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Written by Bi Mingxia, edited by Wang Sizhen, edited by Fang Yiyi - Xia Ye
Parkinson's disease (PD) is a complex neurodegenerative disease characterized by denergic dopamine neuronal degeneration in the substantia nigra dense (SNpc) and misfolded in intracellular Lewy bodies Characterized by aggregation of α-synuclein (α-SYN)[1].
Currently, the diagnostic criterion for PD is dyskinesia, but more than 80 percent of patients with Parkinson's disease have gastrointestinal disorders 15 to 20 years prior to the onset of dyskinesia [2].
。 Neuropathological studies have shown early occurrence of α-syn aggregation in the enteric nervous system (ENS) of PD, further suggesting the role of the gastrointestinal tract and its neural connections with the brain in the pathogenesis of PD [3,4]
。 The gut-brain axis has attracted much attention in homeostatic maintenance [5], and gut microbes play a key role in the regulation of the gut-brain axis [6].
。 Therefore, the role of the microbiome-gut-brain axis between PD and the gut microbiota has attracted attention [7].
In addition, the gut microbiota can influence the specificity of an individual's response to drugs, which also act on the gut microbiota [8].
Therefore, understanding the correlation between the gut microbiota and PD, and then using the microbiome-gut-brain axis to regulate the gut microbiota, will achieve the development of new treatments and improve the effectiveness of
drugs.
Recently, the team of Professor Liu Shuangjiang of the Institute of Microbiology Technology of Shandong University published a report entitled "Emerging insights between gut microbiome dysbiosis and Parkinson's disease" in Ageing Research Reviews : Pathogenic and clinical relevance".
This review describes the latest research advances in the pathogenesis of gut microbiota in the pathogenesis of PD and its clinical relevance to non-motor symptoms and motor symptoms of PD, and discusses the complex interactions between the gut microbiota and PD drugs for development PD diagnostic markers and treatment options provide new ideas
.
Intestinal microbiome imbalance and PD pathology
Traditionally, the clinical manifestations of PD have been mainly dyskinesia
.
It was not until 1900 that the evidence for the complex interaction between the gastrointestinal tract and brain in PD was clarified [9-11].
In recent years, studies have also supported the role of gastrointestinal disorders in PD [4,12].
Patients with PD experience a prodromal gastrointestinal dysfunction that represents an early form of PD that precedes motor symptoms [13].
The pathology of α-Syn is thought to be present in SNpc, but α-Syn is prevalent in the peripheral autonomic nervous system [14-15], especially PD patients in the
gastrointestinal tract.
α-Syn in the gastrointestinal tract is transported to the brain via the vagus nerve and may induce PD, but the mechanism of how α-Syn forms and spreads needs more research to demonstrate
.
The functional amyloid fiber Curli, present in the gut, is part of the extracellular matrix, the main component of the intestinal biofilm, and is also present in
bacterial biofilms.
E.
coli is thought to express Curli [16] and promote α-Synon pathology in the intestine and brain, accelerating host neurodegeneration [17,18] , but other Curli-containing bacteria still require further identification
.
Groundbreaking research suggests that gut microbiome dysregulation can serve as a potential biomarker for
patients with PD.
Numerous studies have provided evidence of gut microbial disorders in PD, with significant differences in intestinal microbial diversity in PD patients and changes
in the gut microbiome in PD models.
However, the influence of internal and external factors such as individual differences, disease progression, and sample preparation cannot be ruled out, suggesting that more rigorous and standardized studies should be carried out for PD patients, and in-depth research on intestinal microbes using metagenomic and multi-omics methods should be used to more clearly elucidate the relationship between intestinal microbiome changes and the pathogenesis of PD.
Changes in gut microbial metabolites in PD patients help regulate host homeostasis and chronic neuroinflammation
.
Short-chain fatty acids (SCFAs) such as acetic acid, propionic acid, butyric acid, and valeric acid regulate energy metabolism, participate in transmitter synthesis, and relieve intestinal inflammation [19,20].
In the brain, SCFAs regulate microglial maturation, neurotrophic factor production, and inflammatory responses [21,22].
However, SCFAs may also play a pathological role in PD [23].
Bile acids interact with their receptors to inhibit apoptosis, inflammation, and oxidative stress [24].
The gut microbiota can also regulate the production of transmitters such as serotonin, γ-aminobutyric acid (GABA), and dopamine, which can be transported to the central nervous system, affecting brain function
.
H2 produced in the gut affects the microbiota and host
through anti-inflammatory and antioxidant properties.
