Wednesday, December 14, 2016

Microbiome and the Parkinson's

Photo 1: An essay on the shaking palsy.
Greetings

The concept of microbiome being involved with clinical conditions is now a heavily discussed concept. I have written several posts about this topic and readers are referred to my earlier posts for details. Most recently, a paper published in Cell has explored the connection between Microbiome and Parkinson's disease, which is making a lot of news. Certain findings of the paper have been hyped in the media and so I decided to write a detailed post about this paper.

Parkinson's disease (PD) is a chronic, progressive movement disorder (a subtype of motor system disorders) caused due to a loss of dopamine-producing brain cells. The condition was long known but gained its name and importance following a publication "An Essay on the Shaking Palsy" by a London doctor James Parkinson in 1817. PD is a type of Synucleniopathy (or rather called as α-Synucleinopathy). Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of α-synuclein protein in neurons, nerve fibres or glial cells. In PD, it is postulated that the aggregates accumulate in dopaminergic neurons leading to death of the cells. However, there is no single explanation for the pathogenesis and biological pathway leading to PD.

The concept of gut microbiota and its link with Central nervous system is a theme I have talked about several times in this blog. Association of microbiome with neurodegenerative diseases is not a new publication, neither is the association with Parkinsons. A paper published in 2014 by Filip Scheperjans and colleagues, showed by fecal microbiome study from 72 patient vs 72 control subjects that there is a significant drop in abundance of Prevotellaceae in feces of PD patients by as much as 77.6%. In fact, Prevotella is also negatively assocaited with autism. Prevotella species is known to influence higher levels of neuroactive short chain fatty acids (SCFA) and a high capacity for biosynthesis of thiamine and folate, which is also in agreement with findings of lowered levels of short chain fatty acids in PD feces sample. Here is an interesting observation. Using intestinal biopsy of PD patients before onset, α-synuclein has been shown to be positive by immunostaining but negative for healthy controls. It has been shown that that newly diagnosed PD patients had increased intestinal permeability and abnormal accumulation of α-synuclein in enteric neurons. This also correlates with a significant number of papers showing that more than 70% of the PD patients on average have some gastrointestinal abnormalities, which precedes the appearance of motor symptoms.

In the latest paper in cell by Sampson et al; 2016, they looked into if microbiome can influence the Synucleinopathy. As stated by the senior author Mazmanian, "Because GI problems often precede the motor symptoms by many years, and because most PD cases are caused by environmental factors, we hypothesized that bacteria in the gut may contribute to PD."

Fig 1: Graphical abstact of the paper.
Source
The experiments were conducted using mice engineered to overexpress the protein α-synuclein. In the first experiment, 3 groups of mice was prepared- 2 groups had complex intestinal microbiome and one group was germ free (GF). Experiments measuring motor skills showed that germ-free performed much better. They also showed that GF mice treated with microbially produced SCFA activated microglia.

In the next set of experiment, GF mice were transplanted with fecal samples from human patients with and without Parkinson's disease. The germ-free mice who received transplants from PD patients showed a significant increase in PD symptoms. See Fig 1, for a summary.

Sarkis Mazmanian comments, "Our findings provide a completely new paradigm for how environmental factors may contribute to Parkinson's disease and possibly other neurodegenerative disorders. The notion that these diseases may be impacted by pathology in the gut and not only in the brain is a radical departure from conventional research in neuroscience. Parkinson's disease is complex and there are several genetic predispositions and environmental risks that play a role, but we believe our findings shed light on a previously unrecognized and potentially important part of this puzzle."

It must be noted that this study uses a mouse model overexpressing α-Synuclein. It is unilkely that human PD can be treated with fecal microbiome transfer or use of probiotics. But what is more likely is use of probiotc may alleivate the PD symptoms.

References

1. Scheperjans F, Aho V, Pereira P, Koskinen K, Paulin L, Pekkonen E et al. Gut microbiota are related to Parkinson's disease and clinical phenotype. Movement Disorders. 2014;30(3):350-358. 

2. Shannon K, Keshavarzian A, Dodiya H, Jakate S, Kordower J. Is alpha-synuclein in the colon a biomarker for premotor Parkinson's Disease? Evidence from 3 cases. Movement Disorders. 2012;27(6):716-719. 

3. Sampson T, Debelius J, Thron T, Janssen S, Shastri G, Ilhan Z et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell. 2016;167(6):1469-1480.e12.

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