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Abbreviations:

ASO mice: alpha synuclein over-expressing mice

aSyn: alpha-synuclein

BBB: Blood Brain Barrier

IBD: Inflammatory Bowel Disease

IBS: Irritable Bowel Syndrome

MSA: multiple system atrophy, Shy–Drager syndrome

PD: Parkinson’s Disease

SCFAs: Short Chain Fatty Acids

SIBO: Small Intestinal Bacterial Overgrowth

 

According to the Merck Manual, Parkinson’s disease (PD) is defined as: “a slowly progressive, degenerative disorder characterized by resting tremor, stiffness (rigidity), slow and decreased movement (bradykinesia), and gait and/or postural instability.” There is no known cure for this disorder.

As a neurodegenerative disease, it affects the dopamine secreting neurons in the substantia nigra of the brain, leading to progressive cell death. Remaining neurons show the presence of what are called Lewy bodies, which are accumulations of a neural protein known as alpha-synuclein (aSyn). I’ll have more to say about this protein in a bit.

PD ranks second only to Alzheimer’s as far as neurodegenerative disorders go. Globally, PD affects approximately seven to ten million people with about one million of those living in the United States. Average age of onset is 60, although about 10% of cases occur in younger people. Between 5 to 10% of those who go on to develop Parkinson’s have a genetic mutation predisposing them to the disorder. However, genes are not destiny so there are clearly environmental and dietary factors at play here.

This disease entered my life when a neighbor and friend was diagnosed with the condition several years ago. Seeing the degeneration in her physical abilities—she had been very fit, trim and active—was heartbreaking to witness.

Today I want to discuss an epidemiological study out of Denmark that investigated the link between early onset of inflammatory bowel diseases (IBD) like Crohn’s disease and ulcerative colitis, and the subsequent development of Parkinson’s and one other related neurodegenerative disorder known as multiple system atrophy (MSA).(1) MSA is also known as Shy–Drager syndrome and is a rare brain disease that shares many of the same symptoms of PD.

I need to emphasize that this was a epidemiological or population study, so all a study of this type can show is an association between two factors, in this case a previous diagnosis of IBD and subsequent development of either PD or MSA. A study of this type is inherently incapable of proving causation so keep that in mind as you read what follows.

Because of Denmark’s comprehensive and free national health care system, these researchers were able to go back to 1977 and review the medical records of all people aged 15 years or older living in Denmark between 1977 and 2014 that had been diagnosed with either Crohn’s disease or ulcerative colitis. These patients were then matched against non-IBD patients for gender and date of birth plus or minus a week.

The final IBD group numbered 76,477 people matched against 7,548,259 non-IBD sufferers. During more than a collective 8.3 million years of follow-up, a total of 335 patients with IBD and 39,784 non-IBD patients were eventually diagnosed with PD. Furthermore, 13 IBD patients and 866 non-IBD patients were diagnosed with MSA at a later date.

So what was the increase in risk of developing either neurodegenerative disorder if a Danish citizen had been previously diagnosed with IBD? Well for Parkinson’s, the risk increased by a significant 24%. This increased risk was similar for both men and women and it didn’t seem to matter at what age they were diagnosed. Risk was similar for those diagnosed before the age of 40, between the ages of 40 to 65 or those diagnosed after 65. As for MSA, there was no statistically significant correlation between that disorder and previous IBD diagnosis.

However, do note that 39,784 non-IBD patients subsequently came down with PD, so having IBD was not a necessary prerequisite. That said, a major limitation of this study, in my humble opinion, was that it failed to look at a broader segment of the population that may have received a diagnosis of either irritable bowel syndrome (IBS) or small intestinal bacterial overgrowth (SIBO) during the same period.

The reason I mention this is because a number of studies have shown a strong association between SIBO and a subsequent diagnosis of PD compared to healthy controls. (2) (3) (4) It should also not shock you to learn that increased intestinal permeability is also characteristic of patients with both SIBO and Parkinson’s. (5) (6) (7)

Another interesting fact is that chronic constipation is often a complaint experienced by those who subsequently go on to develop the disease. (8) (9) (10) (11) For example, middle-aged men with less than one bowel movement per day had four times the risk of developing PD in the next 20 to 25 years compared to age-matched men with daily bowel movements. Middle-aged men with less than three bowel movements in a week were five times more likely to develop PD in the following six years. Middle-aged women with less than three bowel movements a week were three times more likely to develop PD in the following six years than women of comparable age who had daily movements.

