The Nature Review's long review analyzes how intestinal-related factors affect the incidence and treatment of Parkinson's disease?

*For medical professionals only

More than 200 years ago, British surgeon James Parkinson published a paper on "tremor paralysis", 60 years later, in his honor, the disease was named "Parkinson's disease", and today, more than 200 years later, Parkinson's disease (PD) has become one of the fastest growing neurological diseases in the world [1], which is related to many factors, including population aging and environmental

When Dr.

Nevertheless, in the next 150 years, the study of PD-related gastrointestinal dysfunction was almost dormant, arguably without any progress, and it was only in the last 20 years that the pace of pace was slightly accelerated [2], from symptoms and effects on quality of life, to the basis of pathophysiology and its potential role in pathogenesis, and, based on major advances in the field of microbiology, the relationship between the gut microbiome and disease was gradually valued, and the proposal of the intestinal-brain axis gave us a new understanding of PD

To help you systematically understand the progress of entero-brain connectivity research into PD to date, Nature Review Neurology published a review article[4] summarizing the evidence in the clinical, preclinical, and epidemiological fields, discussing the potential of gut- and microbial-based therapies as new therapies for PD, and summarizing current challenges and future directions

Parkinson's disease with intestinal-brain axis

α-synuclein (α-Syn) aggregates into The Lewis body and the Louis Neurite, and the death of specific neurons, mainly dopaminergic nigra, is a neuropathological marker

According to this theory, some kind of damage that occurs in the gut triggers misfolding and aggregation of α-Syn, starting with ENS, spreading through a cell-cell manner like a prion, and eventually transferring to the brain [6,7].

In the course of the argument for this theory, a large number of animal experiments and observational studies have not reached the same conclusions, so more studies are needed in the future to give clear conclusions, and based on the complexity, heterogeneity, and multi-faceted nature of intestinal-brain interaction of PD, this pathway may play a role in PD, but the degree of effect varies

In addition to ENS, increased intestinal permeability and inflammation also have an effect on PD cases, but are equally highly heterogeneous, non-invasive biomarkers such as fecal calcitein, alpha1-antitrypsin, and concatenated proteins help help us better understand the role of

Parkinson's disease and gut microbes

There are complex interactions between gut microbes and host physiology, and when explaining the relationship between changes in the composition and function of gut microbes and diseases, the multidimensionality of interactions and the changes of individual microorganisms with lifestyle are important factors

Age-related changes in gut microbiome can be attributed to intestinal physiological aging (thinning of the mucous membranes, slowing of bowel movements, and immune aging), lifestyle changes (diet, exercise, and living conditions), and changes in health status (comorbidities, medications, and weakness).

To complicate matters further, aging-related changes may also be responsible for chronic inflammation, while intestinal microbes with strong adaptive viability may have a competitive advantage over changes in the intestinal physiological and nutritional environment, resulting in unique gut microbial composition characteristics [8].

Clinical evidence of Parkinson's disease and intestinal microbiosis

With the development of second-generation sequencing (NGS) technology, the scale and depth of gut microbial research have been greatly expanded
.

At present, the research is mainly concentrated in the bacterial group, and the fungal group and the virus group have gradually received attention
in recent years.

This review included 30 independent case-control NGS studies
from 11 countries through a literature search.

Although the vast majority of them are based on 16S rRNA sequencing to classify and identify fecal bacteria, they still exhibit great heterogeneity in methods, including stool collection and storage methods, sequencing areas and depths, and differences
in analyzing pipelines.

Still, almost all studies have found significant differences in gut microbial composition between people with PD and healthy people, and some studies have remained significant
after correcting for factors such as age, diet, constipation, weakness, and PD medications.

However, the mediating effect of this difference was modest, and two meta-analytical studies [9,10] showed that the PD status was only able to account for microbiome differences of 0.
4 to 1.
0 percent, while one study reduced to about 0.
3 percent after correcting for confounding factors [10].

Compared to other studies that have found an association between declining microbial diversity and unhealthy aging, studies conducted in patients with PD have mostly shown that microbial diversity in patients with PD either did not differ significantly or increased
compared to healthy controls.

Differences in gut bacteria between patients with PD in at least 42 families, 102 genera, and 44 species were reported, but only about 1/4 were reproven in one or more studies
.

The most consistent microbial change in patients with PD was increased abundance in Ackermannia spp.
(14/30 studies), belonging to the microbacterium verrucosa, and increased abundance was also found in 12 studies
.

Other more consistent changes included increased abundance in Bifidobacterium spp.
(10 trials) and Lactobacillus spp.
(7 items), and decreased abundance in butyrate-producing Rosebria spp.
(8 genera), Bacillus perchosaurs (8 trials), and Brotella spp
.
(7 items).

There are few
studies involving smaller classifications, such as strains.

What is more special is that most of these bacteria are so-called "beneficial bacteria", especially Ackermann's, Bifidobacterium and Lactobacillus, and the reason for their increased abundance is not clear
.

It must be said that the function of bacteria is likely to be strain-specific, the current research results based on genus and species level may not provide enough information, and there are still a large number of gut bacterial gene functions that have not yet been elucidated, which also hinders our interpretation of
enterobacterial changes and PD relationships.

