammatory substances, and a potential mechanism is summarized in Figure 2.

Figure 2.

A proposed schematic representation of gut microbiota(GM) dysbiosis-inflammation-Parkinson’s disease(PD) mechanisms. GM dysbiosis contributes to the disruption of intestinal barrier and gut inflammation, promoting the production of pro-inflammatory cytokines and the accumulation as well as misfolding of α-syn. Misfolded α-syn may propagate to the brain through the vagus nerve or the blood circulation, while pro-inflammatory cytokines reach the central nervous system(CNS) via the humoral pathway. Both α-syn and pro-inflammatory cytokines may destruct the blood–brain barrier and activate the microglia in the CNS, which will result in the neuroinflammation and neurodegeneration in PD.

As one of the hallmarks of PD, α-syn is much more widespread in PD patients as compared to the physical condition.¹⁰⁵ Physically, α-syn is crucial for the regulation for neurotransmission, while in neurodegenerative diseases, α-syn may have an impact on triggering and/or enhancing the activation of microglia and astroglia.¹⁰⁶ The abundance of α-syn in the gut is tightly correlated with the GM alterations which contribute to the disruption of intestinal barrier and gut inflammation. Gut inflammation may lead to the misfolding of α-syn or downregulate the clearance of it, resulting in the accumulation of α-syn and its inflammatory cascades. Numerous studies have supported that the propagation of α-syn through the vagus nerve, known as the Braak hypothesis.¹⁰⁷ It was inspired by the finding that lesions in the ENS precede those in the CNS.¹⁰⁸ In PD animal models, the transmission of aberrant α-syn was prevented by vagotomy,¹⁰⁹ thus prohibiting the misfolding of α-syn in intermuscular neurons and relieving the symptoms of PD. Recently. there has been some controversy on the results of vagotomy, indicating another pathway of α-syn propagation. Arotcarena et al.¹¹⁰ observed an increase in the concentration of α-syn in the whole blood of the monkeys that were enteric-injected with α-syn-containing Lewy body extracts from PD patients, thus proposing the general circulation pathway for the long-distance transmission of α-syn between the gut and CNS. However, more studies are needed to confirm this hypothesis.

The pro-inflammatory substances produced by GM include pro-inflammatory cytokines and other metabolites like LPS. Other than the traditional blood circulation pathway, these substances can possibly propagate through lymphatic circulation, which was supported by the discovery of a network of lymphatic vessels existing in dural sinuses and connecting the GI tact with CNS.¹¹¹ Pro-inflammatory cytokines and LPS may contribute to neuroinflammation by disrupting the BBB and activating microglia, which resembles the process in the gut.¹¹² In addition, LPS can interact with α-syn by binding to it and initiating the fibrilization in the gut that facilitates the propagation of α-syn to the CNS.⁹¹ LPS-induced neuroinflammation and memory loss in mice was reduced after administration of Lactobacilli-fermented cow’s milk, indicating the possible effects of probiotics on LPS-mediated pathology of PD.¹¹³

GM-targeted therapeutic strategies for PD

Due to the limited knowledge of PD pathogenesis, there has been no comprehensive therapeutic approach to prevent the progression of PD. Since the crucial role of GM in PD pathophysiology, altering the composition as well as metabolites of GM may be a promising intervention to slow the progression and relieve the symptoms of PD. These GM-targeted interventions mainly include antibiotics, probiotics and/or prebiotics, fecal microbiota transplant (FMT) and dietary changes.

Antibiotics

Known as one of the most powerful tools to alter GM composition, antibiotics has been reported in various studies on PD. More recently, Koutzoumis et al.¹¹⁴ studied the influence of antibiotics on PD. After injecting with broad-spectrum antibiotics together with oxidopamine, 90% of the GM richness was reduced, of which the abundance of Firmicutes decreased, while the abundance of Proteobacteria, Verrucomicrobia, Bacteroidetes, and Cyanobacteria increased. These alterations of GM decreased the levels of IL-1b and TNF-a in the striatum, reduce the damage to dopaminergic neurons and alleviated motor deficits in PD rodent models.¹¹⁵ Emerging studies focused on the role of minocycline. It was shown to reduce the Firmicutes/Bacteroidetes ratio, re-establishing the GM homeostasis to the normal condition¹¹⁶ and exerting a beneficial influence on the CNS via MGBA. For example, minocycline was observed to prohibit the activation of microglia, decelerate the depletion of dopamine in striatum and nucleus accumbens and prevent the neurodegeneration of nigrostriatal dopaminergic neurons in MPTP-induced PD mice .¹¹⁷ In addition, minocycline may serve as a scavenger for peroxynitrite detoxification and thus inhibit the aggregation and misfolding of α-syn.¹¹⁷ However, there are some contradictions on the specific effect of minocycline on PD. A study found an amplified damage to dopaminergic neurons in spite of the prohibited microglial activation,¹¹⁸ and similar results were reported in several other animal models.¹¹⁹

Considering the unknown specific correlation between GM and PD, as well as the side effects of antibiotics, further fundamental studies and in-vivo experiments are expected before the application on PD patients.

