The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options

Differences in bacterial taxa of family between healthy controls and Parkinson’s disease patients

Research	Prevotellaceae	Lactobacillaceae	Verrucomicrobiaceae	Lachnospraceae	Bifidobactellaceae	Enterobacteriaceae	Pasteurellaceae	Enterococcaceae	Christensenellaceae
Keshavarzian et al.²⁸			↑	↓
Scheperjans et al.²⁹	↓	↑	↑
Unger et al.³⁰	↓	↓				↑		↓
Bedarf et al.³¹	↓		↑
Hill-Burns et al.³²		↑	↑	↓	↑		↓		↑
Hopfner et al.³³		↑						↑
Li et al.²⁷						↑		↑
Heintz-Buschart et al.³⁴			↑
Lin et al.³⁵				↓	↑		↓
Aho et al.²⁶	↓
Barichella et al.²³		↑	↑	↓	↑	↑			↑
Gorecki et al.³⁶			↑
Li et al.²⁴		↓	↑
Li et al.³⁷	↓		↑	↑			↑
Pietrucci et al.³⁸		↑		↓		↑		↑

Research	Prevotellaceae	Lactobacillaceae	Verrucomicrobiaceae	Lachnospraceae	Bifidobactellaceae	Enterobacteriaceae	Pasteurellaceae	Enterococcaceae	Christensenellaceae
Keshavarzian et al.²⁸			↑	↓
Scheperjans et al.²⁹	↓	↑	↑
Unger et al.³⁰	↓	↓				↑		↓
Bedarf et al.³¹	↓		↑
Hill-Burns et al.³²		↑	↑	↓	↑		↓		↑
Hopfner et al.³³		↑						↑
Li et al.²⁷						↑		↑
Heintz-Buschart et al.³⁴			↑
Lin et al.³⁵				↓	↑		↓
Aho et al.²⁶	↓
Barichella et al.²³		↑	↑	↓	↑	↑			↑
Gorecki et al.³⁶			↑
Li et al.²⁴		↓	↑
Li et al.³⁷	↓		↑	↑			↑
Pietrucci et al.³⁸		↑		↓		↑		↑

↑ = a significantly increased abundance of gut microbiota at family level; ↓ = a significantly decreased abundance of gut microbiota at family level.

Table 1

Differences in bacterial taxa of family between healthy controls and Parkinson’s disease patients

Research	Prevotellaceae	Lactobacillaceae	Verrucomicrobiaceae	Lachnospraceae	Bifidobactellaceae	Enterobacteriaceae	Pasteurellaceae	Enterococcaceae	Christensenellaceae
Keshavarzian et al.²⁸			↑	↓
Scheperjans et al.²⁹	↓	↑	↑
Unger et al.³⁰	↓	↓				↑		↓
Bedarf et al.³¹	↓		↑
Hill-Burns et al.³²		↑	↑	↓	↑		↓		↑
Hopfner et al.³³		↑						↑
Li et al.²⁷						↑		↑
Heintz-Buschart et al.³⁴			↑
Lin et al.³⁵				↓	↑		↓
Aho et al.²⁶	↓
Barichella et al.²³		↑	↑	↓	↑	↑			↑
Gorecki et al.³⁶			↑
Li et al.²⁴		↓	↑
Li et al.³⁷	↓		↑	↑			↑
Pietrucci et al.³⁸		↑		↓		↑		↑

Research	Prevotellaceae	Lactobacillaceae	Verrucomicrobiaceae	Lachnospraceae	Bifidobactellaceae	Enterobacteriaceae	Pasteurellaceae	Enterococcaceae	Christensenellaceae
Keshavarzian et al.²⁸			↑	↓
Scheperjans et al.²⁹	↓	↑	↑
Unger et al.³⁰	↓	↓				↑		↓
Bedarf et al.³¹	↓		↑
Hill-Burns et al.³²		↑	↑	↓	↑		↓		↑
Hopfner et al.³³		↑						↑
Li et al.²⁷						↑		↑
Heintz-Buschart et al.³⁴			↑
Lin et al.³⁵				↓	↑		↓
Aho et al.²⁶	↓
Barichella et al.²³		↑	↑	↓	↑	↑			↑
Gorecki et al.³⁶			↑
Li et al.²⁴		↓	↑
Li et al.³⁷	↓		↑	↑			↑
Pietrucci et al.³⁸		↑		↓		↑		↑

↑ = a significantly increased abundance of gut microbiota at family level; ↓ = a significantly decreased abundance of gut microbiota at family level.

Recent studies have disclosed a decreased abundance of Prevotellaceae and Lachnospraceae families (including the genus Roseburia), along with an increase in the Verrucomicrobiaceae family (including the genus Akkermansia) and Lactobacillaceae family.²³^,²⁴^,²⁶^,^28–38 Prevotellaceae is a commensal mucin-degrading intestinal bacterium that is involved in the formation of intestinal mucus and affects the normal production of short-chain fatty acids (SCFAs) through fibre fermentation. Reduced levels of intestinal mucus and the production of microbe-derived SCFAs may therefore be a mechanism by which the host experiences increased intestinal permeability, resulting in an increased risk of local inflammation across the intestinal canal.³⁷^,³⁹ Interestingly, Prevotellaceae has been suggested to play a possible protective role in the neurodegenerative process of Parkinson’s disease via mucin synthesis and ghrelin secretion.²⁹^,⁴⁰ Intriguingly, the increase in Lactobacillaceae and decrease in Prevotellaceae are related to the decrease in the gastrointestinal hormone ghrelin, which can maintain and protect the normal dopamine function of the substantia nigra and striatum by changing mitochondrial respiration and reactive oxygen species production.⁴¹ In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, ghrelin has a protective effect on dopaminergic neurons by inhibiting the accumulation and phosphorylation of α-synuclein, promoting autophagy and inhibiting endoplasmic reticulum-mediated apoptosis.⁴² In addition, in a clinical study, the total and active levels of plasma ghrelin decreased in patients with Parkinson’s disease, indicating that the level of plasma ghrelin may be a target for the diagnosis and treatment of the disease.⁴³

Akkermansia utilize mucin as a source of energy and may therefore reduce barrier function and increase exposure to more microbial substrates across the epithelial lining.⁴⁴^,Akkermansia muciniphila may also have beneficial effects on metabolic disorders in obese mice as well as metabolic syndrome lipid metabolism.⁴⁵ Campos-Peña et al.⁴⁶ reported that metabolic syndrome, including insulin resistance and obesity, is an essential risk factor for cognitive impairment and dementia disorders.⁴⁶ Recently, Ou et al.⁴⁷ suggested that A. muciniphila may improve the insulin resistance of Alzheimer’s disease mice, reduce the decrease in colonic mucous cells, improve intestinal barrier dysfunction and dyslipidaemia, and delay pathological changes in the brain, indicating that there is a close connection between gut microbiota and neurological disorders; therefore, microbial intervention could provide a novel strategy for the prevention and treatment of Alzheimer’s disease.⁴⁷

Most clinical studies use intestinal faecal samples and 16S rRNA-based sequencing to evaluate the structure of gut microbiota, while one study by Bedarf et al.³¹ used metagenomics shotgun analyses to allow detection of changes in species levels and to reduce viral loads in patients with Parkinson’s disease.³¹ The study findings vary due to differences in methodology, geographical regions, age and dietary habits. There were also differences in the composition of microbiota between faecal samples and sigmoid mucosa samples in patients with Parkinson’s disease.²⁸ Some studies suggested that there was no significant difference in the amount of microbiota in the nasal cavity of patients with Parkinson’s disease, but the nasal microbiota exhibited a higher variability in different individuals.³⁴ There was a strong correlation between the alterations in oral-specific microbial taxa and functional indexes in patients with Parkinson’s disease.⁴⁸

The results of the studies on animal models of Parkinson’s disease are similar to those in humans. A study on the composition of caecal mucosa-associated and luminal microbiota in rotenone-induced Parkinson’s disease mice showed that in the caecal mucosa, the relative abundance of the phyla Bacteroidetes and Firmicutes significantly increased in the experimental group, whereas the relative abundance of Actinobacteria and beneficial symbiotic bacteria Bifidobacterium significantly decreased.⁴⁹ A decreased abundance of mucin-degrading Verrucomicrobiae was found in a human α-synuclein overexpressing mouse model.³⁶ Intriguingly, the abundance of some gut microbiota increased in mice that were colonized by the faeces of patients with Parkinson’s disease, including Proteus sp., Bilophila sp. and Roseburia sp., with a decrease in the Lachnospiracae, Rikenellae, Peptostreptococacae and Butyricicoccus sp.⁵⁰ In addition, Lai et al.⁵¹ discovered that the gut microbiota of the MPTP-induced model was significantly altered, especially in the Lachnospiraceae, Erysipelotrichaceae, Prevotellaceae, Clostridiales, Erysipelotrichales and Proteobacteria.⁵¹

Several lines of evidence in recent studies have shown that the composition of gut microbiota is affected by antibiotics, leading to the imbalance of host immune homeostasis and increased susceptibility to disease. Antibiotics may also influence the growth and colonization of bacteria in the gastrointestinal tract. Most antibiotics interfere with the composition and enzyme activity of the intestinal microbiota and inhibit enzyme activity.⁵² For example, Dethlefsen and Relman⁵³ examined the effect of ciprofloxacin on human distal intestinal microbiota and found a decrease in bacterial diversity and a significant change in microbiota composition within a 3–4-day treatment, after which it began to return incompletely to the initial state.⁵³ Another study analysed the alteration of gut microbiota in 12 healthy males treated with 4-day antibiotic intervention and found that the composition of gut microbiota returned to initial baseline within 1.5 months.⁵⁴ Thus, the duration and recovery time of the alterations in gut microbiota caused by antibiotics seem uncertain. Antibiotic administration in specific pathogen-free mice temporarily altered the composition of the microbiota with a significant increase in Firmicutes and Actinobacteria and a decrease in Bacteroidetes and Proteobacteria and increased exploratory behaviour.⁵⁵ In addition, by investigating the effect of early antibiotics on intestinal microbiota, a study revealed that the composition of intestinal microbiota changed significantly and the metabolism of SCFAs was altered after treatment with subtherapeutic antibiotic therapy.⁵⁶

In summary, the abundance of gut microbiota in patients with Parkinson’s disease is significantly altered and has obvious characteristics, which may be used as potential biomarkers or therapeutic targets. However, due to differences in research methods, living environments and individuals and the time points and types of altered gut microbiota, the specific mechanisms have not been clearly elucidated.

Clinical correlations between gut microbiota and Parkinson’s disease

In recent years, clinical evidence has demonstrated the relationship between gut microbiota, clinical symptoms (including motor and non-motor symptoms) and disease stage in Parkinson’s disease. The correlation between microbiota and the diagnosis of Parkinson’s disease has been extended to the association with motor symptoms.²⁹ Recent studies on the clinical correlations between gut microbiota and Parkinson’s disease are summarized in Table 2. Investigators have shown that the gut microbiota is significantly related to the duration,²⁸^,³⁵ onset time,³⁵ and motor and non-motor symptoms²³^,²⁵^,²⁹^,³⁴^,⁴⁰ of Parkinson’s disease. There were also differences found in gut microbiota among different clinical motor phenotypes.³⁵ Minato et al.⁵⁷ investigated the relationship between intestinal disorders and disease progression through a 2-year follow-up of patients with Parkinson’s disease and found that the decreased abundance of Bifidobacterium and Bacteroides fragilis was related to the deterioration of the Unified Parkinson’s Disease Rating Scale (UPDRS)-I score, suggesting that the gut microbiota may be seriously influenced by disease progression.⁵⁷ Most studies only recorded the eating habits of participants and did not provide details on dietary habits. Because of the different dietary structures in different countries and regions, the composition of gut microbiota is also different. Non-motor symptoms such as gastrointestinal dysfunction, depression and anxiety may interact with gut microbiota to play a crucial role in the microbiota-gut-brain axis in Parkinson’s disease. Patients with Parkinson’s disease and irritable bowel syndrome-like symptoms (abdominal pain) had more non-motor symptoms, along with lower levels of Prevotella (genus and family), indicating that the gut microbiota of these patients has the potential to become a reference for exploring the gut microbiota associated with premotor symptoms in Parkinson’s disease as biomarkers or therapeutic targets.⁵⁸

Table 2

Research studies on the clinical correlations between gut microbiota and Parkinson’s disease

Research	Gut microbiota	Clinical correlations
Keshavarzian et al.²⁸	Lachnospiraceae ↓	Disease duration
Scheperjans et al.²⁹	Prevotellaceae ↓	UPDRS Part III total score
Heintz-Buschart et al.³⁴	Anaerotruncus sp., Clostridium XIVa, Lachnospiracae ↑	Motor symptoms
Lin et al.³⁵	Pasteurellaceae ↑	Early onset
Qian et al.²⁵	Bifidobacterium ↓ Genera Butyricicoccus, Clostridium XlVb ↑ Genera Escherichia/Shigella↑	HAMD（Hamilton Depression Scale）scores Cognitive impairment Disease duration
Barichella et al.²³	Lactobacillaceae ↑ Christensenellaceae ↑ Lachnospiraceae ↓	Motor symptoms (UPDRS Part III total score) NMS Quest total score Gait disturbances
Pietrucci et al.³⁸	Enterobacteriaceae ↑ Lachnospiraceae ↓	Disease severity and motor impairment

Research	Gut microbiota	Clinical correlations
Keshavarzian et al.²⁸	Lachnospiraceae ↓	Disease duration
Scheperjans et al.²⁹	Prevotellaceae ↓	UPDRS Part III total score
Heintz-Buschart et al.³⁴	Anaerotruncus sp., Clostridium XIVa, Lachnospiracae ↑	Motor symptoms
Lin et al.³⁵	Pasteurellaceae ↑	Early onset
Qian et al.²⁵	Bifidobacterium ↓ Genera Butyricicoccus, Clostridium XlVb ↑ Genera Escherichia/Shigella↑	HAMD（Hamilton Depression Scale）scores Cognitive impairment Disease duration
Barichella et al.²³	Lactobacillaceae ↑ Christensenellaceae ↑ Lachnospiraceae ↓	Motor symptoms (UPDRS Part III total score) NMS Quest total score Gait disturbances
Pietrucci et al.³⁸	Enterobacteriaceae ↑ Lachnospiraceae ↓	Disease severity and motor impairment

↑ = a positive correlation between the microbiota and symptoms; ↓ = a positive correlation between the microbiota and symptoms. HAMD = Hamilton Depression Scale; NMS Quest = Non-motor Symptoms Questionnaire; UPDRS = Unified Parkinson’s Disease Rating Scale

Table 2

Research studies on the clinical correlations between gut microbiota and Parkinson’s disease

Research	Gut microbiota	Clinical correlations
Keshavarzian et al.²⁸	Lachnospiraceae ↓	Disease duration
Scheperjans et al.²⁹	Prevotellaceae ↓	UPDRS Part III total score
Heintz-Buschart et al.³⁴	Anaerotruncus sp., Clostridium XIVa, Lachnospiracae ↑	Motor symptoms
Lin et al.³⁵	Pasteurellaceae ↑	Early onset
Qian et al.²⁵	Bifidobacterium ↓ Genera Butyricicoccus, Clostridium XlVb ↑ Genera Escherichia/Shigella↑	HAMD（Hamilton Depression Scale）scores Cognitive impairment Disease duration
Barichella et al.²³	Lactobacillaceae ↑ Christensenellaceae ↑ Lachnospiraceae ↓	Motor symptoms (UPDRS Part III total score) NMS Quest total score Gait disturbances
Pietrucci et al.³⁸	Enterobacteriaceae ↑ Lachnospiraceae ↓	Disease severity and motor impairment

Research	Gut microbiota	Clinical correlations
Keshavarzian et al.²⁸	Lachnospiraceae ↓	Disease duration
Scheperjans et al.²⁹	Prevotellaceae ↓	UPDRS Part III total score
Heintz-Buschart et al.³⁴	Anaerotruncus sp., Clostridium XIVa, Lachnospiracae ↑	Motor symptoms
Lin et al.³⁵	Pasteurellaceae ↑	Early onset
Qian et al.²⁵	Bifidobacterium ↓ Genera Butyricicoccus, Clostridium XlVb ↑ Genera Escherichia/Shigella↑	HAMD（Hamilton Depression Scale）scores Cognitive impairment Disease duration
Barichella et al.²³	Lactobacillaceae ↑ Christensenellaceae ↑ Lachnospiraceae ↓	Motor symptoms (UPDRS Part III total score) NMS Quest total score Gait disturbances
Pietrucci et al.³⁸	Enterobacteriaceae ↑ Lachnospiraceae ↓	Disease severity and motor impairment

↑ = a positive correlation between the microbiota and symptoms; ↓ = a positive correlation between the microbiota and symptoms. HAMD = Hamilton Depression Scale; NMS Quest = Non-motor Symptoms Questionnaire; UPDRS = Unified Parkinson’s Disease Rating Scale

Gastrointestinal dysfunction may be closely interrelated to small intestinal bacterial overgrowth and gastrointestinal Helicobacter pylori colonization.⁵⁹ Small intestinal bacterial overgrowth is characterized by an increased number and/or irregular type of bacteria in the small intestine and is related to symptoms including diarrhoea, flatulence, abdominal pain and abdominal distension.⁶⁰ Recently, the positive rate of small intestinal bacterial overgrowth in patients with Parkinson’s disease was found to be significantly increased, and it was associated with the deterioration of gastrointestinal symptoms and motor function.⁶¹ Another clinical study observed that small intestinal bacterial overgrowth was significantly associated with severe defecatory fluctuations, which can be attributed to peripheral factors, including changes in levodopa pharmacokinetics.⁶² Since levodopa is mainly absorbed in the jejunum, small intestinal bacterial overgrowth may reduce drug absorption through intestinal mucosal inflammation or cause alterations in the metabolism of levodopa by bacteria in the lumen. In addition, antibiotics (rifaximin) can alleviate the gastrointestinal symptoms and motor fluctuations caused by small intestinal bacterial overgrowth, illustrating the importance of correcting it.⁶²

In summary, changes in gut microbiota composition are associated with the occurrence and development of Parkinson’s disease. However, most studies have been cross-sectional, involving different selected populations and research methods, with no data on the relationship between the composition of specific gut microbiota and disease progression. Longitudinal cohort studies to investigate the alteration of gut microbiota in different stages of the disease will provide additional insights.

