At present, the progression of Parkinson’s disease (PD) symptoms cannot
be halted and the disease process seems to progress relentlessly. Medications
and treatments aim at alleviating clinical symptoms – at best slowing down
disease progression. We do not fully understand when, where and why PD actually
starts. It is thus of utmost importance to shed light on the contributors to
disease progression and to find ways to diagnose PD as early as possible.
Traditionally, PD has been considered a prototypic neurological
disorder. According to the presumed neurodegenerative process, it is
conceptualized as a protein aggregation disease, associated with the formation
of cytoplasmic aggregates of misfolded α-synuclein (SNCA) in neurons of the
central nervous system (CNS), known as Lewy bodies.
Over the past 10 years however, mounting evidence has suggested
that the gut and the enteric nervous system (ENS) might play an important,
perhaps even pivotal role in PD etiology. The aggregation of SNCA may spread
from the gut to the brainstem via the ENS to the vagus nerve and further into
the CNS.
This concept of disease progression calls for an alternative
etiological concept, including the existence of exogenous agents (such as
bacteria or viruses) which could reside in the gut of a susceptible individual.
The Microbiome
The human body is made up of approximately 10 billion cells and
current estimates predict at least as many bacteria. The microbiome is involved
in many vital processes, including metabolism, vitamin production and immune
defense.
"Several studies have shown consistent changes
in the composition of the gut microbiota, both in early and advanced PD
patients"
Some researchers, among them Nobel laureate Joshua Lederberg,
have suggested that the microflora is not only part of the human metabolic
system but in some locations like the large intestine rather forms an organ in
itself.
As to the exact role of the gut and the gut microbiota in PD
development, the data is just beginning to emerge. Several studies have shown
consistent changes in the composition of the gut microbiota, both in early and
advanced PD patients.
Prevotella has been reported to be decreased in PD
patients compared to healthy controls while Akkermansia were
increased. While using 16S rDNA based descriptions of the fecal microbial
composition is easy and relatively economical to employ, it suffers from
methodological limitations, i.e. restriction to genus level inherent biases.
We aimed to circumvent these restrictions by randomly sequencing
all DNA in a given sample (i.e. metagenomics), taking advantage of marker
genes, from which the taxonomic identity can be more accurately reconstructed,
as well as avoiding PCR biases.
We hypothesized, that a particular predisposition and/or
susceptibility of the intestinal system, in particular the composition of the
microbiome including phages and viruses, might play a role and performed shotgun sequencing of colonic fecal samples in early PD
patients.
This confirmed the taxa found in previous studies, but also let
us determine the exact species. We found Prevotella copri, Eubacterium
biforme, and Clostridium saccharolyticumdecreased in PD
patients and Akkermansia muciniphila and Alistipes
shahii increased. The metagenomic approach also allowed us to research
changes in bacterial metabolic pathways.
"We found Prevotella copri, Eubacterium
biforme, and Clostridium saccharolyticumdecreased in PD
patients and Akkermansia muciniphila and Alistipes
shahii increased"
Knowing the functional pathways is of particular relevance, as
certain types of bacteria are shared by a majority of individuals, but can
differ markedly in their genetic composition. For instance, two Escherichia
coligenomes may differ by up to 40 percent in the genes that are in their
genome, despite being the same species.
Viruses had previously been linked to the development of PD, and
strong experimental support has been provided by Jang
et al. who demonstrated, that H5N1 virus travels from the
peripheral nervous system into the CNS and on to higher levels of the
neuro-axis of infected mice. The surviving infected animals displayed changes
in the CNS, reminiscent of human PD, long after resolution of the infection,
when virus DNA was no longer detectable. This “hit and run” mechanism would be
especially challenging to detect.
Interestingly, we found viruses being decreased in the stool of
PD patients. The direct link to PD so far is unclear to us, but certainly
warrants further investigation.
What is still to come?
The exploration of the so-called gut-brain axis has, with good
reason, gotten more attention over the past few years, and PD is a prime target
for this kind of research. There are many promising avenues to follow up on in
the investigation of PD and the gut microbiome.
Clearly, changes in particular bacterial taxa are associated
with PD, but we do not know yet the exact mechanism of how this would influence
the host and disease.
Experimental models with mice and intervention studies with
human patients will be required to test the various hypotheses. Even fecal
microbiota transfer would be warranted, given the dire consequences of this
disease and the limited effect of current therapeutics. Further, we think that
the so far barely explored gut virome might yield a new perspective on PD.
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