Rethinking Parkinson's Disease

If you having been reading my blogs for a while then my line of thinking may not be new to you. If you are reading my writing for the first time then you may want go back and review some of my previous blogs, my TedX Boulder Talk "Do Gut Bacteria Predict or Cause Diseases Like Parkinson's", my White House Microbiome 2016 Talk about the need for a new research paradigm and listen to some of the many Podcast interviews (list provided at the bottom) I have done over the past few years.

In my White House speech I used the analogy of a pointillist painting. I gave that speech back in 2016, just over seven years ago. While much progress has been made in studying Parkinson's and the microbiome, very little progress has been made in connecting this research to clinical approaches for potentially preventing and possibly curing Parkinson's disease. Here is my closing challenge to the audience of scientists and heads of all of the alphabet government agencies from that speech:

" Simply put the causes of Parkinson's may be in the gut and that's where we will find the answers. We should think of scientific findings as spots of color on a pointillist painting. Only when we step back do we see the full meaning and importance of the whole picture. So just like a Seurat painting, I hope to inspire all of you to think in a broader context, to paint together on the canvas so that we may finally see the full picture that before us is hidden in our many separate dots. I am undaunted at that prospect"

In these seven long years there has been much progress along the path of knowledge but little progress in translating this in to something meaningful and actionable for people with Parkinson's. My relationships with a few out of the box researchers has grown and my expanded knowledge of the microbiome has helped me, help John do much better than he would have otherwise. All of this knowledge still hasn't resolved all of his symptoms because it needs to be translated in to clinical practice with a physician who actually understands and treats the underlying causal factors. There are things I have learned along the way that have helped me paint more spots on the canvas but I still struggle to get a neurologist who will stand in front of my canvas with me and help me paint those missing spots.

Yesterday, looking over many pieces of the puzzle I was overcome with the desire to paint my picture again,this this time not for the doctors and researchers who may never read this but for YOU - those of you with Parkinson's or with a loved one with Parkinson's. YOU are the people who will get the doctors and researchers you know to take a fresh look, think outside the box and take the steps needed to change the paradigm. You have heard the saying "Be the Change you want to see in the world." I'll also ask you to think about this in the context of Alzheimer's because the concepts I am going to cover will apply in equal measure but slightly different application to Alzheimer's.

As I have traveled this path for many years, I have reviewed the different animal models used to study Parkinson's looking for clues. After all, if you can make an animal model that can mimic the symptoms or outcomes of the disease then shouldn't you ask yourself "how is this potentially occurring in human Parkinson's?" When I came across the LPS animal model of Parkinson's (551 published peer reviewed papers) that's exactly what I asked myself.

How is this "model" happening in real life to real people with Parkinson's?

What is LPS and what does it do? LPS is short for Lipopolysaccharide. If you deconstruct the word Lipo means fat, poly means many and saccharide means sugar. A many sugared fat molecule. But what is it? LPS is what makes up the cells walls of Gram negative bacteria and it is highly inflammatory. There are 4,700+ papers in PubMed on LPS and neuroinflammation. Well, what then are Gram negative bacteria? Britannica.com describes Gram negative bacteria as follows:

"Gram-negative bacterium, any of various types of bacteria that are characterized by having a thin peptidoglycan cell wall surrounded by an outer membrane containing lipopolysaccharide that is in turn enveloped by a capsule. These bacteria are so-named because of their reaction to the Gram stain, a microbiological staining technique that is used to identify and characterize bacteria. Gram-negative bacteria characteristically stain pink or red following the Gram reaction, owing to their thin cell walls; this is in contrast to Gram-positive bacteria, which stain purple, owing to their thick cell walls.

There are many different types of Gram-negative bacteria; some examples include Enterobacter, Escherichia, Haemophilus, Klebsiella, Pseudomonas, Salmonella, Shigella, and Yersinia. Many of these organisms are capable of causing severe illness in humans; for example, diseases such as meningitis, pneumonia, sepsis, and urinary tract infections often are attributed to infection with Gram-negative organisms. Although susceptible to antibiotics, disruption of the outer membrane of Gram-negative bacteria results in the release of substances known as endotoxins, which can worsen symptoms of infection."

Braak's hypothesis was first published in 2003, TWENTY years ago. His hypothesis stated that an unknown bacteria or virus would colonize through the nose and/or the gut and overtime colonize the brain leading to the staging of disease progression. There are now 208 publications in PubMed with Braak's hypothesis. There are also numerous publications on potential microorganisms that could be causing or contributing to Parkinson's and these include Gram positive and Gram negative bacteria:

E coli: 520 papers

Haemophilus: 21 papers and a key organism from our machine learning work with Ardigen

Klebsiella: 18 papers and organism that continues to show up in John's sputum and fecal samples

Salmonella: 54 results a common bacteria in food poisoning

Porphyromonas gingivalis: 12 results an oral bacteria prevalent in gum disease and more closely associated with Alzheimer's and one that we worked very hard to eliminate from John's oral samples

Nocardia: 18 papers

Mycobacteria: 65 papers

Toxoplasma: 42 papers I've discussed this in a few of my Podcast interviews

Desulfovibrio: 11 papers see separate blog on this one.

Gram negative bacteria: 692 papers !!!

List of Gram negative bacteria includes Lyme, H.pylori, Bordetella, Legionella, Aeromonas

Any number of these organisms could be contributing factors to neuroinflammation in Parkinson's disease and they are not all Gram negative. As I thought about writing this post I returned to a spreadsheet I put together back in 2016 in an attempt to connect dots across the scientific papers I was reading and the long history of books I had read from the past in my journey of self-taught science. Looking at it I was surprised by how well the dots were connected even back then though I am much more capable of articulating the connections now with many more books, papers, lectures and discussions under my belt.