The microbiota-gut-brain axis mediates Parkinson’s disease pathology

Composition of the microbiota-gut-brain axis

Although studies suggest that the microbiota is associated with the pathogenesis of Parkinson’s disease, the specific mechanisms have not fully been elucidated. Changes in bidirectional microbiota-gut-brain interactions are associated with many diseases such as irritable bowel syndrome, autism spectrum disorder and Alzheimer’s disease.^63–65 The bidirectional communication between the CNS and enteric nervous system, known as the gut-brain axis, provides a way for microbiota to mediate brain lesions. The microbiota-gut-brain axis consists of several components of the nervous system, including the CNS, the autonomic nervous system, the enteric nervous system and the hypothalamic-pituitary-adrenal axis. The autonomic nervous system receives afferent signals from the gastrointestinal tract and then passes them along to the CNS through the spinal cord and vagus nerve pathway and also transmits signals from the CNS to the enteric nervous system.⁶⁶^,⁶⁷ Physiologically, gastrointestinal motility, glandular secretion, epithelial barriers and other digestive system functions are controlled by the autonomic nervous system.⁶⁸ Additionally, the CNS regulates the gastrointestinal tract and enteric nervous system through the sympathetic and parasympathetic branches of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis, which can indirectly affect the gut microbiota by changing the gut environment and releasing signal molecules. A schematic overview of the microbiota-gut-brain axis in Parkinson’s disease is shown in Fig. 1.

Figure 1

A schematic overview of microbiota-gut-brain axis in Parkinson’s disease. In the enteric nervous system, the gut microbiota modulates brain function by releasing various signal molecules, which may enter the systemic circulation and reach target sites. The CNS physiologically dominates the gastrointestinal tract via the autonomic nervous system (ANS) hypothalamic-pituitary-adrenal (HPA) axis; in turn, the gut gives feedback to the brain to build bidirectional communication. Drawings were modified from Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License.

The enteric nervous system is a relay station between the gut microbiota and brain and is one of the three branches of the autonomic nervous system (sympathetic, parasympathetic and enteric).⁶⁹ Unlike the CNS, the enteric nervous system is made up of different neural networks in the intestinal wall, where individual small ganglia are connected by dense bundles of fibres.⁷⁰ The human enteric nervous system is composed of the myenteric plexus (Auerbach's plexus), submucosal plexus and enteric glial cells (EGCs). The submucosal plexus is subdivided into three independent plexuses: the inner submucosal plexus (Meissner's plexus) below the mucosal muscle layer; the outer submucosal plexus (Schabadasch's or Henle's plexus) adjacent to the annular muscle layer; and the intermediate plexus between them.⁷¹ The myenteric plexus regulates muscle activity, while the submucosal plexus participates in mucosal function. Nevertheless, this is not followed strictly, because some neurons in the outer submucosal plexus innervate the circular muscle, while the neurons in the myenteric plexus of the human ileum project to the mucosa.⁷¹ EGCs are smaller than neurons and have numerous glial filaments and processes of different shapes and sizes. The markers of mature EGCs consist of glial fibrillary acidic protein (GFAP), S100 calcium binding protein β (S100B), glutamine synthetase and brain fatty acid binding protein.⁷² In the enteric nervous system, EGCs are essential to the development, normal survival and differentiation of neurons, and glial-derived neurotrophic factor (GDNF) plays a fundamental role in maintaining the intestinal epithelial barrier.⁷³

Importantly, the enteric nervous system is affected by microbiota regulation of intestinal movement and function. The average number and density of mucosal EGCs in germ-free mice is significantly decreased, but the EGC network was restored by intragastric administration of conventional intestinal microbiota, indicating that the normal development of the intestinal mucosal EGC network depends on gut microbiota.⁷⁴ In fact, gut microbiota can send a variety of signals to the host to affect the function of the enteric nervous system through intestinal Toll-like receptors (TLRs) and microbial metabolites, including SCFAs, metabolites of bile acids and neuroactive substances like GABA, tryptophan precursors and metabolites, and 5-hydroxytryptamine (5-HT).³⁰^,^75–79 Microbial metabolism and the associated metabolites regulate the homeostasis of the gut and affect the development of the CNS and Parkinson’s disease by regulating the intestinal barrier, drug interactions, neurotrophic factors and the immune response. For instance, some bacterial strains can change the level of neurotransmitter precursors in the intestinal cavity and can even synthesize or regulate neurotransmitters.⁸⁰ Concentrations of norepinephrine, dopamine and 5-HT in the striatum of germ-free mice were significantly increased compared to those of specific pathogen-free mice with normal gut microbiota.⁸¹ As a result, the regulation of intestinal transmitters such as 5-HT, melatonin, GABA, histamine and acetylcholine is a possible mechanism mediating the role of gut microbiota.

Immunity and inflammation

Peripheral inflammation, infection and Parkinson’s disease pathology

Research findings have suggested that both innate immunity and adaptive immunity are dysregulated in neurodegenerative diseases, especially in Parkinson’s disease.⁸²^,⁸³ Peripheral monocytes have been shown to enhance phagocytosis in autologous serum of patients with Parkinson’s disease, supporting the involvement of innate immunity.⁸⁴ Overexpression of α-synuclein promoted pro-inflammatory C-C chemokine receptor type 2 (CCR2)-positive peripheral monocyte entry into the CNS in a mouse model of Parkinson’s disease, and deletion of CCR2 could prevent monocyte infiltration, α-synuclein mediated inflammation and subsequent dopaminergic neuronal death.⁸⁵ These findings support the hypothesis that peripheral derived cells may play an essential role in neuroinflammation and neurodegeneration in Parkinson’s disease.

A recent study reported an increased number of T cells in post-mortem midbrains of Parkinson’s disease, and T cells induced neuronal death via interleukin (IL)-17 and NF-κB activation in human induced pluripotent stem cell-derived midbrain neurons from patients with Parkinson’s disease.⁸⁶ Other authors have demonstrated that cytotoxic CD8⁺ T cell infiltration occurred earlier than α-synuclein aggregation and neuronal death, suggesting adaptive immune system involvement.⁸⁷ In an α-synuclein transgenic mouse model, infiltration of CD3⁺/CD4⁺ helper T (Th) cells was increased in the brain (in close proximity to astrocytes and microglia) and this was accompanied by glial activation and enhanced expression of tumour necrosis factor (TNF) genes.⁸⁸ This suggests that infiltrating peripheral adaptive immune cells are involved in activating resident immune cells in the brain, thus enhancing neuroinflammation.⁸⁸ In addition, Th17 cells, a subset of CD4⁺ T lymphocytes, have been shown to infiltrate into the substantia nigra in an MPTP-induced mouse model. In a cell model of Parkinson’s disease, Th17 cells exacerbated dopaminergic neuron death and glial activation, which was dependent on interaction with LFA-1/ICAM1.⁸⁹ Intriguingly, T cell deficiency can decrease the loss of dopamine neurons and microglial major histocompatibility complex II expression.⁹⁰ Astrocytes have been found to express co-stimulatory molecules that are necessary to activate CD4⁺ T cells.⁹¹^,⁹² Although disruption of the blood–brain barrier (BBB) may provide a pathway for peripheral immune cell infiltration, leading to CNS inflammation and neuron death,⁹³ it remains unclear whether the peripheral immune response is the cause or a result of CNS pathology.

T cells can recognize certain α-synuclein antigenic epitopes, and this is largely mediated by CD4⁺ T cells and CD8⁺ T cells in patients with Parkinson’s disease.⁹⁴ A strong CD4⁺ T cell response to α-synuclein epitopes can be detected before the onset and diagnosis of Parkinson’s disease.⁹⁵ The level of autoantibodies to α-synuclein has been found to be significantly increased in CSF and associated with impaired cognition in patients with Parkinson’s disease.⁹⁶ These findings suggest that autoimmunity may play a role in the pathogenesis of Parkinson’s disease, although it is unclear yet whether α-synuclein antibodies are pathogenic. Genome-wide association studies have alluded to a significant genetic overlap between Parkinson’s disease and autoimmune diseases.⁹⁷ Studies have shown that patients with inflammatory bowel diseases have a higher risk of Parkinson’s disease. In addition, inflammatory bowel diseases and Parkinson’s disease share some common genetic factors.⁹⁸ In autoimmune conditions, peripheral inflammation caused by gut inflammation may trigger α-synuclein aggregation, increasing the permeability of intestinal tract and BBB and leading to neuroinflammation.⁹⁸ In a rotenone-induced Parkinson’s disease mouse model, stress aggravated intestinal hyperpermeability and caused alterations to gut microbiota and inflammation in the colon as well as increased neuroinflammation in the brain.⁹⁹^,Porphyromonas gingivalis-induced peripheral inflammation altered the gut microbiota, increased gut permeability and microglial activation and reduced dopaminergic neurons in the substantia nigra in a genetic mouse model of Parkinson’s disease.¹⁰⁰ In another mouse model, the peripheral injection of lipopolysaccharide (LPS) increased the expression of proinflammatory cytokines in the brain and microglia activation in the substantia nigra via the NLRP3-IL-1β signalling pathway, resulting in neurodegeneration.¹⁰¹ The NLRP3 inflammasome has been found to play a critical role in microbiota-mediated intestinal/peripheral inflammation and neuroinflammation in CNS diseases.¹⁰² Previous evidence has indicated that systemic inflammation can increase the reactive oxygen species, activation of microglia and degeneration of dopaminergic neurons in the brain through peripheral inflammatory factors.¹⁰³^,¹⁰⁴ Another study revealed that the numbers of circulating lymphocytes and neutrophils were decreased with the increased plasma levels of proinflammatory cytokines after LPS injection in a 6-hydroxydopamine (6-OHDA) rat model compared with controls, suggesting that peripheral immune disorder was involved in neurodegeneration associated with Parkinson’s disease.¹⁰⁵ In addition, lipoteichoic acid from Bacillus subtilis increased plasma levels of proinflammatory cytokines and caused BBB dysfunction, contributing to peripheral inflammation and neuroinflammation.¹⁰⁶ In a mouse model, it was found that gastric infection by Helicobacter suis resulted in gastric inflammation and increased gastrointestinal permeability, accompanied by an increased level of proinflammatory cytokines in serum, which was associated with systemic inflammation.¹⁰⁷ Additionally, this study showed inflammation at the choroid plexus, increased blood–CSF barrier permeability with subsequent neuroinflammation and activation of microglia in the brain, indicating that peripheral infection can lead to neuroinflammation in the brain via disruption of the blood–CSF barrier and systemic immune response.¹⁰⁷ In summary, these findings suggest that peripheral inflammation, including gut microbiota-induced intestinal inflammation, can induce systemic and CNS inflammation.

Microbiota, enteric nervous system inflammation and α-synuclein

Microbiota can mediate enteric nervous system inflammation. The gastrointestinal tract provides a place for microbiota to grow and function. The intestinal mucosa, composed of monolayer intestinal epithelial cells, provides physical and chemical barriers to protect the intestine and peripheral organs from symbiotic or pathogenic microbiota. Intestinal epithelial cells regulate the diversity and function of the gut microbiota; in turn, gut microbiota are crucial to the growth and function of these cells.¹⁰⁸ The gut microbiota plays a vital part in the occurrence and development of colitis induced by dextran sulphate sodium, and the lack of gut microbiota significantly reduces colitis.¹⁰⁹ As shown in recent studies, there are inflammatory responses in the colonic tissues of patients with Parkinson’s disease and animal models, including the elevation of proinflammatory cytokines and chemokines such as TNF, IL-1β, IL-17, interferon-gamma (IFN-γ) and IL-6, as well as ECG-reactive proliferation and inflammatory cell activation.⁵¹^,⁷⁷^,^110–113 Similarly, Schwiertz et al.¹¹⁴ showed that calprotectin, a marker of intestinal inflammation and alpha-1-antitrypsin and zonulin, markers of intestinal barrier dysfunction, were significantly increased in patients with Parkinson’s disease, which proved the hypothesis that intestinal inflammation is a contributing factor in the pathogenesis of Parkinson’s disease.¹¹⁴ Additionally, Keshavarzian et al.²⁸ observed that the putative proinflammatory bacteria Ralstonia in the intestinal mucosa of patients with Parkinson’s disease were significantly abundant, and the putative proinflammatory bacteria Akkermansia, Oscillospira and Bacteroides were significantly increased in faecal samples.²⁸ Another study in Asian population observed that Bacteroides was associated with plasma TNF levels, while Verrucomicrobiaceae abundance was correlated with plasma IFN-γ levels, suggesting that alterations in the microbiota may be closely related to the systemic inflammatory response.⁴⁰ The decrease in Roseburia is a characteristic of patients with Parkinson’s disease. Roseburia can upregulate innate immune genes, including antimicrobial peptide genes, intestinal barrier function genes, and TLR-related genes such as TLR5 to enhance intestinal barrier function and reduce intestinal inflammation. In addition, Roseburia has a negative regulatory effect on the NF-κB pathway, promoting immune homeostasis by downregulating this inflammatory cascade.¹¹⁵ Therefore, gut microbiota and its metabolites may be involved in the pathophysiology of Parkinson’s disease through intestinal inflammation, and the proinflammatory intestinal environment may trigger the pathogenesis of Parkinson’s disease.¹¹⁶Figure 2 highlights a potential inflammatory mechanism of the microbiota-gut-brain in Parkinson’s disease.

Figure 2

A potential inflammatory mechanism of microbiota-gut-brain in Parkinson’s disease. Gut microbiota and their metabolites are involved in the occurrence of intestinal inflammation by regulating the integrity of the intestinal mucosal barrier by activating inflammatory cells, releasing pro-inflammatory factors and accumulating α-synuclein in the gut. Microbial metabolites such as LPS can also participate in intestinal inflammation and neuroinflammation through the expression of TLRs. Blood circulation and the vagus nerve provide a pathway for intestinal inflammation and the transmission of α-synuclein by which the neurotoxins produced in the gut enter the brain. The lack of BBB integrity, activation of microglia, proliferation of astrocytes and production of pro-inflammatory factors are specific manifestations of microbiota-mediated neuroinflammation. DA = dopaminergic.

TLRs, a type of pattern recognition receptor, can recognize molecules of microbial origin, which are called microbiota-associated molecular patterns. Currently, 13 types of TLRs have been reported in mammals, among which TLR2 and TLR4 are expressed at low levels in the human colon, with high expression of TLR3 in the small intestine and colon while TLR5 is mainly expressed in the colon.¹¹⁷ In particular, TLR2 is expressed in enteric neurons, glial cells and smooth muscle cells of the intestinal wall.¹¹⁸ Researchers observed that TLR2 gene-deficient (Tlr2^−/−) mice had significantly reduced enteric neurons and glial cells and showed stronger colonic inflammation in response to external stimulation.¹¹⁸ The increased expression of TLRs can increase the permeability of the intestinal epithelial barrier and increase the susceptibility of host colonic inflammation, indicating that they play a crucial role in maintaining intestinal immune homeostasis.¹¹⁹^,¹²⁰ In the study of intestinal biopsies from patients with Parkinson’s disease, it was reported that the immune response of TLR4, cytokines and chemokines, as well as the number of CD3+ T cells, increased in the lamina propria of colonic tissue.¹²⁰ Microarray analysis of sigmoid mucosa samples illustrated that the expression of TLR4 mRNA was significantly higher compared with that in controls. Intriguingly, TLR4 gene knockout significantly alleviated the effects of rotenone on intestinal barrier destruction, reduced the expression of GFAP in the myenteric plexus and colonic α-synuclein aggregation, decreased microglial activation in the substantia nigra and the loss of dopaminergic cells and alleviated the impairment of motor function.¹²⁰ These findings suggest that gut microbiota may trigger immune activation of the colonic mucosa through the TLR4 signalling pathway, leading to neuroinflammation and subsequent neurodegeneration in Parkinson’s disease. Faecal microbiota transplantation (FMT) can improve the metabolic disorder of gut microbiota in MPTP mice by inhibiting the TLR4/TBK1/NF-κB/TNF signalling pathway, thus reducing intestinal inflammation and neuroinflammation, verifying the mechanism of communication between the gut and the brain.¹²¹ In addition, the increase in Bacteroides spp., Enterobacteriaceae and Clostridium in rats with acute colitis mediates the occurrence of intestinal inflammation by upregulating TLR2 and TLR4.¹²⁰ The increase in TLR4, TLR5 and the proinflammatory factor IL-6 and the decrease in the anti-inflammatory factor IL-10 in the mucosa of patients with irritable bowel syndrome were related to alterations in the gut microbiota.¹²² Cytokines and chemokines related to gut microbiota or pathogen-derived products may be involved in the pathogenesis of intestinal inflammation via TLRs.¹²² The gut microbiota also activated intestinal cells that produce IL-10 in MyD88/TLR2/PI3K-dependent pathways to maintain mucosal homeostasis.¹²³ In addition, TLR4 plays an important role in regulating enteric neuron survival and intestinal motility; moreover, by activating TLR4, the gut microbiota can regulate gastrointestinal motility.

Furthermore, similar to Tlr2^−/− mice, the wild-type mice lacking gut microbiota also have enteric nervous system and GDNF deficiencies, which can be partially repaired by administration of TLR2 agonists.¹¹⁸ This research suggests that TLR2 signalling can regulate intestinal inflammation by modulating enteric nervous system structure, neurochemical coding and intestinal neuromuscular function. A recent study found that a TLR2 activator can restore the inhibition of enteric nervous system neurogenesis caused by decreased gut microbiota and modulate the structure and function of the system.¹²⁴ Additionally, the activation of TLR2 can restore intestinal neurogenesis and increase the number of nitrergic neurons in germ-free mice.¹²⁴ Intestinal longitudinal smooth muscle cells activate TLR2 and TLR5 to produce specific neurotrophic factors such as GDNF under the stimulation of bacterial pathogen-associated molecular patterns, which recognize conservative microbial products, to correct the abnormal phenotype of enteric neurons in Tlr2^−/− mice.¹²⁵ These results suggest that the gut microbiota can regulate the structure and function of the enteric nervous system through the TLR signalling pathway.

