I have been following the research into Parkinson’s disease for years, having been forced to watch the inevitable physical decline in several friends now who developed the illness frighteningly early in life (40s and 50s). See here and here for just a couple of examples. I keep hoping that with the significant advancements scientists seem to have made in recognizing the causes, more effective treatments are not that far in the future. And thus, today’s post.
I’ve had a paper sitting on my desk for several months which I have only just found time to read, and the first sentence alone is so upsetting that it almost went unread for another few months! The paper reports that the global prevalence of the disease is expected to increase by 92% by 2050.[i] With over 6 million people in the world already suffering from the illness by 2016, that is a depressing statistic.
Since only 3-5% of PD cases are genetic in origin: “Over the past years, researchers have published significant numbers of papers which suggests that the motor effects the progressive degeneration and loss of preferential dopaminergic neurons in the substantia nigra seen in PD patients, might be related to factors other than a predominantly genetic cause.” Research has focused on the link between increase iron and copper levels found in PD patients (both systemically and in the brain), the role of the microbiome, and dysregulated inflammatory markers (including those originating from bacteria).
The authors of this paper present the argument that PD is associated with both dysregulated circulating inflammagens (an irritant that causes inflammation) including ones released by gut bacteria, leading to the conclusion that dysbiosis may be central in the development of the disease. Thus, they argue, the way to treat PD is to find the reason for this immune activation: “We argue that this origin is microbial…central to its cause might be microbiome dysregulation, translocation, and comorbidities including periodontitis and gingivitis.” This was the first time I had read about gum diseases being associated with the onset of PD. (Coincidentally, just this morning, I also posted on my Biome Buzz’ Facebook page research associating gum diseases and bacteria to Alzheimer’s.)
This was also the first time I had read about iron dysregulation in the disease. Apparently it occurs in both the brain and in circulation, and prior research has shown that those with PD have iron dysregulation issues including in storage, uptake and release and this is known to be a major cause of oxidative stress. Both male and female PD patients have significantly increased ferritin (stored iron) levels and this was correlated with PD severity stages and duration. Iron dysregulation in the sustantia nigra is “…considered one of the fundamental reasons for dopaminergic neurons dysfunction and death.” So what is causing this dysregulation of iron metabolism in the body? “The origin of dysregulated circulating inflammatory biomarkers could therefore involve bacteria, and particularly their inflammagens, entering the body via gut dysbiosis and translocation(when microbes appear in places other than their normal location).”
So where does PD start? No one knows for sure yet but we do know that, “Parkinson’s disease patients have a significantly higher incidence of comorbid gastrointestinal dysfunction, with between 60% and 80% of patients suffering from constipation and intestinal inflammation. Gastrointestinal dysfunction is, therefore, a very well-known accompaniment to PD and also precedes the onset of motor symptoms by several years.” I have talked about this in other posts such as those I link to above. We know that gram-negative bacteria like E.coli and H.pylori secrete a variety of pro-inflammatory molecules which can act as neurotoxins. Another point of entry for pathogenic bacteria is diseased gums: “One of the Gram-negative bacteria that has been implicated as a causative agent in periodontitis and gingivitis is Porphyromonas gingivalis (P. gingivalis), and its inflammagens have been associated with the development of various inflammatory conditions.It is mainly a bacterium from the mouth, however, after oral administration in animal studies, it may also induce gut dysbiosis and impaired gut barrier function, and can induce systemic inflammation.” Retrospective studies show that there is an increased risk of developing PD after having chronic periodontal inflammatory diseases.
So does all this lead to any therapeutic possibilities? Iron chelation with a drug called deferiprone has shown some “…promising efficacy with regard to neurodegeneration.” However, there are really no longitudinal clinical data that shows efficacy in slowing disease progression: trials that have been conducted were small and only 6 month long, and worse, deferiprone is considered only a weak chelator. Better medicines and larger and longer trials are urgently needed.
There are no definitive studies on the use of antibiotics or probiotics in PD. One study did show that probiotics may alter clinical progression of the illness and could alleviate constipation and gut-related issues, but we don’t have nearly enough information yet. And antibiotic treatments have really only focused on alleviating constipation and gut dysbiosis. One promising treatment though is the antibiotic, minocycline, which also has been shown to be anti-inflammatory in the brain: “…there is a growing body of evidence to suggest that minocycline elicits neuroprotective effects in PD…” Fecal transplant is also suggested to be a treatment, but again, we are in the very early stages of knowing how best to use this. Animal studies look promising but controlled trials are needed.
The authors conclude that, “Targeting underlying mechanisms of PD, such as gut dysbiosis and iron toxicity, have elucidated a wide variety of novel treatments, which could not only relieve the characteristic motor deficits seen in PD but also might significantly slow the progression of the disease.” Unfortunately, it feels like I always have to conclude these posts with the statement that way more clinical trials are necessary before we know for sure if these treatments will work and how to use them for optimal efficacy.
[i] Vuuren MJV, Nell TA, Carr JA, Kell DB, Pretorius E. Iron Dysregulation and Inflammagens Related to Oral and Gut Health Are Central to the Development of Parkinson’s Disease. Biomolecules. 2020 Dec 29;11(1):30. doi: 10.3390/biom11010030. PMID: 33383805; PMCID: PMC7823713.