Finally, a number of studies have found that chronic constipation can predate a diagnosis of Parkinson’s disease anywhere from 15.6 to 24 years! (12) (13) Yes, you read that right. So anyone who tells you that chronic constipation is nothing to worry about is smoking some serious wacky tobacky during their leisure hours.

But chronic constipation and bowel disorders aren’t the only early manifestations of PD. So too are dream enacting behaviors like sleep walking, frequent nightmares, excessive daytime sleepiness, post meal fullness, sporadic tremors, loss of smell, mood disturbances, excessive sweating, fatigue, joint pain, urinary problems, low blood pressure and erectile dysfunction. (14) I maintain that all of these symptoms can be caused by endotoxemia induced immune activation mediated by activation of both the hypothalamic-pituitary-adrenal axis (HPA) and the cortisol-cortisone shunt.

But like I said, association is never proof of causation so are there any animal studies that implicate the gut-brain axis in the etiology of this disorder? Glad you asked!

A 2016 study was conducted on mice that have been genetically altered to over-produce alpha-synuclein (ASO mice), which serves as a model for studying Parkinson’s disease. Recall that aSyn is the neural protein accumulated in the brains of PD patients. These mice typically begin to show motor defects at twelve weeks of age.

However, when these mice are raised in a germ-free state devoid of gut flora (surgically taken from the womb right before birth and raised in a sterilized environment), their motor abilities resemble that of normal mice. While they do eventually go on to exhibit motor defects because of their genetic predisposition, they do so at a much later date.

Conventionally raised ASO mice suffer from impaired gastrointestinal motility and constipation, much like people who eventually go on to develop PD. But in germ-free ASO mice, constipation ceases to be an issue suggesting that the same microbes are responsible for both decreased gastrointestinal motility and PD development.

When analyzing the brain of these rodents, germ-free ASO mice displayed appreciably fewer accumulations of the aSyn protein than did normally raised ASO animals. Differences in microglia activation were also noted. Microglia are resident macrophage immune cells that are found throughout the brain and spinal cord. They are the main defense immune cells of the central nervous system and are constantly scavenging for pathogens, plaque and damaged neurons or synapses.

Microglia body diameter was larger in the conventionally raised ASO mice than in the germ-free ASO mice, suggesting heightened immune activation and inflammation. And not surprisingly, pro-inflammatory cytokines like our “old friends” tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were elevated in conventional ASO mice in contrast to their genetically identical germ-free cousins.

Administering antibiotics to deplete the gut flora of standard ASO mice caused these mice to show little motor dysfunction much like germ-free ASO mice. Constipation was also relieved. Reintroducing gut bacteria to previously germ-free mice once again produced the motor symptoms characteristic of Parkinson’s.

The next phase of this study found that feeding short chain fatty acids (SCFA) like butyrate, acetate and propionate to germ free ASO mice and conventional ASO mice increased inflammatory markers in the brain along with alpha synuclein accumulation in contrast to conventional mice fed the same. Nonetheless, we know from numerous studies that these same SCFAs are important for many health promoting functions in both rodents and humans including preventing leaky gut and maintaining the integrity of the blood brain barrier (BBB), so why would it be different here? (15) (16)

Well in the case of the germ-free mice, the explanation is pretty simple. Since these mice are devoid of beneficial bacteria, their gut walls and BBBs are as leaky as a sieve and their immune system is underdeveloped. And because of this, germ-free mice are especially prone to immune reactions from any ingested dietary substance, including fat. In the case of conventionally raised ASO mice, I suspect the same gut wall and BBB dysfunction, but with the added negative impact of pathogenic strains crossing the gut wall and activating inflammatory immune responses.

SCFAs are important for maintaining the integrity of both the gut wall and blood-brain barrier. However, they do so in concert with beneficial bacteria that are essential for preventing pathogen over-colonization of the gut and resultant endotoxemia.

The last segment of this rodent study confirmed that pathogenic bacteria were in fact drivers of Parkinson’s development. Stool samples from six newly diagnosed PD patients as well as six matched healthy controls were collected and transplanted into the gastrointestinal tracts of germ-free ASO and conventional mice.