Gut microbiota mediates the aggregation of α-synuclein in the enteric nervous system. EGCs play a key role in maintaining intestinal permeability and regulating intestinal inflammation.¹²⁶ Changes in the expression and phosphorylation of intestinal GFAP were found in colon biopsies of patients with Parkinson’s disease, indicating that there is reactive proliferation of EGCs in Parkinson’s disease, which leads to local inflammation and may spread to the CNS.¹¹⁰ EGCs may act as an entrance for enterotoxin into the CNS, especially in neurodegenerative diseases. Intestinal barrier dysfunction and increased intestinal permeability caused by inflammation in patients with Parkinson’s disease provide conditions for the circulation of inflammatory factors and the exposure of the enteric nervous system to the microbiota and their harmful products.⁷⁷ Increased intestinal permeability is associated with increased bacteria and exposure to the bacterial endotoxin in Parkinson’s disease, while increased intestinal α-synuclein and 3-nitrotyrosine staining (associated with oxidative stress) leads to high intestinal permeability.¹²⁷ LPS produced by gut microbiota treatment can increase the accumulation of α-synuclein in the enteric nervous system and increase intestinal permeability.¹²⁸ An increase in Gammaproteobacteria, an LPS-producing Gram-negative bacterium, was found in the faeces of patients with Parkinson’s disease.³⁶ Moreover, LPS intervention resulted in a significant decrease in the tight junction proteins zona occludens 1 (ZO-1) and e-cadherin in intestinal epithelial cells of Thy1-α-synuclein mice, indicating that there is a relationship between gut microbiota and the pathogenesis of Parkinson’s disease, thus supporting the hypothesis that α-synuclein spreads from the intestine to the CNS in the pathogenesis of Parkinson’s disease.³⁶ In addition to LPS, gut microbiota may affect the aggregation of α-synuclein through other products or metabolites. Functional amyloid proteins are widely found in the microbiota, including Escherichia coli, which produce curly amyloid fibres to regulate gut and host function.¹²⁹ Microbial functional amyloids can also induce the accumulation of neuronal proteins such as A-β, α-synuclein and tau, mediating the transmission of the disease through the gut-brain axis.¹³⁰ Exposure to curli-producing bacteria increases the deposition and accumulation of α-synuclein in intestinal ganglion cells (myenteric plexus and submucosa) and the brain, respectively, as well as increasing the inflammatory response in the brain.¹³¹ In particular, the components of the bacterial amyloid protein CsgA can accelerate the production of α-synuclein aggregation. Colonization of curli-producing E. coli in α-synuclein-overexpressing mice aggravated motility injury and gastrointestinal dysfunction, while promoting the accumulation and inflammatory response of α-synuclein in the intestine and brain, resulting in increased expression of the proinflammatory cytokines IL-6 and TNF in brain-derived CD11b+ microglia.¹³² Moreover, the increased production of cytokines in the midbrain and colon indicates that microbiota play an important role in α-synuclein production and neuroinflammation.¹³²

Recently, pathological changes in α-synuclein in the enteric nervous system of Parkinson’s disease patients were observed, which provided a new direction for hypotheses on the pathogenesis and pathological origin of Parkinson’s disease.¹³³ According to Braak’s hypothesis, environmental factors may start a pathological process via the olfactory bulb or the intestinal nerve plexus. Inflammation and oxidative stress are caused by swallowing nasal secretions, which leads to the accumulation of α-synuclein in the CNS.¹³⁴ The double-hit hypothesis proposed by Hawkes et al.¹³⁵ supports their theory, pointing out that α-synuclein pathology is transmitted to the midbrain through two different routes, namely, from the nasal cavity to the temporal lobe or from the stomach, followed by nasal secretions in swallowed saliva.¹³⁵ After penetrating the epithelium, the pathogen can enter the axon of Meissner’s plexus and transmit through the synapse to the preganglionic parasympathetic motor neurons of the vagus nerve. At present, many animal experiments have observed the spread of α-synuclein pathology from the intestine to the brain along the gut-brain axis, and pathological changes in the CNS can be observed by injecting α-synuclein into the intestinal wall of the gastrointestinal tract.^136–139 Recently, using non-human primate models, investigators have observed that α-synuclein aggregated from patients with Parkinson’s disease can induce nigra-striatal injury and enteric nervous system pathology after intestinal or striatal injection, indicating that α-synuclein may spread not only rostrally but also caudally, that is, from the gut to the brain and from the brain to the gut.¹⁴⁰ It is suggested that the pathological process of Parkinson’s disease is not limited to the brain-gut or gut-brain, but it is also possible that the pathological processes in the enteric nervous system and CNS develop separately during disease progression. In Parkinson’s disease, the vagus nerve seems to play a fundamental role in the gut-brain transmission of pathological α-synuclein.¹⁴¹ Vagotomy can prevent the transmission of pathological α-synuclein to the CNS in animal models.¹³⁷^,¹³⁸ Further study reported that vagotomy could prevent the development of Parkinson’s disease symptoms in rats and inhibit the misfolding of α-synuclein in intermuscular neurons.¹⁴² A cohort study in Denmark showed that total vagotomy can significantly reduce the risk of secondary Parkinson’s disease.¹⁴³ In contrast, another study with a follow-up of patients after vagotomy argued that vagotomy was not associated with the risk of Parkinson’s disease in Sweden.¹⁴⁴ However, the results of a 5-year follow-up indicated that the risk of Parkinson’s disease was lower 5 years after vagotomy, and similar results were also observed in the 10-year follow-up after vagotomy. The possible reason is that during selective or highly selective vagotomy, α-synuclein pathology caused in other parts of the gastrointestinal tract may still find a way to the vagus nerve and then to the brainstem. Remarkably, a recent study did not find pathological damage to α-synuclein in the vagus nerve in an animal model of Parkinson’s disease, which does not support the hypothesis that α-synuclein pathology is transmitted through the vagus nerve and the dorsal motor nucleus of the vagus nerve.¹⁴⁰ They observed that the concentration of α-synuclein in whole blood of monkeys, who received the injection of pathological α-synuclein into the enteric nervous system, was significantly higher compared to the control group and positively correlated with the immunoreactivity of α-synuclein in enteric neurons. Therefore, they proposed a possible mechanism by which the general circulation acts as a pathway for the long-distance bidirectional transmission of endogenous α-synuclein between the intestinal tract and CNS.

CNS inflammation

Microbiota may trigger CNS neuroinflammation. Neuroinflammation, including microglial proliferation, T cell infiltration, increased expression of inflammatory factors and glial cell activation, has been proven to be an important pathology of Parkinson’s disease.¹⁴⁵^,¹⁴⁶ In recent years, studies have implied that gut microbiota may be involved in this process. Erny et al.¹⁴⁷ illustrated that germ-free animals display global deficiency in microglia and the genes needed to express type I interferon receptors such as Janus kinase 3 (Jak3) and signal transducer and activator of transcription 1 (Stat1), were reduced.¹⁴⁷ Additionally, major histocompatibility complex class I-related β2 microglobulin (B2m), used as a marker of early immune function of microglia, was also found to be decreased. In addition, most of the cytokines and chemokine pathways in the microglia of germ-free mice are affected, which leads to a decrease in the innate immune response, resulting in a decline in the ability to resist bacterial and viral infections.¹⁴⁷ The function of microglia can be restored by the reconstruction of gut microbiota or their metabolites, indicating that microbiota may also be involved in the activity of the innate immune system in the brain via microbial metabolites and intestinal secretions.¹⁴⁷ The decreased activation of CNS microglia and proinflammatory factors, including TNF and IL-6, was found to reduce α-synuclein aggregation and improve motor function in germ-free-α-synuclein overexpressing mice compared with specific pathogen-free α-synuclein overexpressing mice, which suggests that the microbiota is involved in the process of neuroinflammation in Parkinson’s disease mice.⁵⁰ FMT can reduce the increased number of astrocytes, decrease the activation of microglia in the MPTP mouse model and participate in suppressing neuroinflammation by inhibiting the TLR4/TBK1/NF-κB/TNF-α signalling pathway.¹²¹

A clinical study revealed that the level of serum LPS-binding protein in patients with Parkinson’s disease was lower than that in controls, indicating that increased intestinal permeability and increased invasion of Gram-negative bacteria leads to an increase in LPS in the circulatory system.¹⁴⁸ Additionally, predictive meta-genomics showed a significant increase in genes involved in endotoxin biosynthesis and the type III bacterial secretion system (associated with pathogens) in the faecal microbiome of patients with Parkinson’s disease.²⁸ Recently, a predictive analysis of the function of gut microbiota by functional prediction analysis showed that pathways involved in the biosynthesis of LPS and LPS proteins increased in Parkinson’s disease.³⁸ Microbial LPS has a potential effect on CNS inflammation. The peripheral inflammation induced by systemic LPS administration increased the activation of microglia and proinflammatory cytokines, destroyed the BBB, and aggravated the polarization of the A1 phenotype of astrocytes and the loss of dopamine neurons in the substantia nigra and striatum of MPTP mice.¹⁴⁹ The overactivation of microglia may also lead to the loss of dopaminergic neurons. Therefore, peripheral inflammation also plays a vital role in the pathogenesis of Parkinson’s disease. In animal experiments, intranasal injection of LPS could activate microglia in the olfactory bulb and substantia nigra through IL-1β/IL-1R1 signalling, increase pS129 α-synuclein-positive cells in the olfactory bulb and substantia nigra and reduce the number of tyrosine hydroxylase (TH)-immunoreactive cells, suggesting the loss of dopaminergic cells.¹⁵⁰ Microglia are the most abundant immune cells in the brain, and they are also the first responders to bacterial or viral infection in the brain, mediating downstream immune responses activated by pathogens.¹⁴⁷^,¹⁵¹ Microglia in the CNS express pattern recognition receptors such as TLRs, which respond to pathogen-associated molecular pattens and recognize invasive pathogens as immune mechanisms for host defense.¹⁵² Excessive activation of microglia can lead to the production of inflammatory cytokines such as TNF, IL-1β, IL-6 and INF-γ, which may have harmful effects on dopaminergic neurons.¹⁵³ It has been reported that paraquat activates innate immunity via the TLR4-MyD88-dependent pathway, inducing microglial activation and inflammation. Inhibition of TLR4 can downregulate this process, indicating that this receptor plays an important role in paraquat-mediated microglial inflammation.¹⁵⁴^,¹⁵⁵ TLR4 gene-deficient mice partially resist MPTP toxicity by suppressing the activation of microglia in the substantia nigra.¹⁵⁶ A recent in vitro cell experiment revealed that TLR4 gene knockout could polarize BV-2 microglia treated with paraquat to the M1 phenotype, inhibit the expression of proinflammatory factors and reduce the migration and phagocytic activity of microglia, suggesting that TLR4 mediates the neuroinflammation of microglia.¹⁵⁷ TLRs are expressed not only in microglia but also in neurons.¹⁵⁸ The activation of neuronal TLR2 in the brains of patients with Parkinson’s disease results in increased proinflammatory cytokine (TNF) levels and recruitment of microglia to amplify neuroinflammation as well as increased expression of α-synuclein.¹⁵⁸ Most Lewy bodies with positive immunoreactivity towards α-synuclein have strong TLR2 immunoreactivity, which confirms that there is a strong correlation between TLR2 and α-synuclein pathology in the Parkinson’s disease brain.¹⁵⁸ Pathological α-synuclein aggravates the progression of Parkinson’s disease by activating microglia, while the absence or overstimulation of microglia can affect the spread of α-synuclein in the brain.¹⁵³^,¹⁵⁹ Increased activation of TNF/TNFR1 signalling following chronic activation of microglia can give rise to TNF-mediated necroptotic neuronal cell death,¹⁶⁰ which represents a possible therapeutic target in Parkinson’s disease.¹⁶¹

The BBB consists of the endothelial cell layer and its basement membrane, the connected tight junction proteins and the surrounding pericytes and astroglial end feet.¹⁶² Its function is to separate circulating blood and regulate the transport of solutes in the blood to the brain and from the brain to the blood. Dysfunction of the BBB is associated with neurodegenerative diseases.¹⁶³ The BBB was shown to be damaged in MPTP-treated mice.⁸⁹^,¹⁶⁴ Similarly, BBB damage induced by 6-OHDA is related to the loss of dopamine neurons and activated microglia.¹⁶⁵ Microglia have dual effects on the integrity of the BBB. In the process of systemic inflammation, microglia can migrate to cerebral vessels to regulate the integrity of the BBB due to the release of the chemokine CCL5 from endothelial cells.¹⁶⁶ In the early stage of inflammation, microglia form tight junctions by expressing the CLDN5 gene (claudin-5) to maintain the integrity of the BBB, which can also help a series of toxic circulatory molecules (such as inflammatory cytokines, ions and immune cells) activate microglia and astrocytes and aggravate neuroinflammatory damage and BBB dysfunction.¹⁶⁶ With the development of inflammation, microglia form a phagocytic phenotype to destroy the integrity of the BBB by phagocytosis of the terminal feet of astrocytes.¹⁶⁶ maintain

Braniste et al.¹⁶⁷ demonstrated that BBB permeability was increased due to the destruction of tight junction structure and the low expression of transmembrane tight junction proteins (including occludin and claudin-5) in the brains of germ-free mice compared with pathogen-free mice.¹⁶⁷ The integrity of the BBB in germ-free mice was enhanced by transplanting faecal microbiota from the pathogen-free mice or by using microbial SCFAs, suggesting that the microbiota can regulate the function of the BBB.¹⁶⁷ There is an interaction between intestinal microbial metabolites and the BBB. Sodium butyrate (NaB) can improve BBB damage in Parkinson’s disease mice by upregulating occludin and ZO-1 after its intragastric administration in an MPTP mouse model.¹⁶⁸ Propionic acid inhibits the pathways associated with non-specific microbiota infection through CD14-dependent mechanisms, inhibits the expression of LRP-1 and protects the BBB from oxidative stress through nuclear factor erythroid 2-related factor 2 (NRF2) signals.¹⁶⁹ In contrast, another study reported that NaB significantly increased the BBB permeability of a traumatic brain injury mouse model by increasing the expression of tight junction-related proteins (occludin and ZO-1).¹⁷⁰ Peripheral injection of LPS aggravated BBB damage in the substantia nigra and striatum of MPTP mice.¹⁴⁹ LPS may increase the blood-to-brain uptake of α-synuclein by destroying the BBB.¹⁷¹ In addition, LPS affects the transport of neurotoxins by changing the expression of plasma membrane monoamine transporters on the BBB, leading to disease.¹⁷²

Microbial metabolites

Short chain fatty acids

Intestinal SCFAs, including formic acid, acetic acid, propionic acid and butyric acid, are molecules produced in food fermented by gut microbiota.¹⁷³ Studies have found that SCFAs are associated with a variety of diseases such as rectal cancer,¹⁷⁴ pancreatitis,¹⁷⁵ abnormal energy metabolism,¹⁷⁶ constipation,¹⁷⁷ blood lipid metabolism,¹⁷⁸ sleep disorders¹⁷⁹ and Alzheimer’s disease.¹⁸⁰ Microbial SCFAs play a key role in microbiota-gut-brain axis signal communication and are involved in immune, neural and endocrine gut-brain axis communication to mediate the occurrence of disease.¹⁸¹ However, in the gut-brain axis of Parkinson’s disease, the specific mechanism of SCFAs remains unknown. The faecal microbiota of patients with Parkinson’s disease shows a decrease in the production of SCFAs or their producing microbiota in most clinical studies.²⁸^,³⁰^,³⁷^,⁷⁷^,¹⁸² A similar study confirmed the overabundance of opportunistic pathogens in the gut microbiota of patients with Parkinson’s disease with reduced levels of SCFA-producing bacteria and/or increased levels of carbohydrate metabolites.¹⁸³ The decrease in SCFAs may promote intestinal inflammation and greatly increase the risk of α-synuclein deposition in the gastrointestinal tract.²⁷ However, several studies have revealed that butyric acid in faecal samples significantly increased compared to the control group in an MPTP-induced mouse model.¹²¹^,¹⁸⁴ Microbial SCFAs modulate Parkinson’s disease via the microbiota-gut-brain axis, as shown in Fig. 3.

Figure 3

A potential mechanism of SCFA involvement in the gut-brain axis in Parkinson’s disease. Microbial metabolite SCFAs can directly or indirectly affect intestinal and brain function in Parkinson’s disease. SCFAs can reduce intestinal inflammation by regulating the release of inflammatory factors and protecting the intestine from inflammation in a Ffar2-dependent manner. In addition, SCFAs regulate the tight junction between intestinal epithelial cells to maintain the integrity of the intestinal barrier. In the brain, SCFAs play an essential role in the growth and differentiation of synapses and neurons via the release of neurotrophic factors. SCFAs also reduce neuroinflammation, inhibit the activation of microglia and protect the BBB in Parkinson’s disease. DA = dopmainergic.