So let's return to LPS. Lipopolysaccharides are bacterial toxins. LPS are composed of three parts: The O antigen (or O polysaccharide), the Core oligosaccharide, and Lipid A. I want to keep this post approachable and understandable which necessitates providing some definitions but not going deeply in to each scientific piece of discovery. The O antigen component of LPS is a further connection for me as it relates to our own, BioCollective, microbiome data where we have seen increased O-antigen biomarkers in the microbiome data of people with Parkinson's.

What is an antigen? An antigen is a toxin that the body recognizes to mount an immune response. Our typical first response is from our innate immune system which is then followed by more specific antibodies to a particular pathogen. This specific immune response is where autoimmunity may come in to play but I won't specifically address that here. You may find this Podcast interview helpful in understanding molecular mimicry, antigens and autoimmune connections to the microbiome and Parkinson's. I have done a number of talks to Parkinson's groups where I talk about bacterial protein toxins but I find these are often a bit too technical.

The Core oligosaccharides are primarily sugar based molecules but can also be non-carbohydrates. These are attached to the Lipid A and have an inner and outer core.

Lipid A covers the surface of most Gram negative bacteria and it is this part of the bacterium that has the function of endotoxin. Lipid A stimulates the Toll-like-receptor 4 on the surface of host (that's you) cells and causes a series of reactions, producing different cytokines, which are cell signaling molecules that can help signal the immune system to mount a defense against a pathogen. When the immune system mounts its defense and kills the Gram negative bacteria, these Lipid fragments containing endotoxins are released in the blood stream and may cause fever and diarrhea. The presence of endotoxins in the blood (endotoxemia) typically leads to hypotension (low blood pressure), respiratory failure and reduced oxygen delivery (hypoxia). Low grade endotoxemia affects the blood vessels and contributes to atherosclerosis and reduces blood flow to the brain.

Below is a diagram we have adapted from a paper by Dr. Isaac Ginsburg of Hebrew University on the post infection sequelae (symptoms) after bacteria are lysed (killed or broken down). In his paper he discussed how this bacterial flotsam and jetsam, including LPS, contributes to tissue damage and chronic inflammation.

Some inflammation we can see on the surface of our skin or felt if our lungs are inflamed with a chest cold. But we can't see the inflammation in our brain. We might have a headache or some symptom that we don't associate with an infection we believe has already been addressed. In the diagram above we see a bacterial infection that is attacked by the neutrophils in the immune system and our macrophages move in to "eat up and kill the bacteria". The pink and teal dots represent the immune receptors that are triggered by the LPS and other bacterial cell wall components - peptidoglycan and lipteichoic acid.

These signals trigger immune system activation, oxidative stress and potential chronic inflammation over time as this debris is never fully cleared from the body.

Think of it like having a grain of sand in your shoe but not removing it and the longer you walk in the sand the more grains you get in the shoe. If you don't remove them, eventually you are going to have a blister from the irritation.

The diagram above is a representation of inflammation and oxidative stress over time mapped to immune status and antibody generation. When there is a chronic low grade infection many metabolic and immune functions are altered. In most cases neurologists do not do blood work or evaluate any biomarkers of metabolic health. The two most frequent co-morbidities with Parkinson's are dyslipidemias (cholesterol metabolism) and glycemic issues (diabetes/blood sugar metabolism). Severe infection or sepsis is associated with high blood sugar. Hypercholesterolemia has also been observed in sepsis and is a predictor of poor outcomes. While Parkinson's doesn't show the signs of severe sepsis, many of the metabolic issues and symptoms are connected to what is seen in sepsis.

I've spoken with Parkinson's patients who first developed symptoms after antibiotic treatment for an infection. Others I speak with tell me of frequently urinary tract infections that never seem to fully clear up. UTIs are often cause by e Coli, a Gram negative bacterium that has become increasingly resistant to antibiotics. Similar stories have been told to me of parents with Alzheimer's who will have worsening memory issues with a UTI and then become fully lucid again after a course of antibiotics. In another case, a friend with Parkinson's who participated in our research showed a high level of Proteobacteria in her fecal samples, more than 10% relative abundance. These are Gram negative bacteria. I tried to help her get her neurologist to refer her to an infectious disease neurologist, to no avail. There is a wide gap in the knowledge from infectious disease to the basic practice of neurology.

Do I think this is the only cause of Parkinson's? No, I don't. But I do believe that bacterial toxins along with heavy metal toxins, autoimmune antibodies to foods like wheat, corn and spinach, inadequate nutrition and herbicide and pesticide toxins are primary drivers of Parkinson's. Many of these things can be addressed and lessen the burden on the immune system to allow the body to heal.

There are doctors who see these connections and are working on protocols in Alzheimer's, ALS and Parkinson's. But the work they are doing isn't typically covered by insurance and it can be quite expensive because it is really personalized medicine. Dr. Dale Bredesen's The End of Alzheimer's Program, Amy Jarmillo in Miami is working with ALS, PD and Alzheimer's, Terry Wahl's works with many chronic diseases but started with her own MS and Laura Mischley's Nutrition and Neuroscience.

My goal in bringing these things to your attention is for you to discuss these concepts with your internist, neurologist or any other specialists you are seeing. The issues in the body are interconnected. Only when physicians begin to see these connections and treat the underlying causes will we make progress.

With gratitude,

Martha

Podcast interviews https://www.youtube.com/playlist?list=PLEjNaVAQua0RV6Bq4srFnSDSAmRiaoJnE

After first publication of this I found this 2023 paper from Cambridge on the Endotoxin Hypothesis of Parkinson's