Probiotics, prebiotics, and synbiotics

Probiotics are microbes conferring healthy benefits on human hosts.¹²⁰ Living in the GI tract, probiotics are involved in the homeostasis of GM, modulation of immune responses and the integrity of intestinal barrier.¹²¹ Recent studies have found that probiotics might reduce the neuroinflammation in the CNS via MGBA and inhibit the subsequent loss of dopaminergic neurons,¹²² indicating their possible application in PD. Various studies focused on Lactobacilli and Bifidobacteria. More recently, Magistrelli et al.¹²³ further demonstrated the mechanisms. L. salivarius LS01 and L. acidophilus LA02 significantly reduced the production of pro-inflammatory cytokines while increased the production of anti-inflammatory ones in PD patients. Furthermore, most strains of genus Lactobacillus and Bifidobacterium also regulate the membrane integrity and inhibit the overgrowth of several pathogenic bacteria, such as E. coli and Klebsiella pneumoniae, which may lead to GM dysbiosis and the consequent inflammatory cascades. Additionally, Castelli et al.¹²⁴ found that a mixture of nine probiotic strains was involved in the modulation of neuroinflammation and brain-derived neurotrophic factor (BDNF) signaling pathway. It can also increase the expression of several neuroprotective proteins and might decrease the counteracting ones, exerting a neuroprotective effect. In addition to their direct impact of neuroprotection, probiotics may also influence the synthesis and transformation of levodopa. Bacillus sp. JPJ can directly synthesize levodopa from L-tyrosine in-vitro.¹²⁵ Besides, more than 50 Enterococcus strains, several Lactobacillus and Staphylococcus may convert levodopa to dopamine through the tyrosine decarboxylase encoded in their genomes.¹²⁶ Combination of these probiotics and levodopa may improve the efficacy of traditional treatment. However, the exact influence of probiotics on the pharmacodynamics and pharmacokinetics of levodopa remains to be studied.

Prebiotics refer to the complex carbohydrates facilitating the growth of probiotics, of which Galacto-oligosaccharides (GOS) and fructo-oligosaccharides (FOS) are most well-known.¹²⁷ By metabolizing them, probiotics can synthesize SCFAs. SCFAs are involved in the modulation of intestinal barrier, BBB and immune reponses, affecting the homeostasis of CNS.⁴⁹ In addition, butyrates, one type of SCFAs, was shown to induce Atg5-and PI3K/Akt/mTOR-related autophagy pathway, causing α-syn degradation in a pesticide-induced PD rat model.¹²⁸

Synbiotics are the combination of probiotics and prebiotics,¹²⁰ introducing the probiotic bacteria to the gut and promoting their growth simultaneously. Rajkumar et al.¹²⁹ found that probiotic Lactobacillus salivarius reduced the inflammatory markers in the serum of healthy subjects, and the reduction seemed more evident when combined with prebiotic FOS. Similarly, administration of a symbiotic yogurt (containing probiotic Bifidobacterium animalis together with prebiotic FOS) significantly improved the bowel movement in a patient with functional constipation,¹³⁰ indicating the possible relief of constipation in PD patients.

Since the correlation between GM and PD is still unclear, we should be more cautious when considering probiotics, prebiotics or synbiotics as therapeutic strategies for PD. Further studies in both animal models and PD patients should focus on the exact probiotic strains, the proportion of probiotics and prebiotics, treatment durations as well as dosages.

Fecal microbiota transplantation

Fecal microbiota transplantation (FMT) is a technique transplanting fecal filtrate from healthy donors to patients, which can restore the normal GM homeostasis in the gut.¹³¹ First proposed to treat GI disorders, FMT has been used in various other diseases including neurodegenerative diseases.¹³¹ Aside from benefits on the GI symptoms like constipation, FMT can also markedly relieve the non-GI symptoms in PD patients.¹³² Possible mechanisms may include the amelioration of GM dysbiosis, which is indicated by decreased fecal SCFAs and improved motor symptoms.⁵¹ FMT can also downregulate the TLR4/TNF signaling pathway, alleviate inflammation in the gut and CNS.⁵¹ Based on the limited amount of studies, there are several problems remaining to be solved. Most in-vivo studies did not assess the extent of inflammation and α-syn aggregation, which features the progression of PD.¹³² Considering the ethical issues and the potential side effects, large-scale applications of FMT in PD patients should be put off until further studies on the fundamental theories and long-term effects are conducted.