SCFAs play a crucial role in intestinal inflammation and intestinal barrier function. In a mouse model of intestinal inflammation, the amount of inflammation was found to be negatively correlated with the total concentration of SCFAs and butyrate.¹⁸⁵ The intervention of acetate could alleviate inflammation in a dextran sulphate sodium-induced colitis mouse model, reduce the proinflammatory factors TNF-α and IL-17 in colon tissue and increase the anti-inflammatory factor IL-10 but had no significant effect on Ffar2^−/− (GPR43-deficient) mice, suggesting that SCFAs may be located in GPR43 and affect the immune response.¹⁸⁶ Furthermore, acetate can inhibit the production of TNF-α by LPS-stimulated mononuclear cells.¹⁸⁶ SCFAs could regulate the size and function of the colonic regulatory T cell (cTreg) pool in mice and protect mice from colitis in a Ffar2 (the gene that encodes GPR43)-dependent manner, and cTregs regulate colonic homeostasis and control inflammation by limiting the proliferation of CD4 T cells, indicating that microbial metabolites modulate adaptive immunity and contribute to maintaining gut and host homeostasis.¹⁸⁷ Arpaia et al.¹⁸⁸ reported that propionic acid and butyric acid in the faeces of germ-free mice and microbiota-deficient mice treated with a broad-spectrum antibiotic intervention were significantly decreased compared with specific pathogen-free animals, while commensal bacteria produced butyrate and propionate could promote the differentiation of extrathymic CNS1-dependent Treg cells and participate in the regulation of inflammation.¹⁸⁸ Butyrate can also promote the production of IL-10 by regulating the differentiation of Th1 and Th17 cells and inducing the expression of mature protein 1 (Blimp1), ameliorating colonic inflammation and maintaining intestinal homeostasis.¹⁸⁹ IL-10 is an important anti-inflammatory cytokine that plays an essential role in regulating intestinal homeostasis and inhibiting intestinal inflammation. In addition, butyrate intervention can reduce the level of endotoxin in faeces and serum to suppress inflammation.¹⁹⁰ The destruction of the intestinal barrier provides an entrance for intestinal pathogenic microbiota, and SCFAs serve important function in the maintenance of intestinal barrier function. Butyrate can protect cells from increased paracellular permeability and destruction of the epithelial barrier by LPS, increase the expression of tight junction claudins by activating the Akt/mTOR signalling pathway and downregulate the expression of TLR4 to decrease the expression of the inflammatory cytokines.¹⁹¹ In addition, the protective role of SCFAs on intestinal barrier function is also shown in colonic oxygen metabolism. Butyrate protects intestinal barrier function by maintaining hypoxia inducible factor, a transcription factor that coordinates intestinal barrier protection.¹⁹² Nevertheless, several studies have indicated that a higher concentration of SCFAs in faeces is associated with a lower diversity of gut microbiota, higher intestinal permeability (measuring plasma LPS-binding protein), obesity and cardiac metabolic disorders.¹⁹³

SCFAs may be able to modulate neuroinflammation in Parkinson’s disease. NaB, as a histone deacetylase inhibitor (HDACi), can reduce the degeneration of dopaminergic neurons and improve dyskinesia in a rotenone-induced Drosophila Parkinson’s disease model.¹⁹⁴ Furthermore, HDAC-knockout Drosophila melanogaster is resistant to rotenone-induced motor injury and early death.¹⁹⁴ SCFAs play a crucial role in regulating dopamine neuron loss, the CNS inflammatory response, microglial function and neurotrophic factor production. NaB can regulate apoptosis-related proteins (Bcl-2 and Bax) in the brains of Parkinson’s disease mice to reduce neuronal apoptosis.¹⁶⁸ In a 6-OHDA rat model, NaB reduced oxidative stress, decreased the level of the proinflammatory cytokine TNF, increased BDNF and H3 histone acetylation, rescued the decrease in dopamine levels and prevented neuronal loss and neuronal pyknosis in the striatum.¹⁹⁵ NaB can also reduce α-synuclein-induced DNA damage in a dopaminergic neuronal model by upregulating the genes involved in DNA repair.¹⁹⁶ A recent study on the effect of propionate on rotenone-treated dopaminergic neurons showed that the survival rate of TH+ dopaminergic neurons increased significantly, indicating that propionic acid increased the expression of the TH gene, decreased the expression of the α-synuclein gene, and increased the expression of intracellular STAT3 protein to promote neuroprotection.¹⁹⁷ In addition, SCFAs from intestinal microbiota are key molecules regulating the maturation, morphology and function of microglia.¹⁴⁷ Microglial defects in germ-free mice are reversible and can be reconstructed by reintroducing microbial metabolites such as SCFAs.¹⁴⁷ Using human THP-1 monocytic cells and differentiated human HL-60 myelomonocytic cells to simulate the selective immune function of human microglia, Wenzel et al.¹⁹⁸ found that single or mixed use of SCFAs could inhibit the secretion of IL-1β, monocyte chemoattractant protein-1 and TNF by stimulated human THP-1 microglia-like cells.¹⁹⁸ Formate and valerate significantly decreased the phagocytosis of stimulated human THP-1 microglia-like cells and the production of reactive oxygen species.¹⁹⁸ These results suggested that SCFAs can regulate the homeostasis of neuroinflammation by regulating the function of damaged microglia. Neurotrophic factors including nerve growth factor, GDNF and BDNF can regulate the growth, survival and differentiation of neurons and synapses in the CNS and play an important role in learning and memory ability.¹⁹⁹^,²⁰⁰ NaB attenuated MPTP-induced neuronal loss in the nigral striatal pathway and prevented activation of astrocytes and microglia by upregulating BDNF and GDNF.²⁰¹ Lai et al.²⁰² found the protective effect of valproic acid on dopaminergic neurons in the substantia nigra after injection of 6-OHDA, and the BDNF levels in the striatum and substantia nigra of rats treated with valproic acid were also significantly increased compared with levels in the control group.²⁰² Moreover, a study also revealed that NaB increased the number of cells expressing BDNF in different brain regions after cerebral ischaemia.²⁰³ Most studies found that SCFAs have beneficial effects on Parkinson’s disease by reducing oxidative stress, anti-inflammation and neuroprotection. However, some studies showed that the increase in SCFA levels was related to the pathophysiology of Parkinson’s disease mice and led to neuroinflammation.⁵⁰ In summary, SCFAs seem to play a protective role in Parkinson’s disease, but the specific mechanism remains to be explored.

Bile acids

Bile acids are metabolites produced by cholesterol in the liver, which are further metabolized by gut microbiota to unconjugated, secondary and tertiary bile acids in the intestine. In recent years, it has been found that there is an important bidirectional relationship between intestinal microbiota and bile acids. Bacteria can regulate the composition of bile acids in the lumen, and intestinal microbiota can produce different kinds and quantities of bile acid derivatives; in turn, bile acids have an effect on the survival and growth of microbiota, which is vital to human health and disease.^204–206

Gut microbiota and metabolite bile acids may interact in the intestinal tract and affect immunity. Cholic acid treatment can alter the balance of gut bacterial phyla in rats, by increasing Firmicutes and decreasing Bacteroidetes.²⁰⁷ Bile acids can, moreover, eliminate bacterial overgrowth and reduce bacterial translocation and endotoxemia.²⁰⁸ The activation of the bile acid receptor FXR (farnesoid X receptor) can protect the distal small intestine from the proliferation of bacteria and their harmful effects, while maintaining the integrity of the epithelial barrier.²⁰⁹ In dextran sulphate sodium-induced colitis mice, bile acids can increase the number of RAR-related orphan receptor γ + Treg cells in the intestine and reduce the symptoms and signs of colitis in mice.²⁰⁶ However, the gut microbiota also plays an important role in bile acid metabolism. Sayin et al.²¹⁰ analysed the bile acids of the whole gut-liver system of germ-free and routinely-fed mice and showed that in the role of gut microbiota, the bile acid levels decreased in the gall bladder and small intestine, while they increased in the caecum, colon, faeces and serum, indicating that gut microbiota influenced the composition of bile acids in various parts of the enterohepatic circulatory system.²¹⁰ The gut microbiota may inhibit the synthesis of cholesterol 7a-hydroxylase (CYP7A1) and bile acids by promoting the expression of FXR-dependent fibroblast growth factor 15.²¹⁰ In addition, the gut microbiota plays a pivotal role in deconjugation and dehydroxylation and in bile acid desulphation. Gut dysbiosis in patients with inflammatory bowel diseases leads to bile acid dysmetabolism, which is strongly associated with chronic gut inflammation.²¹¹ The changes in bile acids in the faeces of rats treated with antibiotics indicated that alterations in the intestinal microbiota would have an impact on the bile acid pools in plasma and faeces.²¹²

Importantly, bile acids play a neuroprotective role in neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease.²¹³ Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, has a neuroprotective effect in models of Parkinson’s disease.^214–216 TUDCA plays a neuroprotective role by regulating c-Jun N-terminal kinase activity and the cellular redox threshold and activating the Akt survival pathway.²¹⁴ In the MPTP-induced model, TUDCA regulated the number of functional mitochondria through the PINK1/Parkin-mediated pathway and upregulated mitochondrial reversal, which can prevent MPTP-induced neuronal apoptosis, cortical neuronal production of reactive oxygen species and ATP depletion to exert its neuroprotective effect.²¹⁶ In addition, TUDCA plays an antioxidant role by promoting NRF2 activation and further enhances the expression and activity of its downstream target enzyme glutathione peroxidase in the brains of MPTP mice.²¹⁷ The results demonstrated that TUDCA can not only induce the expression of antioxidant enzymes but also improve their biological activity and eliminate the toxic effect of reactive oxygen species.²¹⁷ Furthermore, TUDCA also relieves neuroinflammation in Parkinson’s disease by inhibiting the activation of astrocytes and microglia, regulating the synthesis of ANXA1 in microglia and preventing the upregulation of proinflammatory factors and the decrease in anti-inflammatory factors in the brain.²¹⁵^,²¹⁸ A recent study found that TUDCA can alleviate the typical motor symptoms of Parkinson’s disease caused by MPTP, including spontaneous activity, the ability to initiate movement and tremor.²¹⁸ In general, TUDCA can improve the loss of dopaminergic neurons and decreased ATP levels as well as mitochondrial dysfunction and neuroinflammation in Parkinson’s disease models. In addition, ursodeoxycholic acid (UDCA) has a protective effect on the function of mitochondria and dopaminergic neurons in a Parkinson’s disease model.²¹⁹ In a rotenone model, UDCA can reduce dyskinesia, prevent the decrease in striatal dopamine content and reduce the expression of NF-κB, TNF and IL-1β.²²⁰ UDCA can also downregulate the expression of the striatal proapoptotic gene Bax and upregulate the expression of the anti-apoptotic gene Bcl2 to inhibit apoptosis and restore the integrity of mitochondrial morphology and function induced by rotenone.²²⁰ Generally, bile acids, affected by the metabolism of intestinal microbiota, play an essential role in antioxidant, anti-inflammatory and neuroprotective activities in the pathogenesis of Parkinson’s disease.

Neurotransmitters

Gut microbiota can also mediate disease by affecting the release of neurotransmitters in the intestine. Serotonin is a monoamine neurotransmitter. The vast majority of 5-HT in the human body is synthesized by enterochromaffin cells, a type of enteroendocrine cell, via the rate-limiting enzyme tryptophan hydroxylase 1 (TPH1).²²¹ In the periphery, serotonin plays an important role in regulating intestinal peristalsis and epithelial secretion, while promoting the development and maintenance of enteric neurons. The gut microbiota plays a key role in promoting serotonin secretion, inducing enteric nervous system maturation by releasing 5-HT and activating the 5-HT4 receptor.²²² After antibiotic treatment, the level of 5-HT in the colon and faeces of mice or germ-free mice decreased significantly, and the expression of TPH1 in colon tissue also decreased, while the reconstruction of intestinal microbiota recovered the decrease in 5-HT in germ-free mice.⁷⁹^,²²³ Gut microbiota and their metabolites, such as SCFAs and cholate, can increase TPH1 expression and 5-HT production in the colon by signalling to enterochromaffin cells.⁷⁹^,²²¹^,Clostridium ramosum was found to promote the secretion of 5-HT in the intestinal tract.²²⁴ The level of plasma 5-HT in patients with Parkinson’s disease was decreased compared with that in controls, and the decrease in plasma serotonin markers was related to the severity of depression and pain.²²⁵ Serotoninergic medication may therefore reduce the risk of cognitive decline in Parkinson’s disease.²²⁶ In addition, microbiota also participate in the regulation of neurotransmitters by affecting the production of GABA, the main inhibitory neurotransmitter in the human brain. Intestinal Lactobacilli and Bifidobacteria can produce GABA involved in the regulation of the microbiota-gut-brain axis.²²⁷^,Bacteroides, Parabacteroides and Escherichia species actively express the GABA production pathway to participate in brain signal transduction.²²⁸ The GABA-producing microbiota increased the level of GABA in the lumen of the small intestine, thus affecting the health of the host and improving depression-like behaviour.²²⁹ In the 6-OHDA model, 5-HT, GABA and bone marrow stem cells have protective effects on neuronal injury induced by oxidative stress.²³⁰ The researchers reported that the level of GABA decreased in the basal ganglia in patients with Parkinson’s disease, and there were significant differences in GABA levels among the Parkinson’s disease motor subtypes, indicating that GABA is involved in the pathogenesis of this disease.²³¹ GABA produced by bacteria has a protective effect on degenerative neurons.²³²

Intervention mediated by the microbiota-gut-brain axis

Diet

With alterations in diet, the microbial abundance and production of fermentation products such as SCFAs and phytochemicals will change significantly.²³³ Diet can also affect the composition of the gut microbiota and the neural activity of the CNS through the microbiota-gut-brain axis. Among them, the Mediterranean diet is a well-known healthy diet model characterized by a large number of plant foods, such as fruits, vegetables, cereals, legumes, nuts and bread, low and medium amounts of dairy products, olive oil as the main source of fat, low and medium amounts of fish and meat, and low amounts of red meat, with the use of spices instead of salt.²³⁴ In addition, it is necessary to eat in a pleasant and familiar environment, rest after meals and engage in sports and social activities at the same time. The Mediterranean diet has been associated with the health status of a variety of diseases, such as cardiovascular disease, obesity, metabolic syndrome and cancer.²³⁵ A case-control study reported that the higher the compliance with a Mediterranean diet, the lower the risk of Parkinson’s disease and the lower the score of the Mediterranean diet, the earlier the age of onset of Parkinson’s disease, but it did not indicate whether low Mediterranean dietary compliance was the result or cause of Parkinson’s disease.²³⁶ Adherence to the Mediterranean diet was significantly associated with a low incidence of prodromal Parkinson’s disease, which indicated that the Mediterranean diet is helpful.²³⁷ A recent randomized clinical trial investigated the effect of the Mediterranean diet on cognitive function in patients with Parkinson’s disease and found that adhering to the Mediterranean diet significantly increased executive function, language, attention, memory and improved cognitive function.²³⁸ Therefore, the Mediterranean diet may be a promising intervention strategy to attenuate onset and development of Parkinson’s disease.

High dietary fibre is one of the characteristics of the Mediterranean diet. Dietary fibre is an important energy source for caecal and colonic microbiota. Under specific intestinal conditions, anaerobes activate complex metabolic pathways to produce metabolites such as SCFAs. Dietary fibre and SCFAs stimulate the production and secretion of intestinal mucus to protect the intestinal epithelium from microbial invasion and reduce the chance of infection.²³⁹ Subtle changes in dietary fibre structure may strongly affect the composition and function of gut microbiota.²⁴⁰ De Filippo et al.²⁴¹ compared the faecal microbiota of European children and African children from a rural village in Burkina Faso, among which the latter had a high content of dietary fibre.²⁴¹ The results indicated that the children in Burkina Faso showed an increased abundance and diversity of microbiota with significantly increased levels of Bacteroidetes and reduced levels of Firmicutes. The concentration of SCFAs in the Burkina Faso group was significantly higher than that in European children, and the abundance of Enterobacteriaceae (Shigella and E. coli) was significantly decreased compared with the European children.²⁴¹ Therefore, a high-fibre diet protects children in the Burkina Faso group from inflammation and intestinal inflammatory disease. Similarly, a comparative study analysed the bacterial species in faecal samples of people from different regions in the USA, including urban people with a protein-rich diet and rural people with mainly corn and cassava-based diets and found that there were significant differences in the phylogenetic composition of faecal microbiota among these individuals.²⁴² Furthermore, De Filippo et al.²⁴³ observed that when food rich in fat and monosaccharides was introduced into the African diet, which is traditionally a diet of grains, legumes and vegetables, the gut microbiota was altered, accompanied by a progressive decrease in SCFAs.²⁴³ Accordingly, changes in diet greatly alter the characteristics and functions of gut microbiota to mediate human health.

Olive (Olea europaea L.) oil, the main source of fat in the Mediterranean diet, mainly contains monounsaturated fatty acids, which have antioxidant activity and inhibit synuclein aggregation.²⁴⁴ Phenolic compounds in olive oil have anti-inflammatory, antioxidant, neuroprotective and immunomodulatory activities.²⁴⁵ In addition, the Mediterranean diet contains several antioxidants, including vitamin E, vitamin C, folic acid and polyphenols.²⁴⁶ Yang et al.²⁴⁷ prospectively evaluated the relationship between the dietary antioxidants vitamins C and E and carotene and the risk of Parkinson’s disease and found that dietary vitamin E and carotene intake can reduce the risk of developing the disease.²⁴⁷ These antioxidants can neutralize the role of oxygen free radicals to reduce oxidative damage. A recent study in Caenorhabditis elegans Parkinson’s disease models showed that the main olive oil polyphenols, hydroxytyrosol and oleuropein aglycone, can reduce the accumulation of α-synuclein in muscle cells and prevent the neurodegeneration of dopaminergic neurons containing α-synuclein.²⁴⁸

In addition to the familiar Mediterranean diet, dietary treatments related to the prevention or treatment of Parkinson’s disease include a ketogenic diet and fasting therapy. A ketogenic diet was found to improve motor and nonmotor symptoms in patients with Parkinson’s disease.²⁴⁹ Additionally, Zhou et al.¹⁸⁴ reported that a fasting-mimicking diet can reduce the loss of dopaminergic neurons in the substantia nigra of MPTP-induced Parkinson’s disease mice.¹⁸⁴ Intermittent fasting can protect neurons in animal models of disease, reduce the number of dopaminergic neurons and improve motor function in Parkinson’s disease.²⁵⁰ Although animal experiments have shown that a ketogenic diet and fasting are effective in preventing Parkinson’s disease, a large number of clinical trials and detailed consensus on standardized programmes are needed to explore whether they are beneficial to patients with Parkinson’s disease. In summary, diet can regulate the alteration of gut microbiota and has an impact on the brain by anti-inflammation, reducing oxidative stress and neuroprotection. Diet-mediated therapy can be used as a new strategy for the treatment and prevention of Parkinson’s disease (Fig. 4).