In addition, the role of gut bacteria cannot be seen in isolation, and the interaction between bacteria and bacteria with the host should be considered, as well as their metabolic function in the microenvironment, so the study of enterobacterial metabolites may help us to understand the role of
enterobacteria in health and disease in a deeper understanding.

Animal research evidence of Parkinson's disease and intestinal microbiome disorders

Changes in the intestinal flora have been confirmed in a variety of PD mouse models, some studies have identified the causal effect of intestinal changes with PD through germ-free mice, fecal microflora transplantation (FMT) and/or broad-spectrum antibiotic therapy, impaired motor capacity compared to the experimental group, constipation, accompanied by significant neuroinflammation and α-Syn deposition, and improvement of motor function, neurotransmitter levels, and inflammation
by FMT transplantation of normal intestinal flora.

These mouse models laid the groundwork
for the study of the role of the gut microbiota in the pathogenesis of PD.

Still, the problem remains
.

For example, although FMT is able to "transfer" the pathological manifestations of patients to mice, whether bacterial colonization and patient microbiome disorders are consistent with patients in mice has not been sufficiently studied [11].


In addition, most studies used a small number of donor patients and did not necessarily represent a wide range of patient gut microbiota changes
.

What's more, it is also not possible to mimic the intestinal-host interaction and homeostasis, as well as changes
in factors such as diet, lifestyle, and aging over the life cycle.

Microbially oriented therapy for Parkinson's disease

Currently, multiple microbial-directed new therapies offer hope for symptom relief or disease correction, but clinical trials are relatively rare
.

The best example of microbial-directed therapy is FMT therapy for refractory Clostridium difficile infection, which is 90% effective, providing evidence for the clinical application of the concept of microbial-directed therapy [12].

diet

Two small pilot studies experimented with different types of dietary interventions
.

One of them[13] included 44 patients with PD who received a low-fat and ketogenic diet for 8 weeks, with significant improvements in both groups of motor and non-motor symptoms, and more
in the ketogenic diet group.

Another [14] dietary intervention was a 14-day ovo-milk vegetarian regimen with significant improvements
in motor symptoms as assessed by the Uniform Parkinson's Disease Rating Scale (UPDRS) III.

These results have not been validated in larger clinical trials
.

Another double-blind, placebo-controlled randomized trial of 121 patients showed that caffeine supplementation did not improve the patient's motor symptoms [15].

Prebiotics

A small open-label study of 19 patients with PD showed that a diet rich in insoluble fiber improved the bioavailability of constipation and plasma levodopa, as well as exercise symptoms
.

Another open-label study of 87 patients found that patients assigned to the resistant starch intervention group had improved non-motor symptom scores, along with increased butyric acid levels and decreased calcite-glucosin levels in the stool [16].

Probiotics

Improvement in
constipation was observed in two double-blind, placebo-controlled randomized trials [17,18] supplementing patients with PD with fermented dairy products containing compound probiotics or once-daily probiotic capsules, respectively.

Compound probiotics usually contain multiple strains of Lactobacillus, Bifidobacterium, and Enterococcus, although, as mentioned earlier, the abundance of the first two genera tends to be significantly elevated in patients with PD, and enterococci have a strong ability to degrade levodopa, and supplementation in patients with PD should be treated
with caution.

Fecal Bacteria Transplantation (FMT)

FMT's current primary efficacy in improving constipation symptoms in patients with PD has been demonstrated in a six-patient case series [19] and an open-label study of 11 patients [20] with higher
safety profiles.

Currently, two more double-blind, placebo-controlled randomized trials (NCT03671785 and NCT04854291) exploring the effects of FMT on motor and non-motor symptoms
are underway.

Epizootics, small molecule drugs and biologics

Other microbial-directed therapies that may benefit patients with PD include postbiotics, small molecule drugs, and biologics that have not been explored clinically, such as short-chain fatty acids (SCFAs) and other molecules
that target enzymes that inhibit levodopa metabolism.

The two angles of immunomodulation and intestinal barrier reconstruction also deserve further attention
.

Anti-TNF therapy is associated with reducing the incidence of PD in patients with inflammatory bowel disease (IBD) [21], enabling a shift
in the composition of the gut microbiota in patients with IBD to healthy people.

Targeting PD-associated ENS molecular pathological changes, such as α-Syn or gluconocephalusterase, is another new class of cutting-edge therapeutic strategies
.

In one open-label trial, oral squalanine, which competes with α-Syn binding sites in ENS neurons to inhibit its formation of aggregates, is safe and significantly improves constipation symptoms in patients with PD [22].

Overall, at present, the relationship between PD and intestinal-related factors is still largely at the level of correlation, and the transition from observational research to interventional research is needed, of course, there are still many mechanical questions that have not yet been answered, and determining the causal relationship between intestinal-related factors and PD or the proportion of disease development is crucial
for the development of future therapies.

In addition, changes in some factors may be "compensatory responses" (e.
g.
, changes in the composition of the gut microbiome mentioned earlier), so it is necessary to determine whether it is not to the patient's
benefit to "correct" them.

In short, the attack on PD from the gut requires the joint efforts of different geographical regions to establish a large, robust intestinal dataset, while paying attention to the influence of interregional dietary and geographical factors, laying a solid foundation
for this field.

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The author of this article ying Yuyan