Diet

Considered as one of the gateways to the outer environment,¹³³ gut together with the inside GM is vulnerable to the environmental factors including diet. Since there is no effective therapeutic strategy, dietary interventions are necessary in both PD patients and high-risk groups. Diets with adequate fruits, rich vegetables, certain amount of high-quality olive oil and low dietary fat are commonly recommended for early intervention of PD.¹³⁴ Fruits and vegetables are rich in fibers and vitamins, which facilitates the synthesis of SCFAs, improving the intestinal barrier and exerting neuroprotective effects.⁴⁹ Vitamins are also associated with the occurrence and progression of PD, possibly by affecting GM composition.^135-137 Higher level of vitamin E contributes to a lower risk of PD,^135,137 while low intake of vitamin B6 increases the risk of PD.¹³⁸ Adequate intake of vitamin D3 prevents the progression of Hoehn and Yahr stage in PD patients,¹³⁶ and long-term administration of vitamin B2 improves the motor symptoms of PD patients.¹³⁹ High-quality olive oil may decrease the inflammatory mediators and increase the number of lactic acid bacteria, suppressing the potential inflammatory cascades and regulating GM composition.¹⁴⁰ High fat especially saturated fat may contribute to GM dysbiosis, increasing Firmicutes and Proteobacteria while reducing Bifidobacteria.¹⁴¹ Besides, dietary fat can also disrupt the intestinal barrier, facilitating the intestinal, systematic and even CNS inflammation.¹⁴² A balanced diet plays an essential role in the regulation of GM composition and immune responses,¹⁴³ suggesting diet may be a potential tool to intervene the occurrence and development of PD. However, there are various other environmental factors influencing GM and PD, such as geographical conditions and exercise, which makes it more difficult to examine the precise role of dietary habits in PD. Therefore, studies in larger cohorts and animal models are expected.

Conclusions

Recent studies have indicated the GM alterations in PD patients and the clinical relevance of these changes, which sheds light on the underlying relationship between GM and PD. However, the exact mechanisms await elucidation. GM can communicate with the CNS via humoral or direct neural pathways, in which inflammation plays a crucial role. In the inflammatory cascade, α-syn, pro-inflammatory cytokines and other GM metabolites may serve as major mediators. Further studies are expected to investigate the characteristics of GM alterations in presymptomatic stages of PD, contributing to the earlier diagnosis of PD. Besides, more emphasis should be placed on both pharmacological and dietary interventions which aim at altering GM composition, enhancing the intestinal barrier or alleviating gut inflammation. GM-based therapies for PD patients mainly include antibiotics, probiotics, prebiotics, synbiotics and FMT, while lifestyle changes especially dietary alterations can be applied in both high-risk people and PD patients. However, larger scales of microbial interventions in human require more consideration when the exact mechanism of PD pathology remains unclear. In addition to the safety and efficacy of these therapies, the specific strain types (e.g., Lachnospiraceae,^41,53,79,144 Bifidobacterium,^32,39,145 and Prevotellaceae^36,40,53,61), dosages, durations as well as intervals of the treatment should be considered. Moreover, since the GM composition is environment- and age-affected, GM-targeted therapeutic strategies are likely to be individualized.

Footnotes

Acknowledgment

We would like to acknowledge National Natural Science Foundation of China for supporting this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by National Natural Science Foundation of China (No. 81673137).

ORCID iD

Tong Guo

References

Wang

Liu

Tan

, et al. Bacterial, viral, and fungal infection-related risk of Parkinson’s disease: meta-analysis of cohort and case-control studies. Brain Behav 2020; 10(3): e01549.

Obeso

Stamelou

Goetz

, et al. Past, present, and future of Parkinson’s disease: a special essay on the 200th anniversary of the shaking palsy. Mov Disord 2017; 32(9): 1264–1310.

Kalia

Lang

. Parkinson’s disease. The Lancet 2015; 386(9996): 896–912.

Cersosimo

Raina

Pecci

, et al. Gastrointestinal manifestations in Parkinson’s disease: prevalence and occurrence before motor symptoms. J Neurol 2013; 260(5): 1332–1338.

Kim

Sung

. Gastrointestinal autonomic dysfunction in patients with Parkinson’s disease. J Mov Disord 2015; 8(2): 76–82.

Sveinbjornsdottir

. The clinical symptoms of Parkinson’s disease. J Neurochem 2016; 139(Suppl 1): 318–324.

Gorecki

Preskey

Bakeberg

, et al. Altered gut microbiome in Parkinson’s disease and the influence of lipopolysaccharide in a human α-synuclein over-expressing mouse model. Front Neurosci 2019; 13: 839.