Figure 4

Potential therapies mediated by the microbiota-gut-brain axis in Parkinson’s disease. In the intestine, a high-fibre, low-fat diet can change the types of intestinal microbiota and increase the content of SCFAs. In addition, microbial therapy such as probiotics, prebiotics, synbiotics and FMT increase beneficial microbiota and inhibit pathogenic bacteria. In general, they play a role in anti-inflammation, increasing epithelial barrier function and reducing gastrointestinal dysfunction. In the CNS, diet and microbial therapy can prevent dopamine neurodegeneration and loss, reduce neuroinflammation and play a neuroprotective role. ROS = reactive oxygen species.

Probiotics

The composition of the intestinal microbiota could affect different organ systems, including the cardiovascular, nervous, immune and metabolic systems.²⁵¹ Microbial therapy, in the form of probiotics, may be a novel strategy for the treatment of Parkinson’s disease. Probiotics are defined as non-viable food components that confer health benefits to the host that are associated with modulating the microbiota. Recent studies have shown that probiotics play a role in relieving the gastrointestinal symptoms of Parkinson’s disease, especially constipation, abdominal pain and abdominal distension.²⁵²^,²⁵³ However, the exact mechanisms and safety of using probiotics in Parkinson’s disease have not fully been clarified, although the mechanisms may involve relieving symptoms, inhibiting inflammation, avoiding antioxidant stress and neuronutrition.²⁵⁴^,²⁵⁵ A double-blind placebo controlled study of Symprove^TM, a large bowel active probiotic and non-motor symptoms of Parkinson’s disease (the SymPD study) is currently underway in the UK.²⁵⁶ A clinical study has shown that probiotic bacteria can increase the production of SCFAs and decrease pro-inflammatory cytokines in patients with Parkinson’s disease, indicating that probiotics may be a potential treatment for this disease (Ghyselinck et al., in press).

Prebiotics and micronutrients

Prebiotics are mainly indigestible food fibres, which benefit the host’s health by selectively stimulating the growth and/or activity of some microbiota in the gut. The FAO/WHO defines prebiotics as ‘a nonviable food that confers health benefit(s) on the host associated with modulation of the microbiota’. The most common sources of prebiotics include soybeans, raw oats, unrefined wheat and barley, indigestible carbohydrates and indigestible oligosaccharides. Some artificially produced prebiotics include inulin, galacto-oligosaccharide, fructo-oligosaccharide and single-chain fatty acids.²⁵⁷ Prebiotics have beneficial effects on Parkinson’s disease by promoting gastrointestinal peristalsis, improving immune function and relieving constipation. Eating fermented milk containing a variety of probiotic strains and prebiotic fibre could improve the symptoms of constipation in patients with Parkinson’s disease.²⁵² Studies have shown that prebiotics (including galacto- and fructo-oligosaccharides) can effectively normalize motor and nonmotor abnormalities and restore the level of dopamine transporters in the striatum induced by rotenone.²⁵⁸ The level of BDNF in the hippocampus of rats increased after the administration of galacto- and fructo-oligosaccharides.²⁵⁹ The results proved that the proliferation of intestinal microbiota mediated by prebiotics may increase the expression of BDNF in the brain through the participation of intestinal hormones. BDNF plays an important role in regulating the composition and function of the CNS. The main function of prebiotics is to stimulate the growth and activity of beneficial microbiota in the gastrointestinal tract, thereby bringing health benefits to the host. Prebiotics deliver beneficial effects in Parkinson’s disease by producing microbiota metabolites such as SCFAs. At present, however, there is little clinical evidence on prebiotics in patients with Parkinson’s disease, so a large number of trials are required to thoroughly investigate the mechanism. ingredient

Faecal microbiota transplantation

Faecal microbiota transplantation, known as faecal transplantation or faecal bacteriotherapy, involves injecting or transplanting liquid filtrate from a healthy donor into the recipient’s intestines to treat specific diseases.²⁶⁰^,²⁶¹ FMT can reconstruct gut microbiota, change intestinal microbial diversity and restore abnormal intestinal microbiota comprehensively and extensively. At present, FMT has been used in patients with many diseases, such as recurrent Clostridium difficile infection, inflammatory bowel disease, metabolic syndrome and obesity.^262–265 FMT has been regarded as an effective and safe treatment for patients with recurrent C. difficile and has been approved by the Federal Drug Administration in the USA.²⁶⁶ The results of a recent randomized, single-blind and controlled trial demonstrated that the endoscopic index of Crohn’s disease severity decreased 6 weeks after FMT.²⁶⁷ However, a single FMT may not be enough to induce significant changes in patients; this requires confirmation through large-scale studies.

FMT may be a potential therapeutic method for the regulation of gut microbiota in animal models. Intragastric administration of Faecalibacterium prausnitzii could significantly reduce the severity of colitis in mice with moderate or severe chronic colitis, suggesting that this species is an anti-inflammatory bacterium with the potential to treat inflammatory bowel disease.²⁶⁸ Additionally, F. prausnitzii can produce butyrate to promote Foxp3 and block the downstream pathway of IL-6/STAT3/IL-17 by inhibiting HDAC1, maintaining the Th17/Treg balance and playing a significant anti-inflammatory role in colorectal colitis rodents.²⁶⁹^,F. prausnitzii can also reduce intestinal inflammation by affecting paracellular permeability and enhancing intestinal epithelium barrier function.²⁷⁰^,²⁷¹ In addition, recent studies have reported that Roseburia intestinalis decreased the disease activity index score, intestinal mucosal epithelial injury and mucosal lymphocyte infiltration, while inhibiting intestinal inflammation, by increasing the number of Treg cells and the expression of anti-inflammatory cytokines in a mouse model of colitis.²⁷²^,²⁷³

Moreover, FMT has also been proposed as a therapeutic approach in neurological diseases such as multiple sclerosis, Parkinson’s disease, autism spectrum disorder, Alzheimer’s disease and epilepsy.^274–276 The regulatory effects of FMT on intestinal microbiota may have an impact on the symptoms or progression of nervous system diseases through immune, endocrine, metabolic and neural pathways. In animal experiments, Sampson et al.⁵⁰ found that the high expression of α-synuclein in mice that were colonized by the gut microbiota of patients with Parkinson’s disease increased motor dysfunction.⁵⁰ In addition, these mice showed changes in SCFAs, with lower concentrations of acetate and higher concentrations of propionate and butyrate, substantiating that the alteration of gut microbiota is a crucial risk factor for Parkinson’s disease.⁵⁰ FMT significantly relieved the metabolic disorder of gut microbiota in Parkinson’s disease mice, alleviated body injury and increased the contents of dopamine and 5-HT in the striatum to protect Parkinson’s disease mice by inhibiting nerve inflammation and reducing TLR4/TNF signal transduction.¹²¹ FMT may play a vital role in regulating the gut microbiota, but animal models have some limitations. Whether the results of animal experiments can be extrapolated to humans is unclear. At present, there is limited evidence for the application of FMT in patients with Parkinson’s disease. A clinical study reported that constipation and movement symptoms were significantly relieved after a single FMT treatment in a patient with Parkinson’s disease with constipation, and leg tremor almost disappeared 1 week after FMT treatment.²⁷⁷ However, caution is needed in drawing conclusions from a single case study and future clinical trials are needed to clarify the role of FMT in Parkinson’s disease. For the treatment of nervous system diseases, multiple FMTs may be needed to achieve a sustained effect. The exact mechanism by which gut microbiota plays a role in FMT through the gut-brain axis remains poorly understood.

FMT is associated with adverse reactions and side effects, including diarrhoea, fever and abdominal pain.²⁷⁸^,²⁷⁹ The major challenges with FMT include the high costs of sample preparation and preservation as well as the selection of faecal donors.²⁶² A survey ascertained that doctors have a relatively high awareness and acceptance of FMT but are most concerned about patients’ acceptance of the treatment, followed by a lack of guidelines and ethical constraints.²⁸⁰ Limited studies on the clinical applications of FMT have provided an opportunity to address some of the gaps in knowledge through better designed clinical trials.

Conclusion

Case control studies show changes in gut microbiota composition in patients with Parkinson’s disease compared with healthy individuals, and there are suggestions of a link between microbiota alterations and disease progression. The microbiota-gut-brain axis, which connects the peripheral and central nervous systems, provides a pathway whereby microbiota may contribute to the pathogenesis of Parkinson’s disease, although the exact mechanism remains to be elucidated. The gut microbiota and their metabolites can modulate the immune system and regulate local and systemic inflammation, epithelial barrier function and neurotrophic factors. More studies are needed to investigate the characteristics of microbiota composition at different stages of Parkinson’s disease with the aim of discovering new biomarkers for the early diagnosis and monitoring of disease progression. Microbial therapies such as probiotics and FMT can relieve gastrointestinal symptoms and even motor symptoms of Parkinson’s disease; however, the safety and effectiveness of FMT requires further evaluation in clinical trials.

Funding

This work was supported by the National Natural Science Foundation of China (82071414) to Q.W., National Medical Research Council Singapore to E.-K.T., and Sunway University and LKCM at NTU Singapore to S.P.

Competing interests

The authors report no competing interests.

References

1

Obeso

JA

,

Stamelou

M

,

Goetz

CG

, 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

.

2

Lim

S-Y

,

Tan

AH

,

Ahmad-Annuar

A

, et al.

Parkinson's disease in the Western Pacific Region

.

Lancet Neurol

.

2019

;

18

(

9

):

865

–

879

.

3

Pfeiffer

RF.

Non-motor symptoms in Parkinson's disease

.

Parkinsonism Relat Disord

.

2016

;

22 (Suppl 1

):

S119

–

S122

.

4

Schapira

AHV

,

Chaudhuri

KR

,

Jenner

P.

Non-motor features of Parkinson disease

.

Nat Rev Neurosci

.

2017

;

18

(

7

):

435

–

450

.

5

Ray Chaudhuri

K

,

Poewe

W

,

Brooks

D.

Motor and nonmotor complications of levodopa: Phenomenology, risk factors, and imaging features

.

Mov Disord

.

2018

;

33

(

6

):

909

–

919

.

6

Cersosimo

MG

,

Raina

GB

,

Pecci

C

, et al.

Gastrointestinal manifestations in Parkinson's disease: Prevalence and occurrence before motor symptoms

.

J Neurol

.

2013

;

260

(

5

):

1332

–

1138

.

7

Lee

HM

,

Koh

SB.

Many faces of Parkinson's disease: Non-motor symptoms of Parkinson's disease

.

J Mov Disord

.

2015

;

8

(

2

):

92

–

97

.

8

Dafsari

HS

,

Martinez-Martin

P

,

Rizos

A

, et al. ; EUROPAR and the International Parkinson and Movement Disorders Society Non-Motor Parkinson's Disease Study Group.

EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson's disease

.

Mov Disord

.

2019

;

34

(

3

):

353

–

365

.

9

Yang

D

,

Zhao

D

,

Ali

SS

, et al.

The role of the gut microbiota in the pathogenesis of Parkinson's disease

.

Front Neurol

.

2019

;

10

:

1155

.

10

Gokce

CB

,

Yurtdas

M

,

Keskin

GS

, et al.

Serum glutathione peroxidase, xanthine oxidase, and superoxide dismutase activities and malondialdehyde levels in patients with Parkinson's disease

.

Neurol Sci

.

2017

;

38

(

3

):

425

–

431

.

11

Hirsch

EC

,

Vyas

S

,

Hunot

S.

Neuroinflammation in Parkinson's disease

.

Parkinson Relat Disord

.

2012

;

18

:

S210

–

S212

.

12

Xu

J

,

Fu

X

,

Pan

M

, et al.

Mitochondrial creatine kinase is decreased in the serum of idiopathic Parkinson's disease patients

.

Aging Dis

.

2019

;

10

(

3

):

601

–

610

.

13

Wang

T

,

Yuan

F

,

Chen

Z

, et al.

Vascular, inflammatory and metabolic risk factors in relation to dementia in Parkinson's disease patients with type 2 diabetes mellitus

.

Aging (Albany NY).

2020

;

12

(

15

):

15682

–

15704

.

14

Heiss

CN

,

Olofsson

LE.

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

.

15

Lahiri

S

,

Kim

H

,

Garcia-Perez

I

, et al.

The gut microbiota influences skeletal muscle mass and function in mice

.

Sci Transl Med

.

2019

;

11

(

502

):

eaan5662

.

16

Quigley

EM.

Basic definitions and concepts: Organization of the gut microbiome

.

Gastroenterol Clin North Am

.

2017

;

46

(

1

):

1

–

8

.

17

Nicholson

JK

,

Holmes

E

,

Kinross

J

, et al.

Host-gut microbiota metabolic interactions

.

Science

.

2012

;

336

(

6086

):

1262

–

1267

.

18

Rinninella

E

,

Raoul

P

,

Cintoni

M

, et al.

What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases

.

Microorganisms

.

2019

;

7

(

1

):

14

.

19

Kundu

P

,

Pettersson

S.

Immunology: Mammalian watchdog targets bacteria

.

Nature

.

2014

;

512

(

7515

):

377

–

378

.

20

Jones

L

,

Kumar

J

,

Mistry

A

, et al.

The transformative possibilities of the microbiota and mycobiota for health, disease, aging, and technological innovation

.

Biomedicines

.

2019

;

7

(

2

):

24

.

21

Fan

W

,

Huo

G

,

Li

X

,

Yang

L

,

Duan

C.

Impact of diet in shaping gut microbiota revealed by a comparative study in infants during the six months of life

.

J Microbiol Biotechnol

.

2014

;

24

(

2

):

133

–

143

.

22

Tremlett

H

,

Bauer

KC

,

Appel-Cresswell

S

,

Finlay

BB

,

Waubant

E.

The gut microbiome in human neurological disease: A review

.

Ann Neurol

.

2017

;

81

(

3

):

369

–

382

.

23

Barichella

M

,

Severgnini

M

,

Cilia

R

, et al.

Unraveling gut microbiota in Parkinson's disease and atypical parkinsonism

.

Mov Disord

.

2019

;

34

(

3

):

396

–

405

.

24

Li

C

,

Cui

L

,

Yang

Y

, et al.

Gut microbiota differs between Parkinson's disease patients and healthy controls in Northeast China

.

Front Mol Neurosci

.

2019

;

12

:

171

.

25

Qian

Y

,

Yang

X

,

Xu

S

, et al.

Alteration of the faecal microbiota in Chinese patients with Parkinson's disease

.

Brain Behav Immun

.

2018

;

70

:

194

–

202

.

26

Aho

VTE

,

Pereira

PAB

,

Voutilainen

S

, et al.

Gut microbiota in Parkinson's disease: Temporal stability and relations to disease progression

.

EBioMedicine

.

2019

;

44

:

691

–

707

.

27

Li

W

,

Wu

X

,

Hu

X

, et al.

Structural changes of gut microbiota in Parkinson's disease and its correlation with clinical features

.

Sci China Life Sci

.

2017

;

60

(

11

):

1223

–

1233

.

28

Keshavarzian

A

,

Green

SJ

,

Engen

PA

, et al.

Colonic bacterial composition in Parkinson's disease

.

Mov Disord

.

2015

;

30

(

10

):

1351

–

1360

.

29

Scheperjans

F

,

Aho

V

,

Pereira

PA

, et al.

Gut microbiota are related to Parkinson's disease and clinical phenotype

.

Mov Disord

.

2015

;

30

(

3

):

350

–

358

.

30

Unger

MM

,

Spiegel

J

,

Dillmann

KU

, et al.

Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls

.

Parkinsonism Relat Disord

.

2016

;

32

:

66

–

72

.

31

Bedarf

JR

,

Hildebrand

F

,

Coelho

LP

, et al.

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naive Parkinson's disease patients

.

Genome Med

.

2017

;

9

(

1

):

39

.

32

Hill-Burns

EM

,

Debelius

JW

,

Morton

JT

, et al.

Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome

.

Mov Disord

.

2017

;

32

(

5

):

739

–

749

.

33

Hopfner

F

,

Künstner

A

,

Müller

SH

, et al.

Gut microbiota in Parkinson disease in a northern German cohort

.

Brain Res

.

2017

;

1667

:

41

–

45

.

34

Heintz-Buschart

A

,

Pandey

U

,

Wicke

T

, et al.

The nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behaviour disorder

.

Mov Disord

.

2018

;

33

(

1

):

88

–

98

.

35

Lin

A

,

Zheng

W

,

He

Y

, et al.

Gut microbiota in patients with Parkinson's disease in southern China

.

Parkinsonism Relat Disord

.

2018

;

53

:

82

–

88

.

36

Gorecki

AM

,

Preskey

L

,

Bakeberg

MC

, et al.

Altered gut microbiome in Parkinson's disease and the influence of lipopolysaccharide in a human alpha-synuclein over-expressing mouse model

.

Front Neurosci

.

2019

;

13

:

839

.

37

Li

F

,

Wang

P

,

Chen

Z

,

Sui

X

,

Xie

X

,

Zhang

J.

Alteration of the faecal microbiota in North-Eastern Han Chinese population with sporadic Parkinson's disease

.

Neurosci Lett

.

2019

;

707

:

134297

.

38

Pietrucci

D

,

Cerroni

R

,

Unida

V

, et al.

Dysbiosis of gut microbiota in a selected population of Parkinson's patients

.

Parkinsonism Relat Disord

.

2019

;

65

:

124

–

130

.

39

Kundu

P

,

Blacher

E

,

Elinav

E

,

Pettersson

S.

Our gut microbiome: The evolving inner self

.

Cell

.

2017

;

171

(

7

):

1481

–

1493

.

40

Lin

CH

,

Chen

CC

,

Chiang

HL

, et al.

Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson's disease

.

J Neuroinflamm

.

2019

;

16

(

1

):

129

.

41

Andrews

ZB

,

Erion

D

,

Beiler

R

, et al.

Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism

.

J Neurosci

.

2009

;

29

(

45

):

14057

–

14065

.

42

Wang

H

,

Dou

S

,

Zhu

J

,

Shao

Z

,

Wang

C

,

Cheng

B.

Ghrelin protects dopaminergic neurons against MPTP neurotoxicity through promoting autophagy and inhibiting endoplasmic reticulum mediated apoptosis

.

