• Resting tremors: typically starting in a limb 

• Bradykinesia: slowness of movement 

• Postural instability: impaired balance and coordination

Some premotor GI dysfunctions are:

• Constipation 

• Dysphagia - difficulty in swallowing. It can occur at any stage such as the mouth, throat, or esophagus. Can range from mild to severe problems in eating, drinking, and taking medications. 

• Nausea 

• Vomiting 

• Weight loss

1. Medications. 

• Levodopa which is used to manage motor symptoms of PD. It is converted into dopamine in the brain to help alleviate symptoms. 

• Other medications include dopamine agonists, which help mimic the effects of dopamine in the brain. MAO-B inhibitors or COMT inhibitors.

  2. Deep Brain Stimulation. 

• This involves the surgical implantation of electrode in specific areas of the brain. These electrodes deliver electrical impulses to targeted regions of the brain.

  3. Physical therapy such as exercise. 

• Dietary adjustments such as an increase in fiber intake.

Ongoing research aims to better understand its underlying mechanisms and develop more effective treatments. 

This increases the permeability of the blood-brain barrier, allowing for harmful substances to enter the bloodstream to the brain such as LPS and inflammatory cytokines. As a result, neuroinflammation and cell death of dopaminergic neurons occurs in the substantia nigra (SN) leading to PD. During the whole process, LPS activates immune cells both in the SN and intestinal tracts by interacting with toll-like receptors (TLR4) on their surfaces.

The dopamingeric neuronal death in the SN and the aggregation of alpha-synuclein in the remaining neurons are two dominants pathological hallmarks of PD which contribute to the occurrence of motor symptoms in PD patients. 

Many pathological alterations of microbial taxon abundances have been reported in PD patients such as:

• Elevated abundances in Akkermansia, Bifidobacterium, and Lactobacillus.

• Decreased levels of Blautia and Faecalibacterium.  

• Infection of helicobacter pylori (Hp) has been reported to be associated with PD.

Healthy mice receiving gut microbiota transplants from PD disease donors showed motor dysfunctions in some research. Collectively, these reports suggest that gut microbiota dysbiosis plays a pivotal role in the pathogenesis of PD.

Using a chronic rotenone-induced PD mouse model to assess whether FMT treatment can protect PD and to elucidate the underlying mechanisms as well as explore the potential role of the microbiota-gut-axis in PD pathogenesis.

Many studies have proven that the pathogenesis of the chronic rotenone-induced PD mouse is closely related to gut microbiota dysbiosis

• Sun et al. showed that FMT administration alleviated the MPTP-induced PD mouse model by reducing gut microbiota dysbiosis and neuroinflammation.

This set of data suggests that rotenone intoxication and PD phenotype has implications for weight loss, motor disorders, and GI dysfunctions, and that FMT can attenuate these manifestations.

Western blots revealed that expression of the 3 major tight junction proteins, ZO-1, occludin, and claudin, were seriously impaired in the rotenone mice, but the healthy phenotype was rescued upon FMT administration. This has implications for the leaky gut phenomenon observed in PD and possibly involved in its pathogenesis, and the wider physical manifestations of PD as well as the neuroinflammation that can occur.

There are many reports linking gut microbiota dysbiosis in PD models that also suggest its role in the development of the neurodegenerative disorder. These results serve as compelling evidence to strengthen the connection between the gut and its microbiota and the brain, suggesting that FMT has the potential to be powerful tool to attenuate dysbiosis and PD.

This model allows researchers to study the progression of PD-like symptoms and investigate potential treatments or interventions.

The model group was then further divided into the rotenone (n=15) and the FMT group (n=15). Fecal samples from the control group were used for FMT.

After 4 weeks, the model group was divided into the FMT or rotenone group.

During week 5 and 6, the mice in the FMT group were treated with FMT once per day.

The control group and the rotenone group mice received vehicle administration once a day during this time.

GI function tests and behavioral tests were performed at week 6. Then all the mice were sacrificed for further analysis.

They then used these secondary antibodies to detect those primary antibodies.

These stains are the most widely used histological stain because of its comparative simplicity and ability to demonstrate clearly an enormous number of different tissue structures

Increased LPS and LBP leads to more inflammation because they trigger the immune system via the TLR4 and MyD88 inflammatory pathways. In the FMT mice however there is overall less LPS and LBP, which points to the link between the richness of the microbiota and the decrease in inflammation, or at least the attenuation of these inflammatory molecules. This has important implications for the level of inflammation in the brain that can subsequently occur, as these inflammatory molecules may traffic to the brain via the circulatory system due to the loss of barrier integrity in the gut and in the BBB.

Colon histology is included here due to the bidirectional pathology of PD: what happens in the brain should also be echoed in the colon. We see immune infiltration in the area marked by the black arrow in the rotenone mice, and a fuzzy lack of organization in the tissues...

1. Rota-Rod Test: assesses balance, coordination, and motor skill learning as mice balance on a rotating rod. Their latency to fall is recorded (Xhako, n.d.)

2. Pole Test: evaluates motor coordination, bradykinesia (slowness of movement), and balance. It involves measuring the time it takes for a mouse to turn downward and descend a pole (Brenner, 2015)

3. Adhesive Removal Test: assesses sensorimotor deficits, including tactile sensory function and motor coordination. It involves measuring the time it takes for a mouse to remove adhesive tape applied to its paw. (Hines & Haydon, 2013)

4. Grip Strength Test: measures the maximal force applied by a mouse using its forelimbs to assess muscle strength (Augusta University, 2023).