Goswami

Joshi

Singh

. Neurodegenerative signaling factors and mechanisms in Parkinson’s pathology. Toxicol Vitro 2017; 43: 104–112.

Haddad

Sawalha

Khawaja

, et al. Dopamine and levodopa prodrugs for the treatment of Parkinson’s disease. Molecules 2017; 23(1): 40.

10.

Lee

Koh

. Many faces of Parkinson’s disease: non-motor symptoms of parkinson’s disease. J Mov Disord 2015; 8(2): 92–97.

11.

Lau

ACW

Diggle

Bring

. Improvement in severe orthostatic hypotension following carbidopa dose reduction. Can J Neurol Sci 2018; 45(2): 252–253.

12.

Tran

TNN

Frei

, et al. Levodopa-induced dyskinesia: clinical features, incidence, and risk factors. J Neural Transm 2018; 125(8): 1109–1117.

13.

Heiss

Olofsson

. The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system. J Neuroendocrinol 2019; 31(5): e12684.

14.

Wang

Luo

Ray Chaudhuri

, et al. The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options. Brain 2021; 144(9): 2571–2593.

15.

Thursby

Juge

. Introduction to the human gut microbiota. Biochem J 2017; 474(11): 1823–1836.

16.

Rinninella

Raoul

Cintoni

, et al. What is the healthy gut microbiota composition? a changing ecosystem across age, environment, diet, and diseases. Microorganisms 2019; 7(1).

17.

Cryan

O’Mahony

. The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterology Motil 2011; 23(3): 187–192.

18.

Shi

Duan

, et al. Interaction between the gut microbiome and mucosal immune system. Mil Med Res 2017; 4: 14.

19.

Mayerhofer

Fröhlich

Reichmann

, et al. Diverse action of lipoteichoic acid and lipopolysaccharide on neuroinflammation, blood-brain barrier disruption, and anxiety in mice. Brain Behav Immun 2017; 60: 174–187.

20.

Foster

Mcvey Neufeld

. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 2013; 36(5): 305–312.

21.

Dinan

Cryan

. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology 2012; 37(9): 1369–1378.

22.

Walker

Duncan

Louis

, et al. Phylogeny, culturing, and metagenomics of the human gut microbiota. Trends Microbiol 2014; 22(5): 267–274.

23.

Sommer

Bäckhed

. The gut microbiota - masters of host development and physiology. Nat Rev Microbiol 2013; 11(4): 227–238.

24.

Wallen

Stone

Factor

, et al. Exploring human-genome gut-microbiome interaction in Parkinson’s disease. NPJ Parkinsons Dis 2021; 7(1): 74.

25.

Tremlett

Bauer

Appel-Cresswell

, et al. The gut microbiome in human neurological disease: a review. Ann Neurol 2017; 81(3): 369–382.

26.

Hager

Ghannoum

. The mycobiome: role in health and disease, and as a potential probiotic target in gastrointestinal disease. Dig Liver Dis 2017; 49(11): 1171–1176.

27.

Kowalski

Mulak

. Brain-gut-microbiota axis in Alzheimer’s disease. J Neurogastroenterol Motil 2019; 25(1): 48–60.

28.

Caso

Balanzá-Martínez

Palomo

, et al. The microbiota and gut-brain axis: contributions to the immunopathogenesis of schizophrenia. Curr Pharm Des 2016; 22(40): 6122–6133.

29.

Jangi

Gandhi

Cox

, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 2016; 7: 12015.

30.

Strati

Cavalieri

Albanese

, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 2017; 5(1): 24.

31.

Cui

Yang

, et al. Gut microbiota differs between Parkinson’s disease patients and healthy controls in Northeast China. Front Mol Neurosci 2019; 12: 171.

32.

Qian

Yang

, et al. Alteration of the fecal microbiota in Chinese patients with Parkinson’s disease. Brain Behav Immun 2018; 70: 194–202.

33.

Barichella

Severgnini

Cilia

, et al. Unraveling gut microbiota in Parkinson’s disease and atypical parkinsonism. Mov Disord 2019; 34(3): 396–405.

34.

Aho

VTE

Pereira

PAB

Voutilainen

, et al. Gut microbiota in Parkinson’s disease: temporal stability and relations to disease progression. EBioMedicine 2019; 44: 691–707.

35.

Tang

Jin

Wang

, et al. Current sampling methods for gut microbiota: a call for more precise devices. Front Cell Infect Microbiol 2020; 10: 151.

36.

Bedarf

Hildebrand

Coelho

, et al. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients. Genome Med 2017; 9(1): 39.

37.

Hill-Burns

Debelius

Morton

, et al. Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord 2017; 32(5): 739–749.

38.