Brain Res

.

2020

;

1746

:

147023

.

43

Song

N

,

Wang

W

,

Jia

F

, et al.

Assessments of plasma ghrelin levels in the early stages of Parkinson's disease

.

Mov Disord

.

2017

;

32

(

10

):

1487

–

1491

.

44

Gerhardt

S

,

Mohajeri

MH.

Changes of colonic bacterial composition in Parkinson's disease and other neurodegenerative diseases

.

Nutrients

.

2018

;

10

(

6

):

708

.

45

Everard

A

,

Belzer

C

,

Geurts

L

, et al.

Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity

.

Proc Natl Acad Sci U S A

.

2013

;

110

(

22

):

9066

–

9071

.

46

Campos-Peña

V

,

Toral-Rios

D

,

Becerril-Pérez

F

, et al.

Metabolic syndrome as a risk factor for Alzheimer's disease: Is Aβ a crucial factor in both pathologies?

Antioxid Redox Signal

.

2017

;

26

(

10

):

542

–

560

.

47

Ou

Z

,

Deng

L

,

Lu

Z

, 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

Mihaila

D

,

Donegan

J

,

Barns

S

, et al.

The oral microbiome of early stage Parkinson's disease and its relationship with functional measures of motor and non-motor function

.

PLoS One

.

2019

;

14

(

6

):

e0218252

.

49

Perez-Pardo

P

,

Dodiya

HB

,

Engen

PA

, et al.

Gut bacterial composition in a mouse model of Parkinson’s disease

.

Beneficial Microb

.

2018

;

9

(

5

):

799

–

814

.

50

Sampson

TR

,

Debelius

JW

,

Thron

T

, et al.

Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease

.

Cell

.

2016

;

167

(

6

):

1469

–

1480.e12

.

51

Lai

F

,

Jiang

R

,

Xie

W

, 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

.

52

Kim

DH.

Gut microbiota-mediated drug-antibiotic interactions

.

Drug Metab Dispos

.

2015

;

43

(

10

):

1581

–

1589

.

53

Dethlefsen

L

,

Relman

DA.

Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation

.

Proc Natl Acad Sci U S A

.

2011

;

108 (Suppl 1

):

4554

–

45561

.

54

Palleja

A

,

Mikkelsen

KH

,

Forslund

SK

, et al.

Recovery of gut microbiota of healthy adults following antibiotic exposure

.

Nat Microbiol

.

2018

;

3

(

11

):

1255

–

1265

.

55

Bercik

P

,

Denou

E

,

Collins

J

, et al.

The intestinal microbiota affect central levels of brain-derived neurotropic factor and behaviour in mice

.

Gastroenterology

.

2011

;

141

(

2

):

599

–

609.e1-3

.

56

Cho

I

,

Yamanishi

S

,

Cox

L

, et al.

Antibiotics in early life alter the murine colonic microbiome and adiposity

.

Nature

.

2012

;

488

(

7413

):

621

–

626

.

57

Minato

T

,

Maeda

T

,

Fujisawa

Y

, et al.

Progression of Parkinson's disease is associated with gut dysbiosis: Two-year follow-up study

.

PLoS One

.

2017

;

12

(

11

):

e0187307

.

58

Mertsalmi

TH

,

Aho

VTE

,

Pereira

PAB

, et al.

More than constipation - Bowel symptoms in Parkinson's disease and their connection to gut microbiota

.

Eur J Neurol

.

2017

;

24

(

11

):

1375

–

1383

.

59

Felice

VD

,

Quigley

EM

,

Sullivan

AM

,

O'Keeffe

GW

,

O'Mahony

SM.

Microbiota-gut-brain signalling in Parkinson's disease: Implications for non-motor symptoms

.

Parkinsonism Relat Disord

.

2016

;

27

:

1

–

8

.

60

Sachdev

AH

,

Pimentel

M.

Gastrointestinal bacterial overgrowth: Pathogenesis and clinical significance

.

Ther Adv Chronic Dis

.

2013

;

4

(

5

):

223

–

231

.

61

Niu

X-L

,

Liu

L

,

Song

Z-X

, et al.

Prevalence of small intestinal bacterial overgrowth in Chinese patients with Parkinson's disease

.

J Neural Transm (Vienna)

.

2016

;

123

(

12

):

1381

–

1386

.

62

Fasano

A

,

Bove

F

,

Gabrielli

M

, et al.

The role of small intestinal bacterial overgrowth in Parkinson's disease

.

Mov Disord

.

2013

;

28

(

9

):

1241

–

1249

.

63

Li

Q

,

Zhou

J.

The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder

.

Neuroscience

.

2016

;

324

:

131

–

139

.

64

Liu

S

,

Gao

J

,

Zhu

M

,

Liu

K

,

Zhang

H.

Gut microbiota and dysbiosis in Alzheimer's disease: Implications for pathogenesis and treatment

.

Mol Neurobiol

.

2020

;

57

(

12

):

5026

–

5043

.

65

Quigley

EMM.

The gut-brain axis and the microbiome: Clues to pathophysiology and opportunities for novel management strategies in irritable bowel syndrome (irritable bowel syndrome)

.

J Clin Med

.

2018

;

7

(

1

):

6

.

66

Gibbons

CH.

Basics of autonomic nervous system function

.

Handb Clin Neurol

.

2019

;

160

:

407

–

418

.

67

Coletto

E

,

Dolan

JS

,

Pritchard

S

, et al.

Contractile dysfunction and nitrergic dysregulation in small intestine of a primate model of Parkinson's disease

.

NPJ Parkinsons Dis

.

2019

;

5

:

10

.

68

Wehrwein

EA

,

Orer

HS

,

Barman

SM.

Overview of the anatomy, physiology, and pharmacology of the autonomic nervous system

.

Compr Physiol

.

2016

;

6

(

3

):

1239

–

1278

.

69

Rao

M

,

Gershon

MD.

The bowel and beyond: The enteric nervous system in neurological disorders

.

Nat Rev Gastroenterol Hepatol

.

2016

;

13

(

9

):

517

–

528

.

70

Endres

K

,

Schäfer

K-H.

Influence of commensal microbiota on the enteric nervous system and its role in neurodegenerative diseases

.

J Innate Immun

.

2018

;

10

(

3

):

172

–

180

.

71

Schemann

M

,

Neunlist

M.

The human enteric nervous system

.

Neurogastroenterol Motil

.

2004

;

16 (Suppl 1

):

55

–

59

.

72

Coelho-Aguiar Jde

M

,

Bon-Frauches

AC

,

Gomes

AL

, et al.

The enteric glia: Identity and functions

.

Glia

.

2015

;

63

(

6

):

921

–

935

.

73

Vergnolle

N

,

Cirillo

C.

Neurons and Glia in the enteric nervous system and epithelial barrier function

.

Physiology (Bethesda)

.

2018

;

33

(

4

):

269

–

280

.

74

Kabouridis

PS

,

Lasrado

R

,

McCallum

S

, et al.

Microbiota controls the homeostasis of glial cells in the gut lamina propria

.

Neuron

.

2015

;

85

(

2

):

289

–

295

.

75

Anitha

M

,

Vijay-Kumar

M

,

Sitaraman

SV

,

Gewirtz

AT

,

Srinivasan

S.

Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling

.

Gastroenterology

.

2012

;

143

(

4

):

1006

–

1016.e4

.

76

Caputi

V

,

Marsilio

I

,

Filpa

V

, et al.

Antibiotic-induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice

.

Br J Pharmacol

.

2017

;

174

(

20

):

3623

–

3639

.

77

Perez-Pardo

P

,

Dodiya

HB

,

Engen

PA

, et al.

Role of TLR4 in the gut-brain axis in Parkinson's disease: A translational study from men to mice

.

Gut

.

2019

;

68

(

5

):

829

–

843

.

78

Pokusaeva

K

,

Johnson

C

,

Luk

B

, et al.

GABA-producing Bifidobacterium dentium modulates visceral sensitivity in the intestine

.

Neurogastroenterol Motil

.

2017

;

29

(

1

):

e12904

.

79

Yano

JM

,

Yu

K

,

Donaldson

GP

, et al.

Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis

.

Cell

.

2015

;

161

(

2

):

264

–

276

.

80

Silva

YP

,

Bernardi

A

,

Frozza

RL.

The role of short-chain fatty acids from gut microbiota in gut-brain communication

.

Front Endocrinol (Lausanne)

.

2020

;

11

:

25

.

81

Diaz Heijtz

R

,

Wang

S

,

Anuar

F

, et al.

Normal gut microbiota modulates brain development and behaviour

.

Proc Natl Acad Sci U S A

.

2011

;

108

(

7

):

3047

–

3052

.

82

Tan

EK

,

Chao

YX

,

West

A

,

Chan

LL

,

Poewe

W

,

Jankovic

J.

Parkinson disease and the immune system - Associations, mechanisms and therapeutics

.

Nat Rev Neurol

.

2020

;

16

(

6

):

303

–

318

.

83

Stephenson

J

,

Nutma

E

,

van der Valk

P

,

Amor

S.

Inflammation in CNS neurodegenerative diseases

.

Immunology

.

2018

;

154

(

2

):

204

–

219

.

84

Wijeyekoon

RS

,

Kronenberg-Versteeg

D

,

Scott

KM

, et al.

Monocyte function in Parkinson's disease and the impact of autologous serum on phagocytosis

. Front Neurol

.

2018

;

9

:

870

.

85

Harms

AS

,

Thome

AD

,

Yan

Z

, et al.

Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and neurodegeneration in a model of Parkinson disease

.

Exp Neurol

.

2018

;

300

:

179

–

187

.

86

Sommer

A

,

Marxreiter

F

,

Krach

F

, et al.

Th17 lymphocytes induce neuronal cell death in a human iPSC-based model of Parkinson's disease

.

Cell Stem Cell

.

2018

;

23

(

1

):

123

–

131.e6

.

87

Galiano-Landeira

J

,

Torra

A

,

Vila

M

,

Bové

J.

CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease

.

Brain

.

2020

;

143

(

12

):

3717

–

3733

.

88

Iba

M

,

Kim

C

,

Sallin

M

, et al.

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and alpha-synuclein transgenic models

.

J Neuroinflamm

.

2020

;

17

(

1

):

214

.

89

Liu

Z

,

Huang

Y

,

Cao

BB

,

Qiu

YH

,

Peng

YP.

Th17 cells induce dopaminergic neuronal death via LFA-1/ICAM-1 interaction in a mouse model of Parkinson's disease

.

Mol Neurobiol

.

2017

;

54

(

10

):

7762

–

7776

.

90

Subbarayan

MS

,

Hudson

C

,

Moss

LD

,

Nash

KR

,

Bickford

PC.

T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an alpha-synuclein rat model of Parkinson's disease

.

J Neuroinflamm

.

2020

;

17

(

1

):

242

.

91

Li

K

,

Li

J

,

Zheng

J

,

Qin

S.

Reactive astrocytes in neurodegenerative diseases

.

Aging Dis

.

2019

;

10

(

3

):

664

–

675

.

92

Rostami

J

,

Fotaki

G

,

Sirois

J

, et al.

Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain

.

J Neuroinflamm

.

2020

;

17

(

1

):

119

.

93

Liu

Z

,

Qiu

AW

,

Huang

Y

, et al.

IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson's disease

.

Brain Behav Immun

.

2019

;

81

:

630

–

645

.

94

Sulzer

D

,

Alcalay

RN

,

Garretti

F

, et al.

T cells from patients with Parkinson’s disease recognize α-synuclein peptides

.

Nature

.

2017

;

546

(

7660

):

656

–

661

.

95

Lindestam Arlehamn

CS

,

Dhanwani

R

,

Pham

J

, et al.

α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease

.

Nat Commun

.

2020

;

11

(

1

):

1875

.

96

Akhtar

RS

,

Licata

JP

,

Luk

KC

,

Shaw

LM

,

Trojanowski

JQ

,

Lee

VM.

Measurements of auto-antibodies to alpha-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease

.

J Neurochem

.

2018

;

145

(

6

):

489

–

503

.

97

Witoelar

A

,

Jansen

IE

,

Wang

Y

, et al. ; International Parkinson’s Disease Genomics Consortium (IPDGC), North American Brain Expression Consortium (NABEC), and United Kingdom Brain Expression Consortium (UKBEC) Investigators.

Genome-wide pleiotropy between Parkinson disease and autoimmune diseases

.

JAMA Neurol

.

2017

;

74

(

7

):

780

–

792

.

98

Brudek

T.

Inflammatory bowel diseases and Parkinson's disease

.

J Parkinsons Dis

.

2019

;

9

(

s2

):

S331

–

S344

.

99

Dodiya

HB

,

Forsyth

CB

,

Voigt

RM

, et al.

Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease

.

Neurobiol Dis

.

2020

;

135

:

104352

.

100

Feng

Y-K

,

Wu

Q-L

,

Peng

Y-W

, et al.

Oral P. gingivalis impairs gut permeability and mediates immune responses associated with neurodegeneration in LRRK2 R1441G mice

.

J Neuroinflamm

.

2020

;

17

(

1

):

347

.

101

Zhao

Z

,

Wang

Y

,

Zhou

R

, et al.

A novel role of NLRP3-generated IL-1beta in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: Implications for sepsis-associated neurodegeneration

.

J Neuroinflamm

.

2020

;

17

(

1

):

64

.

102

Pellegrini

C

,

Antonioli

L

,

Calderone

V

,

Colucci

R

,

Fornai

M

,

Blandizzi

C.

Microbiota-gut-brain axis in health and disease: Is NLRP3 inflammasome at the crossroads of microbiota-gut-brain communications?

Prog Neurobiol

.

2020

;

191

:

101806

.

103

Qin

L

,

Wu

X

,

Block

ML

, et al.

Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration

.

Glia

.

2007

;

55

(

5

):

453

–

462

.

104

Qin

L

,

Liu

Y

,

Hong

JS

,

Crews

FT.

NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration

.

Glia

.

2013

;

61

(

6

):

855

–

868

.

105

Engler

H

,

Doenlen

R

,

Riether

C

, et al.

Time-dependent alterations of peripheral immune parameters after nigrostriatal dopamine depletion in a rat model of Parkinson's disease

.

Brain Behav Immun

.

2009

;

23

(

4

):

518

–

526

.

106

Mayerhofer

R

,

Frohlich

EE

,

Reichmann

F

, 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

.

107

Gorle

N

,

Blaecher

C

,

Bauwens

E

, et al.

The choroid plexus epithelium as a novel player in the stomach-brain axis during Helicobacter infection

.

Brain Behav Immun

.

2018

;

69

:

35

–

47

.

108

Soderholm

AT

,

Pedicord

VA.

Intestinal epithelial cells: At the interface of the microbiota and mucosal immunity

.

Immunology

.

2019

;

158

(

4

):

267

–

280

.

109

Hernandez-Chirlaque

C

,

Aranda

CJ

,

Ocon

B

, et al.

Germ-free and antibiotic-treated mice are highly susceptible to epithelial injury in DSS colitis

.

J Crohns Colitis

.

2016

;

10

(

11

):

1324

–

1335

.

110

Clairembault

T

,

Kamphuis

W

,

Leclair-Visonneau

L

, et al.

Enteric GFAP expression and phosphorylation in Parkinson's disease

.

J Neurochem

.

2014

;

130

(

6

):

805

–

815

.

111

Devos

D

,

Lebouvier

T

,

Lardeux

B

, et al.

Colonic inflammation in Parkinson's disease

.

Neurobiol Dis

.

2013

;

50

:

42

–

48

.

112

Morais

LH

,

Hara

DB

,

Bicca

MA

,

Poli

A

,

Takahashi

RN.

Early signs of colonic inflammation, intestinal dysfunction, and olfactory impairments in the rotenone-induced mouse model of Parkinson's disease

.

Behav Pharmacol

.

2018

;

29

(

2 and 3-Spec Issue

):

199

–

210

.

113

Pellegrini

C

,

Fornai

M

,

Colucci

R

, et al.

Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration

.

J Neuroinflamm

.

2016

;

13

(

1

):

146

.

114

Schwiertz

A

,

Spiegel

J

,

Dillmann

U

, et al.

Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson's disease

.

Parkinson Relat Disord

.

2018

;

50

:

104

–

107

.

115

Patterson

AM

,

Mulder

IE

,

Travis

AJ

, et al.

Human gut symbiont roseburia hominis promotes and regulates innate immunity

.

Front Immunol

.

2017

;

8

:

1166

.

116

Matheoud

D

,

Cannon

T

,

Voisin

A

, et al.

Intestinal infection triggers Parkinson's disease-like symptoms in Pink1(-/-) mice

.

Nature

.

2019

;

571

(

7766

):

565

–

569

.

117

Abreu

MT.

Toll-like receptor signalling in the intestinal epithelium: How bacterial recognition shapes intestinal function

.

Nat Rev Immunol

.

2010

;

10

(

2

):

131

–

144

.

118

Brun

P

,

Giron

MC

,

Qesari

M

, et al.

Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system

.

Gastroenterology

.

2013

;

145

(

6

):

1323

–

1333

.

119

Dheer

R

,

Santaolalla

R

,

Davies

JM

, et al.

Intestinal epithelial Toll-Like receptor 4 signaling affects epithelial function and colonic microbiota and promotes a risk for transmissible colitis

.

Infect Immun

.

2016

;

84

(

3

):

798

–

810

.

120

Terán-Ventura

E

,

Aguilera

M

,

Vergara

P

,

Martínez

V.

Specific changes of gut commensal microbiota and TLRs during indomethacin-induced acute intestinal inflammation in rats

.

J Crohns Colitis

.

2014

;

8

(

9

):

1043

–

1054

.

121

Sun

M-F

,

Zhu

Y-L

,

Zhou

Z-L

, et al.

Neuroprotective effects of faecal microbiota transplantation on MPTP-induced Parkinson's disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway

.

Brain Behavior Immunity

.

2018

;

70

:

48

–

60

.

122

Joers

V

,

Masilamoni

G

,

Kempf

D

, et al.

Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series

.

Neurobiol Dis

.