   
   

These tests were likely chosen for this experiment because they provide a comprehensive evaluation of different aspects of motor function that manifest PD like balance and coordination.

Brenner, D. (2015). The role of the CD95 system in Parkinson’s Disease. Research Gate . https://www.researchgate.net/publication/299295188_The_role_of_the_CD95_system_in_Parkinson’s_Disease

DuPont, H. L., Suescun, J., Jiang, Z. D., Brown, E. L., Essigmann, H. T., Alexander, A. S., DuPont, A. W., Iqbal, T., Utay, N. S., Newmark, M., & Schiess, M. C. (2023). Fecal microbiota transplantation in Parkinson's disease-A randomized repeat-dose, placebo-controlled clinical pilot study. Frontiers in neurology, 14, 1104759. https://doi.org/10.3389/fneur.2023.1104759

Fan, H.-X., Sheng, S., & Zhang, F. (2022). New hope for Parkinson’s disease treatment: Targeting gut microbiota. CNS Neuroscience & Therapeutics, 28(11), 1675–1688. https://doi.org/10.1111/cns.13916

Hines, D. J., & Haydon, P. G. (2013a). Inhibition of a snare-sensitive pathway in astrocytes attenuates damage following stroke. The Journal of Neuroscience, 33(10), 4234–4240. https://doi.org/10.1523/jneurosci.5495-12.2013

Ling, J. (2021). Illustration of the H&E staining methods used in histology. Osmosis.org. Osmosis.org. Retrieved from https://www.facebook.com/OsmoseIt/photos/a.293866334077588/2253890288075173/?type=3.

Liu, W., Wang, Z., Zhang, L., Wei, X., & Li, L. (2012). Tight junction in blood‐brain barrier: An overview of structure, regulation, and Regulator Substances. CNS Neuroscience & Therapeutics, 18(8), 609–615. https://doi.org/10.1111/j.1755-5949.2012.00340.x

Neuroinflammation. Neuroinflammation - Creative Diagnostics. (n.d.). https://www.creative-diagnostics.com/neuroinflammation.htm 

Physics channel. (2017, July 10). Transmission electron microscope [Video]. YouTube. https://www.youtube.com/watch?v=1l09mevRfpQ&ab_channel=Physicschannel

Stojanovska, V., Miller, S. L., Hooper, S. B., & Polglase, G. R. (2018). The consequences of preterm birth and chorioamnionitis on brainstem respiratory centers: Implications for neurochemical development and altered functions by inflammation and prostaglandins. Frontiers in Cellular Neuroscience, 12. https://doi.org/10.3389/fncel.2018.00026

Sun, J., Xu, J., Ling, Y. et al. (2019) Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgenic mice. Transl Psychiatry 9, 189. https://doi.org/10.1038/s41398-019-0525-3

Western blot. Biomol GmbH - Life Science Shop. (n.d.). https://www.biomol.com/resources/applications/western-blot/

Westhayl618. (2016). Immunofluorescence Mechanism. Wikimedia Commons. Retrieved from https://commons.wikimedia.org/wiki/File:Immunofluorescence_Mechanism_.png. 

Xhako, E. (n.d.). Snapshot: What is the Rotarod Test? National Ataxia Foundation . Retrieved from https://www.ataxia.org/scasourceposts/snapshot-what-is-the-rotarod-test/.

Zhao, Z., Ning, J., Bao, X. Q., Shang, M., Ma, J., Li, G., & Zhang, D. (2021). Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis. Microbiome, 9(1), 226. https://doi.org/10.1186/s40168-021-01107-9

Methods: Momiji (Momo) Uji

Results: Michelle Lee

Discussion & Outlook: Tra Pham

• Reduction of systemic inflammation can restore blood brain barrier (BBB) impairment and suppress neuroinflammation in in the substantia nigra (SN).

• Composition of microbiome is shown to contain certain type of bacteria that can be found in PD and AD. Each as different roles in the pathology of the disease.

  
  

Another study by Sun et al. (2019):

• Modulates gut microbiota, relieves A-beta accumulations, relieves neuroinflammation.

• Similar influences via the gut-brain axis.

• Similar accumulations of phylum Verrucomicrobial, genus Akkermansia, etc. --> However, not consistent throughout all AD studies.

--> We can see comparable evidence of neuroprotective effects of FMT in its restoration of cognitive deficits and reduction in neuroinflammation.

--> While also observing the similar interplay of bacterial species in the gut microbiome. This comparison highlights the clinical significance of FMT in its protective effects.

• Potential studies related to other models of PD, to see if there is a standardized improvement to different extremes of PD.

• The study may study long-term effects of FMT on PD symptoms.

• The study may potentially explore other PD-related symptoms, may that be psychological, behavioral, etc.

  --> To ultimately assess how it would improve the quality of life.

• Moreover, the interplay of certain bacterial species is another avenue for researchers to investigate. Researchers may explore their underline role before or after treatment.

• Furthermore, researchers may also begin to investigate its potential use in clinical trials.

• Interestingly, subjective motor functions and non-motor symptoms are shown to display temporary improvement compared to baseline.

• With improvements in diversity of the intestinal microbiome which is associated with reduced bowel symptoms and improved gut function.

• Some improvement in quality of life (QOL).

  
  

  --> However, study is only a pilot and is yet to show bigger improvements in QOL and other PD-related symptoms.

  --> This still shows the amazing progression of such treatment.