Hopfner

Künstner

Müller

, et al. Gut microbiota in Parkinson disease in a northern German cohort. Brain Res 2017; 1667: 41–45.

39.

Lin

Zheng

, et al. Gut microbiota in patients with Parkinson’s disease in southern China. Parkinsonism Relat Disord 2018; 53: 82–88.

40.

Lin

Chen

Chiang

, et al. Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson’s disease. J Neuroinflammation 2019; 16(1): 129.

41.

Pietrucci

Cerroni

Unida

, et al. Dysbiosis of gut microbiota in a selected population of Parkinson’s patients. Parkinsonism Relat Disord 2019; 65: 124–130.

42.

Cirstea

Golz

, et al. Microbiota composition and metabolism are associated with gut function in Parkinson’s disease. Mov Disord 2020; 35(7): 1208–1217.

43.

Vascellari

Palmas

Melis

, et al. Gut microbiota and metabolome alterations associated with Parkinson’s disease. mSystems 2020; 5(5): e00561–20.

44.

Wallen

Appah

Dean

, et al. Characterizing dysbiosis of gut microbiome in PD: evidence for overabundance of opportunistic pathogens. Npj Parkinson’s Dis 2020; 6: 11.

45.

Rosario

Bidkhori

Lee

, et al. Systematic analysis of gut microbiome reveals the role of bacterial folate and homocysteine metabolism in Parkinson’s disease. Cel Rep 2021; 34(9): 108807.

46.

Desai

Seekatz

Koropatkin

, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 2016; 167(5): 1339–1353.

47.

Deng

, et al. Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease. Nutr Diabetes 2020; 10(1): 12.

48.

Nishiwaki

Ito

Ishida

, et al. Meta‐analysis of gut dysbiosis in Parkinson’s disease. Mov Disord 2020; 35(9): 1626–1635.

49.

Canani

Costanzo

Leone

, et al. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol 2011; 17(12): 1519–1528.

50.

Nishiwaki

Hamaguchi

Ito

, et al. Short-chain fatty acid-producing gut microbiota is decreased in Parkinson’s disease but not in rapid-eye-movement sleep behavior disorder. mSystems 2020; 5(6): e00797–20.

51.

Sun

Zhu

Zhou

, et al. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav Immun 2018; 70: 48–60.

52.

Lai

Jiang

Xie

, et al. Intestinal pathology and gut microbiota alterations in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. Neurochem Res 2018; 43(10): 1986–1999.

53.

Heintz-Buschart

Pandey

Wicke

, et al. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov Disord 2018; 33(1): 88–98.

54.

Jiang

Ling

Zhang

, et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun 2015; 48: 186–194.

55.

Aizawa

Tsuji

Asahara

, et al. Possible association of bifidobacterium and lactobacillus in the gut microbiota of patients with major depressive disorder. J Affect Disord 2016; 202: 254–257.

56.

Zheng

Zeng

Zhou

, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry 2016; 21(6): 786–796.

57.

Kelly

Borre

O’ Brien

, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 2016; 82: 109–118.

58.

Alifirova

Zhukova

, et al. Correlation between emotional-affective disorders and gut microbiota composition in patients with parkinson’s disease. Vestn Ross Akad Med Nauk 2016; 71(6): 427–435.

59.

Ren

Gao

Qiu

, et al. Gut microbiota altered in mild cognitive impairment compared with normal cognition in sporadic parkinson’s disease. Front Neurol 2020; 11: 137.

60.

Ishii

Furuoka

Kaya

, et al. Oral administration of probiotic bifidobacterium breve improves facilitation of hippocampal memory extinction via restoration of aberrant higher induction of neuropsin in an mptp-induced mouse model of parkinson’s disease. Biomedicines 2021; 9(2): 167.

61.

Scheperjans

Aho

Pereira

PAB

, et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 2015; 30(3): 350–358.

62.

Tan

Chong

Lim

, et al. Gut microbial ecosystem in parkinson disease: new clinicobiological insights from multi‐omics. Ann Neurol 2021; 89(3): 546–559.

63.

Zhang

Yue

Fang

, et al. Altered gut microbiota in Parkinson’s disease patients/healthy spouses and its association with clinical features. Parkinsonism Relat Disord 2020; 81: 84–88.

64.

Boeve

. REM sleep behavior disorder. Ann New York Acad Sci 2010; 1184: 15–54.

65.

Yan

Ren

Duan

, et al. Gut microbiota and metabolites of α-synuclein transgenic monkey models with early stage of Parkinson’s disease. npj Biofilms and Microbiomes 2021; 7(1): 69.

66.

Jones

Rahmani

Garcia

, et al. Gastrointestinal symptoms are predictive of trajectories of cognitive functioning in de novo Parkinson’s disease. Parkinsonism Relat Disord 2020; 72: 7–12.