2020

;

144

:

105027

.

123

Mishima

Y

,

Oka

A

,

Liu

B

, et al.

Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells

.

J Clin Invest

.

2019

;

129

(

9

):

3702

–

3716

.

124

Yarandi

SS

,

Kulkarni

S

,

Saha

M

,

Sylvia

KE

,

Sears

CL

,

Pasricha

PJ.

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.e8

.

125

Brun

P

,

Gobbo

S

,

Caputi

V

, et al.

Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells

.

Mol Cell Neurosci

.

2015

;

68

:

24

–

35

.

126

Clairembault

T

,

Leclair-Visonneau

L

,

Neunlist

M

,

Derkinderen

P.

Enteric glial cells: New players in Parkinson's disease?

Mov Disord

.

2015

;

30

(

4

):

494

–

498

.

127

Forsyth

CB

,

Shannon

KM

,

Kordower

JH

, 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

.

128

Kelly

LP

,

Carvey

PM

,

Keshavarzian

A

, 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

.

129

Shanmugam

N

,

Baker

M

,

Ball

SR

,

Steain

M

,

Pham

CLL

,

Sunde

M.

Microbial functional amyloids serve diverse purposes for structure, adhesion and defence

.

Biophys Rev

.

2019

;

11

(

3

):

287

–

302

.

130

Friedland

RP

,

McMillan

JD

,

Kurlawala

Z.

What are the molecular mechanisms by which functional bacterial amyloids influence amyloid beta deposition and neuroinflammation in neurodegenerative disorders?

Int J Mol Sci

.

2020

;

21

(

5

):

1652

.

131

Chen

SG

,

Stribinskis

V

,

Rane

MJ

, et al.

Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans

.

Sci Rep

.

2016

;

6

:

34477

.

132

Sampson

TR

,

Challis

C

,

Jain

N

, et al.

A gut bacterial amyloid promotes alpha-synuclein aggregation and motor impairment in mice

.

Elife

.

2020

;

9

:

e53111

.

133

Pouclet

H

,

Lebouvier

T

,

Coron

E

, et al.

A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson's disease

.

Neurobiol Dis

.

2012

;

45

(

1

):

305

–

309

.

134

Braak

H

,

Rub

U

,

Gai

WP

,

Del Tredici

K.

Idiopathic Parkinson's disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen

.

J Neural Transm (Vienna)

.

2003

;

110

(

5

):

517

–

536

.

135

Hawkes

CH

,

Del Tredici

K

,

Braak

H.

Parkinson's disease: A dual-hit hypothesis

.

Neuropathol Appl Neurobiol

.

2007

;

33

(

6

):

599

–

614

.

136

Challis

C

,

Hori

A

,

Sampson

TR

, et al.

Gut-seeded alpha-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice

.

Nat Neurosci

.

2020

;

23

(

3

):

327

–

336

.

137

Kim

S

,

Kwon

SH

,

Kam

TI

, et al.

Transneuronal propagation of pathologic alpha-synuclein from the gut to the brain models Parkinson's disease

.

Neuron

.

2019

;

103

(

4

):

627

–

641.e7

.

138

Uemura

N

,

Yagi

H

,

Uemura

MT

,

Hatanaka

Y

,

Yamakado

H

,

Takahashi

R.

Inoculation of alpha-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve

.

Mol Neurodegener

.

2018

;

13

(

1

):

21

.

139

Van Den Berge

N

,

Ferreira

N

,

Gram

H

, et al.

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

.

Acta Neuropathol

.

2019

;

138

(

4

):

535

–

550

.

140

Arotcarena

ML

,

Dovero

S

,

Prigent

A

, et al.

Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates

.

Brain

.

2020

;

143

(

5

):

1462

–

1475

.

141

Knudsen

K

,

Fedorova

TD

,

Hansen

AK

, et al.

In-vivo staging of pathology in REM sleep behaviour disorder: A multimodality imaging case-control study

.

Lancet Neurol

.

2018

;

17

(

7

):

618

–

628

.

142

Anselmi

L

,

Bove

C

,

Coleman

FH

, et al.

Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat

.

NPJ Parkinsons Dis

.

2018

;

4

:

30

.

143

Svensson

E

,

Horvath-Puho

E

,

Thomsen

RW

, et al.

Vagotomy and subsequent risk of Parkinson's disease

.

Ann Neurol

.

2015

;

78

(

4

):

522

–

529

.

144

Liu

B

,

Fang

F

,

Pedersen

NL

, et al.

Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study

.

Neurology

.

2017

;

88

(

21

):

1996

–

2002

.

145

Gao

X

,

Huang

Z

,

Feng

C

, et al.

Multimodal analysis of gene expression from postmortem brains and blood identifies synaptic vesicle trafficking genes to be associated with Parkinson's disease

.

Brief Bioinform

.

2020

;

20

:

bbaa244

.

146

Wang

L

,

Liu

Y

,

Yan

S

, et al.

Disease progression-dependent expression of CD200R1 and CX3CR1 in mouse models of Parkinson's disease

.

Aging Dis

.

2020

;

11

(

2

):

254

–

268

.

147

Erny

D

,

Hrabě de Angelis

AL

,

Jaitin

D

, et al.

Host microbiota constantly control maturation and function of microglia in the CNS

.

Nat Neurosci

.

2015

;

18

(

7

):

965

–

977

.

148

Hasegawa

S

,

Goto

S

,

Tsuji

H

, et al.

Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson's disease

.

PLoS One

.

2015

;

10

(

11

):

e0142164

.

149

Garcia-Dominguez

I

,

Vesela

K

,

Garcia-Revilla

J

, et al.

Peripheral inflammation enhances microglia response and nigral dopaminergic cell death in an in vivo MPTP model of Parkinson's disease

.

Front Cell Neurosci

.

2018

;

12

:

398

.

150

Niu

H

,

Wang

Q

,

Zhao

W

, et al.

IL-1beta/IL-1R1 signaling induced by intranasal lipopolysaccharide infusion regulates alpha-synuclein pathology in the olfactory bulb, substantia nigra and striatum

.

Brain Pathol

.

2020

;

30

(

6

):

1102

–

1118

.

151

Fung

TC

,

Olson

CA

,

Hsiao

EY.

Interactions between the microbiota, immune and nervous systems in health and disease

.

Nat Neurosci

.

2017

;

20

(

2

):

145

–

155

.

152

Ho

MS.

Microglia in Parkinson's disease

.

Adv Exp Med Biol

.

2019

;

1175

:

335

–

353

.

153

Zhang

QS

,

Heng

Y

,

Yuan

YH

,

Chen

NH.

Pathological alpha-synuclein exacerbates the progression of Parkinson's disease through microglial activation

.

Toxicol Lett

.

2017

;

265

:

30

–

37

.

154

Sun

Y

,

Zheng

J

,

Xu

Y

,

Zhang

X.

Paraquat-induced inflammatory response of microglia through HSP60/TLR4 signaling

.

Hum Exp Toxicol

.

2018

;

37

(

11

):

1161

–

1168

.

155

Li

XL

,

Wang

YL

,

Zheng

J

,

Zhang

Y

,

Zhang

XF.

Inhibiting expression of HSP60 and TLR4 attenuates paraquat-induced microglial inflammation

.

Chem Biol Interact

.

2019

;

299

:

179

–

185

.

156

Noelker

C

,

Morel

L

,

Lescot

T

, et al.

Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease

.

Sci Rep

.

2013

;

3

:

1393

.

157

Huang

M

,

Li

Y

,

Tian

T

, et al.

Knockdown of TLR4 represses the paraquat-induced neuroinflammation and microglial M1 polarization

.

Neurotoxicity Res

.

2020

;

38

(

3

):

741

–

750

.

158

Dzamko

N

,

Gysbers

A

,

Perera

G

, et al.

Toll-like receptor 2 is increased in neurons in Parkinson's disease brain and may contribute to alpha-synuclein pathology

.

Acta Neuropathol

.

2017

;

133

(

2

):

303

–

319

.

159

George

S

,

Rey

NL

,

Tyson

T

, et al.

Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease

.

Mol Neurodegener

.

2019

;

14

(

1

):

34

.

160

Iannielli

A

,

Bido

S

,

Folladori

L

, et al.

Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in Parkinsons disease models

.

Cell Reports

.

2018

;

22

(

8

):

2066

–

2079

.

161

Yuan

J

,

Amin

P

,

Ofengeim

D.

Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases

.

Nat Rev Neurosci

.

2019

;

20

(

1

):

19

–

33

.

162

Serlin

Y

,

Shelef

I

,

Knyazer

B

,

Friedman

A.

Anatomy and physiology of the blood-brain barrier

.

Semin Cell Dev Biol

.

2015

;

38

:

2

–

6

.

163

Sweeney

MD

,

Sagare

AP

,

Zlokovic

BV.

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

.

Nat Rev Neurol

.

2018

;

14

(

3

):

133

–

150

.

164

Zhang

QS

,

Heng

Y

,

Mou

Z

,

Huang

JY

,

Yuan

YH

,

Chen

NH.

Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease

.

Acta Pharmacol Sin

.

2017

;

38

(

10

):

1317

–

1328

.

165

Carvey

PM

,

Zhao

CH

,

Hendey

B

, et al.

6-Hydroxydopamine-induced alterations in blood-brain barrier permeability

.

Eur J Neurosci

.

2005

;

22

(

5

):

1158

–

1168

.

166

Haruwaka

K

,

Ikegami

A

,

Tachibana

Y

, et al.

Dual microglia effects on blood brain barrier permeability induced by systemic inflammation

.

Nat Commun

.

2019

;

10

(

1

):

5816

.

167

Braniste

V

,

Al-Asmakh

M

,

Kowal

C

, et al.

The gut microbiota influences blood-brain barrier permeability in mice

.

Sci Transl Med

.

2014

;

6

(

263

):

263ra158

.

168

Liu

J

,

Wang

F

,

Liu

S

, 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

.

169

Hoyles

L

,

Snelling

T

,

Umlai

UK

, et al.

Microbiome-host systems interactions: Protective effects of propionate upon the blood-brain barrier

.

Microbiome

.

2018

;

6

(

1

):

55

.

170

Li

H

,

Sun

J

,

Wang

F

, et al.

Sodium butyrate exerts neuroprotective effects by restoring the blood-brain barrier in traumatic brain injury mice

.

Brain Res

.

2016

;

1642

:

70

–

78

.

171

Sui

YT

,

Bullock

KM

,

Erickson

MA

,

Zhang

J

,

Banks

WA.

Alpha synuclein is transported into and out of the brain by the blood-brain barrier

.

Peptides

.

2014

;

62

:

197

–

202

.

172

Wu

KC

,

Lu

YH

,

Peng

YH

,

Hsu

LC

,

Lin

CJ.

Effects of lipopolysaccharide on the expression of plasma membrane monoamine transporter (PMAT) at the blood-brain barrier and its implications to the transport of neurotoxins

.

J Neurochem

.

2015

;

135

(

6

):

1178

–

1188

.

173

Mulak

A.

A controversy on the role of short-chain fatty acids in the pathogenesis of Parkinson's disease

.

Mov Disord

.

2018

;

33

(

3

):

398

–

401

.

174

Ma

X

,

Zhou

Z

,

Zhang

X

, et al.

Sodium butyrate modulates gut microbiota and immune response in colorectal cancer liver metastatic mice

.

Cell Biol Toxicol

.

2020

;

36

(

5

):

509

–

515

.

175

Pan

X

,

Fang

X

,

Wang

F

, et al.

Butyrate ameliorates caerulein-induced acute pancreatitis and associated intestinal injury by tissue-specific mechanisms

.

Br J Pharmacol

.

2019

;

176

(

23

):

4446

–

4461

.

176

Li

Z

,

Yi

C-X

,

Katiraei

S

, et al.

Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit

.

Gut

.

2018

;

67

(

7

):

1269

–

1279

.

177

Tian

H

,

Chen

Q

,

Yang

B

,

Qin

H

,

Li

N.

Analysis of gut microbiome and metabolite characteristics in patients with slow transit constipation

.

Dig Dis Sci

.

2021

;66(9):

3026

–

3035

.

178

Tayyeb

JZ

,

Popeijus

HE

,

Mensink

RP

,

Konings

M

,

Mokhtar

FBA

,

Plat

J.

Short-chain fatty acids (except hexanoic acid) lower NF-kB transactivation, which rescues inflammation-induced decreased apolipoprotein A-I transcription in HepG2 cells

.

Int J Mol Sci

.

2020

;

21

(

14

):

5088

.

179

Szentirmai

E

,

Millican

NS

,

Massie

AR

,

Kapas

L.

Butyrate, a metabolite of intestinal bacteria, enhances sleep

.

Sci Rep

.

2019

;

9

(

1

):

7035

.

180

Ho

L

,

Ono

K

,

Tsuji

M

,

Mazzola

P

,

Singh

R

,

Pasinetti

GM.

Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms

.

Expert Rev Neurother

.

2018

;

18

(

1

):

83

–

90

.

181

Dalile

B

,

Van Oudenhove

L

,

Vervliet

B

,

Verbeke

K.

The role of short-chain fatty acids in microbiota-gut-brain communication

.

Nat Rev Gastroenterol Hepatol

.

2019

;

16

(

8

):

461

–

478

.

182

Cirstea

MS

,

Yu

AC

,

Golz

E

, et al.

Microbiota composition and metabolism are associated with gut function in Parkinson's disease

.

Mov Disord

.

2020

;

35

(

7

):

1208

–

1217

.

183

Wallen

ZD

,

Appah

M

,

Dean

MN

, et al.

Characterizing dysbiosis of gut microbiome in PD: Evidence for overabundance of opportunistic pathogens

.

NPJ Parkinsons Dis

.

2020

;

6

:

11

.

184

Zhou

ZL

,

Jia

XB

,

Sun

MF

, et al.

Neuroprotection of fasting mimicking diet on MPTP-induced Parkinson's disease mice via gut microbiota and metabolites

.

Neurotherapeutics

.

2019

;

16

(

3

):

741

–

760

.

185

Borton

MA

,

Sabag-Daigle

A

,

Wu

J

, et al.

C Chemical and pathogen-induced inflammation disrupt the murine intestinal microbiome

.

Microbiome

.

2017

;

5

(

1

):

47

.

186

Masui

R

,

Sasaki

M

,

Funaki

Y

, et al.

G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells

.

Inflamm Bowel Dis

.

2013

;

19

(

13

):

2848

–

2856

.

187

Smith

PM

,

Howitt

MR

,

Panikov

N

, et al.

The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis

.

Science

.

2013

;

341

(

6145

):

569

–

573

.

188

Arpaia

N

,

Campbell

C

,

Fan

X

, et al.

Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation

.

Nature

.

2013

;

504

(

7480

):

451

–

455

.

189

Chen

L

,

Sun

M

,

Wu

W

, et al.

Microbiota metabolite butyrate differentially regulates Th1 and Th17 cells' differentiation and function in induction of colitis

.

Inflamm Bowel Dis

.

2019

;

25

(

9

):

1450

–

1461

.

190

Zhai

S

,

Qin

S

,

Li

L

,

Zhu

L

,

Zou

Z

,

Wang

L.

Dietary butyrate suppresses inflammation through modulating gut microbiota in high-fat diet-fed mice

.

FEMS Microbiol Lett

.

2019

;

366

(

13

):

fnz153

.

191

Koval

M

,

Yan

H

,

Ajuwon

KM.

Butyrate modifies intestinal barrier function in IPEC-J2 cells through a selective upregulation of tight junction proteins and activation of the Akt signaling pathway

.

PLoS One

.

2017

;

12

(

6

):

e0179586

.

192

Kelly

CJ

,

Zheng

L

,

Campbell

EL

, et al.

Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function

.

Cell Host Microbe

.

2015

;

17

(

5

):

662

–

671

.

193

de la Cuesta-Zuluaga

J

,

Mueller

NT

,

Alvarez-Quintero

R

, et al.

Higher faecal short-chain fatty acid levels are associated with gut microbiome dysbiosis, obesity, hypertension and cardiometabolic disease risk factors

.

Nutrients

.

2018

;

11

(

1

):

51

.

194

St. Laurent

R

,

O’Brien

LM

,

Ahmad

ST.

Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson's disease

.

Neuroscience

.

2013

;

246

:

382

–

390

.

195

Sharma

S

,

Taliyan

R

,

Singh

S.

Beneficial effects of sodium butyrate in 6-OHdopamine induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity

.

Behav Brain Res

.

2015

;

291

:

306

–

314

.

196

Paiva

I

,

Pinho

R

,

Pavlou

MA

, et al.

Sodium butyrate rescues dopaminergic cells from alpha-synuclein-induced transcriptional deregulation and DNA damage

.

Hum Mol Genet

.

2017

;

26

(

12

):

2231

–

2246

.

197

Ostendorf

F

,

Metzdorf

J

,

Gold

R

,

Haghikia

A

,

Tonges

L.

Propionic acid and fasudil as treatment against rotenone toxicity in an in vitro model of Parkinson's disease

.

Molecules

.

2020

;

25

(

11

):

2502

.

198

Wenzel

TJ

,

Gates

EJ

,

Ranger

AL

,

Klegeris

A.

Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells

.

Mol Cell Neurosci

.

2020

;

105

:

103493

.

199

Kundu

P

,

Lee

HU

,

Garcia-Perez

I

, et al.

Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice

.

Sci Transl Med

.

2019

;

11

(

518

):

eaau4760

.

200

Urbina-Varela

R

,

Soto-Espinoza

MI

,

Vargas

R

,

Quinones

L

,

Del Campo

A.

Influence of BDNF genetic polymorphisms in the pathophysiology of aging-related diseases

.

Aging Dis

.

2020

;

11

(

6

):

1513

–

1526

.

201

Srivastav

S

,

Neupane

S

,

Bhurtel

S

, 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

.

202

Lai

CL

,

Lu

CC

,

Lin

HC

, et al.

Valproate is protective against 6-OHdopamine-induced dopaminergic neurodegeneration in rodent midbrain: A potential role of BDNF up-regulation

.

J Formos Med Assoc

.

2019

;

118

(

1 Pt 3

):

420

–

428

.