Bacterial DNA from the fecal pellets of these mice where then analyzed. Let me quote what the researchers found:

“We reveal that gut bacteria from PD patients promote enhanced motor impairment compared to microbiota from healthy controls when transplanted into genetically susceptible ASO mice. This surprising finding suggests that distinct microbes associated with PD, rather than general microbial stimulation, manifest disease symptoms. Several bacterial taxa are altered in mice receiving fecal transplants from PD patients compared to healthy controls. Additionally, a number of bacterial genera are changed specifically in ASO animals, but not WT mice [non-genetically altered mice], receiving microbes from the same donor. These include depletions in members of family Lachnospiraceae and Ruminococceae in recipient mice, a notable finding as these same genera are significantly reduced in fecal samples directly from PD patients. Conversely, the gut microbiomes in human subjects with PD contain an increased abundance of Proteobacteria, remarkably similar to our results in mice. Whether these specific microbes play a role in disease processes remains unknown. Intriguingly, a recent study demonstrated alterations in fecal SCFA ratios between patients and healthy controls, including an elevated relative concentration of butyrate, possibly implicating a role for SCFAs in PD. Accordingly, we observe altered SCFA abundances in animals colonized with PD donor-derived microbiota, and the discovery that SCFAs are sufficient to generate αSyn-reactive microglia in the brain is consistent with expansive literature showing altered microbial communities impact immune responses in the gut and periphery.”

Apart from these bacterial differences, the significantly altered SCFA profile speaks to a colonic gut flora imbalance and lack of bacterial diversity hinted at by a noticeable decrease in acetate production. Further confirmation of this finding comes from another study that noted decreases in all three SCFAs—butyrate, acetate and propionate—in Parkinson’s disease patients in comparison to age-matched healthy controls. (17)

As to what causes this dysbiotic state in those who go on to develop PD, these researches hypothesize that:

“Physiological functions in affected individuals, such as altered intestinal absorption, reduced gastric motility, or dietary habits, represent factors that may change the microbiome. Epidemiological evidence has linked specific pesticide exposure to the incidence of PD, with some pesticides known to impact microbiome configuration. Given the structure of αSyn and its ability to associate with membranes, it is tempting to speculate that extracellular αSyn may act as an antimicrobial, similar to recent observations with amyloid beta, and shape the PD microbiome. Whether microbial community alterations are caused by extrinsic or intrinsic factors, the PD microbiota may be missing or reduced in protective microbes, harbor increased pathogenic resident microbes, or both. In turn, dysbiosis will result in differential production of microbial molecules in the gut. Metabolites produced by a deranged microbiota may enter the circulation (or even the brain) and impact neurological function. Identification of bacterial taxa or microbial metabolites that are altered in PD may serve as disease biomarkers or even drug targets, and interventions that correct dysbiosis may provide safe and effective treatments to slow or halt the progression of often debilitating motor symptoms.”

The hypothesis that aSyn may be an antimicrobial agent is intriguing to say the least. If true it, like cholesterol buildup in cardiovascular arterial plaque, may be a reaction to the infiltration of gut pathogens to systemic circulation.

The following chart shows some possible pathways that explain how gut dysbiosis can negatively impact the brain of PD patients:

Courtesy: Gut Microbiota Dysfunction as Reliable Non-invasive Early Diagnostic Biomarkers in the Pathophysiology of Parkinson’s Disease: A Critical Review (18)

My only quibble with this chart is that the contents of box number one should also highlight drug and dietary factors. While it is certainly true that man-made pesticide exposure can alter gut flora for the worse, drug and dietary factors play a huge role in the genesis of gut dysbiosis as I’ve extensively noted elsewhere on this blog.

And as far as pesticides go, the overwhelming majority of these come from natural sources, not man-made chemical agents as I wrote here. Wheat germ agglutinin, for example, is an especially insidious and effective plant pesticide that puts many man-made pesticides to shame, and it can easily cross both the gut and blood-brain barrier.

One final point. As chronic constipation is a significant risk factor for developing PD, any diet that consistently slows gastrointestinal motility is obviously not recommended. Recall that constipation is also the number one risk factor for developing small intestinal bacterial overgrowth, a condition that plagues PD patients and those who are at an elevated risk for developing Parkinson’s. The last thing in the world anyone suffering from chronic constipation needs is to eat foods that actively promotes it, and that is doubly true for people dealing with Parkinson’s. Here’s looking at you gluten and A1 dairy opioid peptides!

Until next time!

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