67.

Hui

Fernandez-Hernandez

, et al. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci Translational Medicine 2018; 10(423): eaai7795.

68.

Bialecka

Kurzawski

Klodowska-Duda

, et al. CARD15 variants in patients with sporadic Parkinson’s disease. Neurosci Res 2007; 57(3): 473–476.

69.

Houser

Chang

Factor

, et al. Stool immune profiles evince gastrointestinal inflammation in Parkinson’s disease. Mov Disord 2018; 33(5): 793–804.

70.

Devos

Lebouvier

Lardeux

, et al. Colonic inflammation in Parkinson’s disease. Neurobiol Dis 2013; 50: 42–48.

71.

Lyte

. Microbial endocrinology. Gut Microbes 2014; 5(3): 381–389.

72.

Galland

. The gut microbiome and the brain. J Med Food 2014; 17(12): 1261–1272.

73.

Forsythe

Bienenstock

Kunze

. Vagal pathways for microbiome-brain-gut axis communication. Adv Exp Med Biol 2014; 817: 115–133.

74.

Clairembault

Leclair-Visonneau

Neunlist

, et al.

Enteric glial cells: new players in Parkinson’s disease?

Mov Disord 2015; 30(4): 494–498.

75.

Clairembault

Kamphuis

Leclair-Visonneau

, et al. Enteric GFAP expression and phosphorylation in Parkinson’s disease. J Neurochem 2014; 130(6): 805–815.

76.

Stone

Darlington

. The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br J Pharmacol 2013; 169(6): 1211–1227.

77.

Wang

Chen

, et al. Alteration of the fecal microbiota in North-Eastern Han Chinese population with sporadic Parkinson’s disease. Neurosci Lett 2019; 707: 134297.

78.

Fasano

Bove

Gabrielli

, et al. The role of small intestinal bacterial overgrowth in Parkinson’s disease. Mov Disord 2013; 28(9): 1241–1249.

79.

Tan

Mahadeva

Thalha

, et al. Small intestinal bacterial overgrowth in Parkinson’s disease. Parkinsonism Relat Disord 2014; 20(5): 535–540.

80.

Kelly

Carvey

Keshavarzian

, et al. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson’s disease. Mov Disord 2014; 29(8): 999–1009.

81.

Forsyth

Shannon

Kordower

, et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early parkinson’s disease. PLoS One 2011; 6(12): e28032.

82.

Mulak

Bonaz

. Irritable bowel syndrome: a model of the brain-gut interactions. Med Science Monit 2004; 10(4): RA55–62.

83.

Schemann

Neunlist

. The human enteric nervous system. Neurogastroenterol Motil 2004; 16(Suppl 1): 55–59.

84.

Vergnolle

Cirillo

. Neurons and glia in the enteric nervous system and epithelial barrier function. Physiology 2018; 33(4): 269–280.

85.

Tan

Chao

West

, et al. Parkinson disease and the immune system - associations, mechanisms and therapeutics. Nat Rev Neurol 2020; 16(6): 303–318.

86.

Mogensen

. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 2009; 22(2): 240–273, Table of Contents.

87.

Béraud

Maguire-Zeiss

. Misfolded α-synuclein and toll-like receptors: therapeutic targets for Parkinson’s disease. Parkinsonism Relat Disord 2012; 18(Suppl 1): S17–S20.

88.

Yarandi

Kulkarni

Saha

, et al. Intestinal bacteria maintain adult enteric nervous system and nitrergic neurons via toll-like receptor 2-induced neurogenesis in mice. Gastroenterology 2020; 159(1): 200–213.

89.

Stefanova

Fellner

Reindl

, et al. Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons. Am J Pathol 2011; 179(2): 954–963.

90.

Terán-Ventura

Aguilera

Vergara

, et al. Specific changes of gut commensal microbiota and TLRs during indomethacin-induced acute intestinal inflammation in rats. J Crohn’s Colitis 2014; 8(9): 1043–1054.

91.

Bhattacharyya

Mohite

Krishnamoorthy

, et al. Lipopolysaccharide from gut microbiota modulates α-synuclein aggregation and alters its biological function. ACS Chem Neurosci 2019; 10(5): 2229–2236.

92.

Soderholm

Pedicord

. Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity. Immunology 2019; 158(4): 267–280.

93.

Wang

Liu

Yan

, et al. Disease progression-dependent expression of CD200R1 and CX3CR1 in mouse models of parkinson’s disease. Aging Dis 2020; 11(2): 254–268.

94.

Wakade

Giri

Malik

, et al. Niacin modulates macrophage polarization in Parkinson’s disease. J Neuroimmunol 2018; 320: 76–79.

95.