203

Kim

HJ

,

Leeds

P

,

Chuang

DM.

The HdopamineC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain

.

J Neurochem

.

2009

;

110

(

4

):

1226

–

1240

.

204

Friedman

ES

,

Li

Y

,

Shen

T-CD

, et al.

FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid

.

Gastroenterology

.

2018

;

155

(

6

):

1741

–

1752.e5

.

205

Ridlon

JM

,

Alves

JM

,

Hylemon

PB

,

Bajaj

JS.

Cirrhosis, bile acids and gut microbiota: Unraveling a complex relationship

.

Gut Microbes

.

2013

;

4

(

5

):

382

–

387

.

206

Song

X

,

Sun

X

,

Oh

SF

, et al.

Microbial bile acid metabolites modulate gut RORgamma(+) regulatory T cell homeostasis

.

Nature

.

2020

;

577

(

7790

):

410

–

415

.

207

Islam

KB

,

Fukiya

S

,

Hagio

M

, et al.

Bile acid is a host factor that regulates the composition of the caecal microbiota in rats

.

Gastroenterology

.

2011

;

141

(

5

):

1773

–

1781

.

208

Lorenzo-Zuniga

V

,

Bartoli

R

,

Planas

R

, et al.

Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats

.

Hepatology

.

2003

;

37

(

3

):

551

–

557

.

209

Inagaki

T

,

Moschetta

A

,

Lee

Y

, et al.

Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor

.

Proc Natl Acad Sci U S A

.

2006

;

103

(

10

):

3920

–

3925

.

210

Sayin Sama

I

,

Wahlström

A

,

Felin

J

, et al.

Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist

.

Cell Metabolism

.

2013

;

17

(

2

):

225

–

235

.

211

Duboc

H

,

Rajca

S

,

Rainteau

D

, et al.

Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases

.

Gut

.

2013

;

62

(

4

):

531

–

539

.

212

Behr

C

,

Slopianka

M

,

Haake

V

, et al.

Analysis of metabolome changes in the bile acid pool in feces and plasma of antibiotic-treated rats

.

Toxicol Appl Pharmacol

.

2019

;

363

:

79

–

87

.

213

Kiriyama

Y

,

Nochi

H.

The biosynthesis, signaling, and neurological functions of bile acids

.

Biomolecules

.

2019

;

9

(

6

):

232

.

214

Castro-Caldas

M

,

Carvalho

A

,

Rodrigues

E

, et al.

Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease

.

Mol Neurobiol

.

2012

;

46

(

2

):

475

–

486

.

215

Mendes

MO

,

Rosa

AI

,

Carvalho

AN

, et al.

Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy

.

Mol Cell Neurosci

.

2019

;

96

:

1

–

9

.

216

Rosa

AI

,

Fonseca

I

,

Nunes

MJ

, et al.

Novel insights into the antioxidant role of tauroursodeoxycholic acid in experimental models of Parkinson's disease

.

Biochim Biophys Acta Mol Basis Dis

.

2017

;

1863

(

9

):

2171

–

2181

.

217

Moreira

S

,

Fonseca

I

,

Nunes

MJ

, et al.

NNrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease

.

Exp Neurol

.

2017

;

295

:

77

–

87

.

218

Rosa

AI

,

Duarte-Silva

S

,

Silva-Fernandes

A

, et al.

Tauroursodeoxycholic acid improves motor symptoms in a mouse model of Parkinson's disease

.

Mol Neurobiol

.

2018

;

55

(

12

):

9139

–

9155

.

219

Mortiboys

H

,

Furmston

R

,

Bronstad

G

,

Aasly

J

,

Elliott

C

,

Bandmann

O.

UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo

.

Neurology

.

2015

;

85

(

10

):

846

–

852

.

220

Abdelkader

NF

,

Safar

MM

,

Salem

HA.

Ursodeoxycholic acid ameliorates apoptotic cascade in the rotenone model of Parkinson's disease: Modulation of mitochondrial perturbations

.

Mol Neurobiol

.

2016

;

53

(

2

):

810

–

817

.

221

Reigstad

CS

,

Salmonson

CE

,

Rainey

JF

3rd, et al.

Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells

.

Faseb J

.

2015

;

29

(

4

):

1395

–

1403

.

222

De Vadder

F

,

Grasset

E

,

Mannerås Holm

L

, et al.

ut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks

.

Proc Natl Acad Sci U S A

.

2018

;

115

(

25

):

6458

–

6463

.

223

Ge

X

,

Ding

C

,

Zhao

W

, et al.

Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility

.

J Transl Med

.

2017

;

15

(

1

):

13

.

224

Mandic

AD

,

Woting

A

,

Jaenicke

T

, et al.

Clostridium ramosum regulates enterochromaffin cell development and serotonin release

.

Sci Rep

.

2019

;

9

(

1

):

1177

.

225

Tong

Q

,

Zhang

L

,

Yuan

Y

, et al.

Reduced plasma serotonin and 5-hydroxyindoleacetic acid levels in Parkinson's disease are associated with nonmotor symptoms

.

Parkinsonism Relat Disord

.

2015

;

21

(

8

):

882

–

887

.

226

Kotagal

V

,

Spino

C

,

Bohnen

NI

,

Koeppe

R

,

Albin

RL.

Serotonin, beta-amyloid, and cognition in Parkinson disease

.

Ann Neurol

.

2018

;

83

(

5

):

994

–

1002

.

227

Barrett

E

,

Ross

RP

,

O'Toole

PW

,

Fitzgerald

GF

,

Stanton

C.

gamma-Aminobutyric acid production by culturable bacteria from the human intestine

.

J Appl Microbiol

.

2012

;

113

(

2

):

411

–

417

.

228

Strandwitz

P

,

Kim

KH

,

Terekhova

D

, et al.

GABA-modulating bacteria of the human gut microbiota

.

Nat Microbiol

.

2019

;

4

(

3

):

396

–

403

.

229

Patterson

E

,

Ryan

PM

,

Wiley

N

, et al.

GGamma-aminobutyric acid-producing lactobacilli positively affect metabolism and depressive-like behaviour in a mouse model of metabolic syndrome

.

Sci Rep

.

2019

;

9

(

1

):

16323

.

230

Kuruvilla

KP

,

Nandhu

MS

,

Paul

J

,

Paulose

CS.

Oxidative stress mediated neuronal damage in the corpus striatum of 6-hydroxydopamine lesioned Parkinson's rats: Neuroprotection by serotonin, GABA and bone marrow cells supplementation

.

J Neurol Sci

.

2013

;

331

(

1-2

):

31

–

37

.

231

Gong

T

,

Xiang

Y

,

Saleh

MG

, et al.

Inhibitory motor dysfunction in parkinson's disease subtypes

.

J Magn Reson Imaging

.

2018

;

47

(

6

):

1610

–

1615

.

232

Ribeiro

C

,

Urrutia

A

,

García-Angulo

VA

, et al.

Bacterially produced metabolites protect C. elegans neurons from degeneration

.

PLoS Biol

.

2020

;

18

(

3

):

e3000638

.

233

Wilson

AS

,

Koller

KR

,

Ramaboli

MC

, et al.

Diet and the human gut microbiome: An international review

.

Dig Dis Sci

.

2020

;

65

(

3

):

723

–

740

.

234

Mazzocchi

A

,

Leone

L

,

Agostoni

C

,

Pali-Scholl

I.

The Secrets of the Mediterranean Diet. Does [Only] Olive Oil Matter?

Nutrients

.

2019

;

11

(

12

):

2941

.

235

Sánchez-Sánchez

ML

,

García-Vigara

A

,

Hidalgo-Mora

JJ

,

García-Pérez

M-Á

,

Tarín

J

,

Cano

A.

Mediterranean diet and health: A systematic review of epidemiological studies and intervention trials

.

Maturitas

.

2020

;

136

:

25

–

37

.

236

Alcalay

RN

,

Gu

Y

,

Mejia-Santana

H

,

Cote

L

,

Marder

KS

,

Scarmeas

N.

The association between Mediterranean diet adherence and Parkinson's disease

.

Mov Disord

.

2012

;

27

(

6

):

771

–

774

.

237

Maraki

MI

,

Yannakoulia

M

,

Stamelou

M

, et al.

Mediterranean diet adherence is related to reduced probability of prodromal Parkinson's disease

.

Mov Disord

.

2019

;

34

(

1

):

48

–

57

.

238

Paknahad

Z

,

Sheklabadi

E

,

Derakhshan

Y

,

Bagherniya

M

,

Chitsaz

A.

The effect of the Mediterranean diet on cognitive function in patients with Parkinson's disease: A randomized clinical controlled trial

.

Complement Ther Med

.

2020

;

50

(

102366

):

102366

.

239

Makki

K

,

Deehan

EC

,

Walter

J

,

Backhed

F.

The impact of dietary fiber on gut microbiota in host health and disease

.

Cell Host Microbe

.

2018

;

23

(

6

):

705

–

715

.

240

Tuncil

Y

,

Thakkar

R

,

Arioglu-Tuncil

S

,

Hamaker

B

,

Lindemann

S.

Subtle variations in dietary-fiber fine structure differentially influence the composition and metabolic function of gut microbiota

.

mSphere

.

2020

;

5

(

3

):

e00180-20

.

241

De Filippo

C

,

Cavalieri

D

,

Di

PM

, et al.

Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa

.

Proc Natl Acad Sci U S A

.

2010

;

107

(

33

):

14691

–

14696

.

242

Yatsunenko

T

,

Rey

FE

,

Manary

MJ

, et al.

Human gut microbiome viewed across age and geography

.

Nature

.

2012

;

486

(

7402

):

222

–

227

.

243

De Filippo

C

,

Di

PM

,

Ramazzotti

M

, et al.

Diet, environments, and gut microbiota. A preliminary investigation in children living in rural and urban Burkina Faso and Italy

.

Front Microbiol

.

2017

;

8

:

1979

.

244

Mohammad-Beigi

H

,

Aliakbari

F

,

Sahin

C

, et al.

Oleuropein derivatives from olive fruit extracts reduce α-synuclein fibrillation and oligomer toxicity

.

J Biol Chem

.

2019

;

294

(

11

):

4215

–

4232

.

245

Abdallah

M

,

Marzocco

S

,

Adesso

S

,

Zarrouk

M

,

Guerfel

M.

Olive oil polyphenols extracts inhibit inflammatory markers in J774A.1 murine macrophages and scavenge free radicals

.

Acta Histochemica

.

2018

;

120

(

1

):

1

–

10

.

246

Moosavian

SP

,

Arab

A

,

Paknahad

Z.

The effect of a Mediterranean diet on metabolic parameters in patients with non-alcoholic fatty liver disease: A systematic review of randomized controlled trials

.

Clin Nutr

.

2020

;

35

:

40

–

46

.

247

Yang

F

,

Wolk

A

,

Hakansson

N

,

Pedersen

NL

,

Wirdefeldt

K.

Dietary antioxidants and risk of Parkinson's disease in two population-based cohorts

.

Mov Disord

.

2017

;

32

(

11

):

1631

–

1636

.

248

Brunetti

G

,

Di

RG

,

Scuto

M

, et al.

Healthspan Maintenance and Prevention of Parkinson's-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans

.

Int J Mol Sci

.

2020

;

21

(

7

):

2588

.

249

Phillips

MCL

,

Murtagh

DKJ

,

Gilbertson

LJ

,

Asztely

FJS

,

Lynch

CDP.

Low-fat versus ketogenic diet in Parkinson's disease: A pilot randomized controlled trial

.

Mov Disord

.

2018

;

33

(

8

):

1306

–

1314

.

250

Mattson

MP

,

Longo

VD

,

Harvie

M.

Impact of intermittent fasting on health and disease processes

.

Ageing Res Rev

.

2017

;

39

:

46

–

58

.

251

Azad

MAK

,

Sarker

M

,

Li

T

,

Yin

J.

Probiotic species in the modulation of gut microbiota: An overview

.

Biomed Res Int

.

2018

;

2018

:

9478630

.

252

Barichella

M

,

Pacchetti

C

,

Bolliri

C

, et al.

Probiotics and prebiotic fiber for constipation associated with Parkinson disease: An RCT

.

Neurology

.

2016

;

87

(

12

):

1274

–

1280

.

253

Cassani

E

,

Privitera

G

,

Pezzoli

G

, et al.

Use of probiotics for the treatment of constipation in Parkinson's disease patients

.

Minerva Gastroenterol Dietol

.

2011

;

57

(

2

):

117

–

121

.

254

Castelli

V

,

d'Angelo

M

,

Lombardi

F

, et al.

Effects of the probiotic formulation SLAB51 in and Parkinson's disease models

.

Aging (Albany NY

).

2020

;

12

(

5

):

4641

–

4659

.

255

Tamtaji

OR

,

Taghizadeh

M

,

Daneshvar Kakhaki

R

, et al.

Clinical and metabolic response to probiotic administration in people with Parkinson's disease: A randomized, double-blind, placebo-controlled trial

.

Clin Nutr

.

2019

;

38

(

3

):

1031

–

1035

.

256

Leta

V

,

Chaudhuri

KR.

Gut microbiota and Parkinson’s disease: Background and rationale of the SymPD study

.

Neurodigest

.

2019

;

5

:

10

–

11

.

257

Markowiak

P

,

Slizewska

K.

Effects of probiotics, prebiotics, and synbiotics on human health

.

Nutrients

.

2017

;

9

(

9

):

1021

.

258

Perez-Pardo

P

,

de Jong

EM

,

Broersen

LM

, et al.

Promising effects of neurorestorative diets on motor, cognitive, and gastrointestinal dysfunction after symptom development in a mouse model of Parkinson's disease

.

Front Aging Neurosci

.

2017

;

9

:

57

.

259

Savignac

HM

,

Corona

G

,

Mills

H

, et al.

Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine

.

Neurochem Int

.

2013

;

63

(

8

):

756

–

764

.

260

Borody

TJ

,

Warren

EF

,

Leis

S

,

Surace

R

,

Ashman

O.

Treatment of ulcerative colitis using faecal bacteriotherapy

.

J Clin Gastroenterol

.

2003

;

37

(

1

):

42

–

47

.

261

Zhang

F

,

Cui

B

,

He

X

,

Nie

Y

,

Wu

K

,

Fan

D.

, FMT-standardization Study Group.

Microbiota transplantation: Concept, methodology and strategy for its modernization

.

Protein Cell

.

2018

;

9

(

5

):

462

–

473

.

262

Bakken

JS

,

Polgreen

PM

,

Beekmann

SE

,

Riedo

FX

,

Streit

JA.

Treatment approaches including faecal microbiota transplantation for recurrent Clostridium difficile infection (RCDI) among infectious disease physicians

.

Anaerobe

.

2013

;

24

:

20

–

24

.

263

Kootte

R

,

Levin

E

,

Salojärvi

J

, et al.

Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition

.

Cell Metabolism

.

2017

;

26

(

4

):

611

–

619.e6

.

264

Mańkowska-Wierzbicka

D

,

Stelmach-Mardas

M

,

Gabryel

M

, et al.

The effectiveness of multi-session FMT treatment in active ulcerative colitis patients: A pilot study

.

Biomedicines

.

2020

;

8

(

8

):

268

.

265

Yu

CC

,

Chen

HL

,

Chen

MH

, et al.

Vascular inflammation is a risk factor associated with brain atrophy and disease severity in Parkinson's disease: A case-control study

.

Oxid Med Cell Longev

.

2020

;

2020

:

2591248

.

266

Carlucci

C

,

Petrof

EO

,

Allen-Vercoe

E.

Fecal microbiota-based therapeutics for recurrent Clostridium difficile infection, ulcerative colitis and obesity

.

EBioMedicine

.

2016

;

13

:

37

–

45

.

267

Sokol

H

,

Landman

C

,

Seksik

P

, et al. ; Saint-Antoine IBD Network.

Fecal microbiota transplantation to maintain remission in Crohn's disease: A pilot randomized controlled study

.

Microbiome

.

2020

;

8

(

1

):

12

.

268

Martin

R

,

Chain

F

,

Miquel

S

, et al.

The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models

.

Inflamm Bowel Dis

.

2014

;

20

(

3

):

417

–

430

.

269

Zhou

L

,

Zhang

M

,

Wang

Y

, et al.

Faecalibacterium prausnitzii produces butyrate to maintain Th17/Treg balance and to ameliorate colorectal colitis by inhibiting histone deacetylase 1

.

Inflamm Bowel Dis

.

2018

;

24

(

9

):

1926

–

1940

.

270

Carlsson

AH

,

Yakymenko

O

,

Olivier

I

, et al.

Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis

.

Scand J Gastroenterol

.

2013

;

48

(

10

):

1136

–

1144

.

271

Martin

R

,

Miquel

S

,

Chain

F

, et al.

Faecalibacterium prausnitzii prevents physiological damages in a chronic low-grade inflammation murine model

.

BMC Microbiol

.

2015

;

15

:

67

.

272

Shen

Z

,

Zhu

C

,

Quan

Y

, et al.

Insights into Roseburia intestinalis which alleviates experimental colitis pathology by inducing anti-inflammatory responses

.

J Gastroenterol Hepatol

.

2018

;

33

(

10

):

1751

–

1760

.

273

Zhu

C

,

Song

K

,

Shen

Z

, et al.

Roseburia intestinalis inhibits interleukin17 excretion and promotes regulatory T cells differentiation in colitis

.

Mol Med Rep

.

2018

;

17

(

6

):

7567

–

7574

.

274

Hazan

S.

Rapid improvement in Alzheimer's disease symptoms following faecal microbiota transplantation: A case report

.

J Int Med Res

.

2020

;

48

(

6

):

300060520925930

.

275

Kang

DW

,

Adams

JB

,

Coleman

DM

, et al.

Long-term benefit of microbiota transfer therapy on autism symptoms and gut microbiota

.

Sci Rep

.

2019

;

9

(

1

):

5821

.

276

Li

K

,

Wei

S

,

Hu

L

, et al.

Protection of faecal microbiota transplantation in a mouse model of multiple sclerosis

.

Mediators Inflamm

.

2020

;

2020

:

2058272

.