In addition, physiological concentrations of hydrogen sulfide (H2S) also promote long-term potentiation effects (LTPs) in the hippocampus and regulate the influx or release of Ca2+ in neurons [25-27] (Figure 1).
Figure 1 Role of intestinal microbial metabolites in PD
(Source: Bi M, et al.
, Ageing Res Rev.
2022).
Intestinal microbiome dysregulation is strongly associated
with non-motor symptoms and motor symptoms of PD.
Among non-motor symptoms, gastrointestinal complications are associated with increased abundance of Dorea, Oscillospira and Ruminococcus and Faecalibacterium , Roseburia reduced abundance related [28]; Idiopathic RBD may be associated with increased abundance of Haemophilus, Anaerotruncus, and Faecalicoccus Associated with reduced abundance of Victivallis [29]; Anxiety and depression were associated with increases in Citrobacter rodentium and Campylobacter jejuni and Lactobacillus rhamnosus Associated with a decrease in Bifidobacterium longum [30-33].
In addition, the abundance of Anaerotruncus, ClostridiumXIVa and Enterobacteriaceae increased Lachnospiraceae、Prevotellaceae、Bacteroides fragilis、Clostridium leptum Decreased abundance is associated with motor symptoms of PD [34-38] (Figure 2).
While some studies have shown a key role for gut microbiome dysregulation in PD, a specific microbiota has not been identified as a predictive marker for
this disease.
In future studies, the duration of PD and some confounding factors
need to be considered.
Fig.
2 Effect of intestinal microbial dysbacteriosis on PD symptoms
(Source: Bi M, et al.
, Ageing Res Rev.
2022).
Interaction between the gut microbiome and PD drugs
The gut microbiome has an impact
on the metabolism of PD drugs.
As the main therapeutic drug for PD, the dopamine precursor levodopa, must reach the brain to play its key role, but microorganisms can also metabolize levodopa in the periphery, making dopamine produced in the periphery, reducing the effectiveness of levodopa and causing unwanted side effects [39].
FLZ is a novel PD drug undergoing phase I clinical trials whose main metabolite, M1, can be remethylated to FLZ by microorganisms [40-43], suggesting that the gut microbiome is likely to affect the bioavailability and efficacy
of FLZ.
In addition, some PD clinical drugs also affect microbial profile
.
Entacapone is negatively correlated with propionic acid concentration [44].
Monoamine oxidase B (MAO-B) inhibitors and anticholinergic drugs are associated with butyric acid concentrations [44].
Catechol-O-methyltransferase (COMT) inhibitors are associated with increased abundance of Enterobacteriaceae [45,46
。 All in all, unraveling the complex interactions between the gut microbiota and PD drug metabolism is not an easy task
.
Each drug seems to have unique ways of interacting with the gut microbiome, and it is difficult to come up with a common mechanism
of action.
In PD treatment, the promise of altering the gut microbiome to improve the effectiveness of drugs or reduce their side effects needs to be further explored
.
Summary and prospects
The human gut microbiome is a complex ecology, and there is much evidence that the gut microbiome is involved in PD through the gut-brain axis that connects the peripheral and central nervous systems, and the link between non-motor symptoms and motor symptoms of PD also highlights the role of the gut microbiota and its metabolites Clinical relevance in PD, although the exact mechanism is unclear
.
Understanding the complex roles between the gut microbiome and PD will guide the clinical treatment of PD and help develop specific drugs
based on the gut microbiome.
Nevertheless, consensus on the exact diagnosis of PD is difficult due to the small cohort size of patients with PD, the short follow-up period, the variety of sequencing methods, and the influence of dietary habits, past medical history, or medications.
In addition, most current observations of the gut microbiome focus on the phylum and genus level, and the complexity of human neurological diseases and the existence of limitations in animal models that mimic PD pathology are also major obstacles
.
In conclusion, the correlation between intestinal microbiota and PD has been widely reported, and there is a bright future
for the development of PD targeting intestinal microorganisms and metabolites.
Original link: https://doi.
org/10.
1016/j.
arr.
2022.
101759
The intestinal microbiology laboratory mainly carries out the isolation and culture, physiological metabolism, heredity and interaction with the host of intestinal microorganisms
.
Professor Liu Shuangjiang, the academic leader of the laboratory, has been supported by the National Outstanding Youth Fund and the "Hundred Talents Program" of the Chinese Academy of Sciences.
As a major participant, he initiated and promoted the "Chinese Microbiome Project", and undertook and completed the key deployment project of the Microbiome Program of the Chinese Academy of Sciences ("China Microbiome Program" pre-research).
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End of this article
