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 saccharolyticum decreased 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 coli genomes 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.