Erny

Hrabě de Angelis

Jaitin

, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 2015; 18(7): 965–977.

96.

Kigerl

Gensel

Ankeny

, et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 2009; 29(43): 13435–13444.

97.

Zhang

Q.-S.

Heng

Yuan

Y.-H.

, et al. Pathological α-synuclein exacerbates the progression of Parkinson’s disease through microglial activation. Toxicol Lett 2017; 265: 30–37.

98.

Sweeney

Sagare

Zlokovic

. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018; 14(3): 133–150.

99.

Braniste

Al-Asmakh

Kowal

, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Translational Medicine 2014; 6(263): 263ra158.

100.

Liu

Wang

Liu

, et al. Sodium butyrate exerts protective effect against Parkinson’s disease in mice via stimulation of glucagon like peptide-1. J Neurol Sci 2017; 381: 176–181.

101.

Fujigaki

Yamamoto

Saito

. L-Tryptophan-kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: focus on cell type differences. Neuropharmacology 2017; 112(Pt B): 264–274.

102.

Kortekaas

Leenders

Van Oostrom

JCH

, et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 2005; 57(2): 176–179.

103.

Gray

M. T.

Woulfe

J. M.

Striatal Blood-Brain Barrier Permeability in Parkinson’S Disease. J Cereb Blood Flow Metab 2015; 35(5): 747–750.

104.

Pisani

Stefani

Pierantozzi

, et al. Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson’s disease. J Neuroinflammation 2012; 9: 188.

105.

Barrenschee

Zorenkov

Böttner

, et al. Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson’s disease. Acta Neuropathologica Commun 2017; 5(1): 1.

106.

Sanchez-Guajardo

Tentillier

Romero-Ramos

. The relation between α-synuclein and microglia in Parkinson’s disease: recent developments. Neuroscience 2015; 302: 47–58.

107.

Braak

De Vos

RAI

Bohl

, et al. Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 2006; 396(1): 67–72.

108.

Paillusson

Clairembault

Biraud

, et al. Activity-dependent secretion of alpha-synuclein by enteric neurons. J Neurochem 2013; 125(4): 512–517.

109.

Kim

Kwon

Kam

, et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 2019; 103(4): 627–641.

110.

Arotcarena

Dovero

Prigent

, et al. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates. Brain 2020; 143(5): 1462–1475.

111.

Louveau

Smirnov

Keyes

, et al. Structural and functional features of central nervous system lymphatic vessels. Nature 2015; 523(7560): 337–341.

112.

Block

Zecca

Hong

. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007; 8(1): 57–69.

113.

Musa

Mani

Lim

, et al. Lactobacilli-fermented cow’s milk attenuated lipopolysaccharide-induced neuroinflammation and memory impairment in vitro and in vivo. J Dairy Res 2017; 84(4): 488–495.

114.

Koutzoumis

Vergara

Pino

, et al. Alterations of the gut microbiota with antibiotics protects dopamine neuron loss and improve motor deficits in a pharmacological rodent model of Parkinson’s disease. Exp Neurol 2020; 325: 113159.

115.

Chang

, et al. Antibiotic-induced microbiome depletion protects against MPTP-induced dopaminergic neurotoxicity in the brain. Aging 2019; 11(17): 6915–6929.

116.

Yang

Santisteban

Rodriguez

, et al. Gut dysbiosis is linked to hypertension. Hypertension 2015; 65(6): 1331–1340.

117.

Lin

, et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci 2001; 98(25): 14669–14674.

118.

Yang

Sugama

Chirichigno

, et al. Minocycline enhances MPTP toxicity to dopaminergic neurons. J Neurosci Res 2003; 74(2): 278–285.

119.

Diguet

Fernagut

Wei

, et al. Deleterious effects of minocycline in animal models of Parkinson’s disease and Huntington’s disease. Eur J Neurosci 2004; 19(12): 3266–3276.

120.

Pandey

Naik

Vakil

. Probiotics, prebiotics and symbiotics- a review. J Food Sci Technol 2015; 52(12): 7577–7587.

121.

Hemarajata

Versalovic

. Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Ther Adv Gastroenterol 2013; 6(1): 39–51.

122.

Srivastav

Neupane

Bhurtel

, et al. Probiotics mixture increases butyrate, and subsequently rescues the nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity. J Nutr Biochem 2019; 69: 73–86.

123.

Magistrelli

Amoruso

Mogna

, et al. Probiotics may have beneficial effects in parkinson’s disease: in vitro evidence. Front Immunol 2019; 10: 969.

124.

Castelli

d’Angelo

Lombardi

, et al. Effects of the probiotic formulation SLAB51 in in vitro and in vivo Parkinson’s disease models. Aging 2020; 12(5): 4641–4659.

125.

Surwase

Jadhav

. Bioconversion of l-tyrosine to l-DOPA by a novel bacterium Bacillus sp. JPJ. Amino Acids 2011; 41(2): 495–506.

126.

Van Kessel

Frye

El-Gendy

, et al. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease. Nat Commun 2019; 10(1): 310.

127.

Martins

Ureta

Tymczyszyn

, et al. Technological aspects of the production of fructo and galacto-oligosaccharides. enzymatic synthesis and hydrolysis. Front Nutr 2019; 6: 78.

128.

Qiao

Sun

Jia

, et al. Sodium butyrate causes α-synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway. Exp Cel Res 2020; 387(1): 111772.

129.

Rajkumar

Kumar

Das

, et al. Effect of probiotic lactobacillus salivarius UBL S22 and prebiotic fructo-oligosaccharide on serum lipids, inflammatory markers, insulin sensitivity, and gut bacteria in healthy young volunteers. J Cardiovasc Pharmacol Ther 2015; 20(3): 289–298.

130.

De Paula

Carmuega

Weill

. Effect of the ingestion of a symbiotic yogurt on the bowel habits of women with functional constipation. Acta Gastroenterol Latinoam 2008; 38(1): 16–25.

131.

Sbahi

Di Palma

. Faecal microbiota transplantation: applications and limitations in treating gastrointestinal disorders. BMJ Open Gastroenterol 2016; 3(1): e000087.

132.

Huang

Luo

, et al. Fecal microbiota transplantation to treat Parkinson’s disease with constipation. Medicine 2019; 98(26): e16163.

133.

David

Maurice

Carmody

, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505(7484): 559–563.

134.

Luisi

MLE

Lucarini

Biffi

, et al. Effect of mediterranean diet enriched in high quality extra virgin olive oil on oxidative stress, inflammation and gut microbiota in obese and normal weight adult subjects. Front Pharmacol 2019; 10: 1366.

135.

Miyake

Fukushima

Tanaka

, et al. Dietary intake of antioxidant vitamins and risk of Parkinson’s disease: a case-control study in Japan. Eur J Neurol 2011; 18(1): 106–113.

136.

Suzuki

Yoshioka

Hashimoto

, et al. Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease. Am J Clin Nutr 2013; 97(5): 1004–1013.

137.

Zhang

Hernan

Chen

, et al. Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk. Neurology 2002; 59(8): 1161–1169.

138.

Murakami

Miyake

Sasaki

, et al. Dietary intake of folate, vitamin B6, vitamin B12 and riboflavin and risk of Parkinson’s disease: a case-control study in Japan. Br J Nutr 2010; 104(5): 757–764.

139.

Coimbra

Junqueira

VBC

. High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson’s disease patients. Braz J Med Biol Res 2003; 36(10): 1409–1417.

140.

Ickenstein

Klotz

Langohr

. Virusenzephalitis mit symptomatischem parkinson- syndrom, diabetes insipidus und panhypopituitarismus. Fortschr Neurol Psychiatr 1999; 67(10): 476–481.

141.

Fava

Gitau

Griffin

, et al. The type and quantity of dietary fat and carbohydrate alter faecal microbiome and short-chain fatty acid excretion in a metabolic syndrome ‘at-risk’ population. Int J Obes 2013; 37(2): 216–223.

142.

Kim

Lee

, et al. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 2012; 7(10): e47713.

143.

Perez-Pardo

Dodiya

Broersen

, et al. Gut-brain and brain-gut axis in Parkinson’s disease models: effects of a uridine and fish oil diet. Nutr Neurosci 2018; 21(6): 391–402.

144.

Keshavarzian

Green

Engen

, et al. Colonic bacterial composition in Parkinson’s disease. Mov Disord 2015; 30(10): 1351–1360.

145.

Minato

Maeda

Fujisawa

, et al. Progression of Parkinson’s disease is associated with gut dysbiosis: two-year follow-up study. PLoS One 2017; 12(11): e0187307.

Gut microbiota and inflammation in Parkinson’s disease: Pathogenetic and therapeutic insights

Abstract

Keywords

Introduction

Gut microbiota alterations in PD

Gut microbiota

Alterations of gut microbiota in PD

Clinical correlations between alterations of gut microbiota and PD

Possible GM-inflammation-PD pathogenesis

Gut microbiota, intestinal barrier, and gut inflammation

CNS inflammation

Potential mediators: α-syn and pro-inflammatory substances

GM-targeted therapeutic strategies for PD

Antibiotics

Probiotics, prebiotics, and synbiotics

Fecal microbiota transplantation

Diet

Conclusions

Footnotes

Acknowledgment

Declaration of conflicting interests

Funding

ORCID iD

References