Do Pathological Deposits Migrate From The Intestine To The Brain
More and more studies suggest that Parkinsons actually begins in the digestive system, at least in those affected who had digestive disorders years before being diagnosed.
In March 2017, researchers stated in a study that typical Parkinsons deposits in the brain, the so-called alpha-synuclein protein, which causes nerve cells to die, can migrate from the brain to the stomach via the vagus nerve.
However, some scientists also suspect that the deposits take the opposite route, namely that alpha-synuclein could possibly enter the digestive system with food and travel from there to the brain.
There is talk of a pathologically leaky intestinal mucosa , which together with dysbiosis excessively stimulates the immune system and could lead to chronic inflammation and overactivation of nerve cells, with the subsequent alpha-synuclein formation.
One of the latest and important pieces of research supporting the gut-brain hypothesis for Parkinsons has been published in the journal Neuron and has been conducted by scientists at Johns Hopkins University.
Leaky Gut Flora Disorders And Inflammation
As Dr Scheperjans points out, since alpha-synuclein deposits can also be found in the nervous system of the digestive system, concrete research must now be conducted to determine whether these deposits are actually identical to those in the brain.
Excessive permeability of the intestinal mucosa appears to trigger alpha-synuclein deposits in the intestine. Therefore, it must now be verified whether Parkinsons patients actually have a leaky gut syndrome.
Until now, the so-called immunohistochemistry has been used as a method to locate alpha-synuclein deposits, although with inconsistent results, so it is necessary to develop new methods to achieve more precise results.
Large clinical studies with Parkinsons patients are required to fully investigate the mechanisms that could be behind the influence of the gut in the development of Parkinsons disease. The composition of the intestinal flora of each patient should be examined before and after a diagnosis of Parkinsons.
How Can Gut Bacteria Affect Parkinsons
Researchers around the world have been aware of the link between the gut and the development of Parkinsons for some time. Symptoms such as constipation often happen before other symptoms of Parkinsons occur.
In 2016, researchers from the California Institute of Technology found that symptoms in a mouse model of Parkinsons worsened when given gut bacteria from people with the condition.
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Statistical Analyses Of The Combined Studies
The Agrestis generalized odd ratios estimated for each alpha-diversity index and each individual study were pooled using a random-effect meta-analysis via the function metagen in the R package meta.
Count tables obtained for each dataset were pooled and beta-diversity analyses were performed using the three approaches described above . For each normalization approach, statistical differences between control and PD groups and the marginal effects of study and disease status were tested using the adonis2 function. We then used the distance measure that captured a highest fraction of the variability to compute distance-based redundancy analyses . dbRDAs were performed using the CAP option in phyloseq, which calls the capscale function in the vegan package. Data were clustered without conditioning for studies and without constraining, by conditioning for study, and by conditioning for study and constraining for disease status :
New Study Shows Parkinson’s Disease Begins In The Gut And Creeps Up The Vagus Nerve To The Brain Offering Hope For New Treatments
“It’s a fantastic experience to attend a conference in the US among world-leading scientists in Parkinson’s disease and see that they are really excited about your research. It gives us hope that our work will help to make a difference,” says Elisabeth Svensson, a post-doc from the Department of Clinical Medicine at Aarhus University in Denmark.
She is the lead scientist in a new study just published in the journal Annals of Neurology, suggesting that the vagus nerve — which connects the brain with the abdominal tract — may transport Parkinson’s disease from the stomach up into the brain. If the nerve is severed early, the occurrence of Parkinson’s can be halved.
According to Svensson, whilst they are still unsure how Parkinson’s starts in the gut, this is the first direct evidence that the vagus nerve is involved in the development of the disease in humans.
“It may bring us one step closer to understanding how Parkinson’s develops,” says Svensson.
First symptom is constipation
The new study is extremely important and may settle an on-going dispute amongst scientists studying Parkinson’s disease, according to Per Borghammer, an assistant professor at the Department of Clinical Medicine at Aarhus University in Denmark, and a co-author of the new study.
“We hope that this suppresses doubts over whether or not Parkinsons can start in the stomach, and that more money can be focussed into funding research to look at why the disorder starts here,” he says.
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What Part Does The Gut Play In Parkinsons Disease
The possibility that Parkinsons disease begins in the gut opens up new avenues of our understanding of the disease. We are a long way from translating theories concerning PD and the gut into treatments, but further research into this fascinating connection could bring about new ways to treat and possibly even prevent PD, says Rebecca Gilbert, Chief Scientific Officer of the American Parkinson Disease Association.
New Frontiers In Parkinsons Research
The researchers are hopeful that the results of their study could open up potential ways to detect Parkinsons early and consequently slow its progression. At present, the disease is only detected after a persons brain has suffered from extensive neuronal damage. There are also no reliable treatments for Parkinsons.
Early detection of the disease is key to dealing with Parkinsons, and the findings of the Aarhus study suggest that this is not an impossibility. The team points out that it is possible to detect pathologic alpha-synuclein in the gut as early as 20 years before clinical diagnosis.
However, despite the growing evidence of the guts role in the development of Parkinsons, research involving humans is needed to verify findings, as studies, thus far, have only been conducted on rodents. Moreover, more research needs to be done to ascertain whether the alpha-synuclein aggregates found in the gut are biochemically similar to those found in the brain.
For the latest on Parkinsons research, visit Brain.news.
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Parkinson’s Disease May Originate In Gut
Swedish scientists find link through vagus nerve removal
WEDNESDAY, April 26, 2017 — New research suggests additional evidence that Parkinson’s disease may originate in the gut.
Though experts called the findings preliminary, Swedish scientists found that patients whose main trunk of the vagus nerve — which extends from the brain stem to the abdomen — was removed were markedly less likely to develop the movement disorder than others who didn’t have the surgery. The patients were followed for at least five years.
The study authors said the findings suggest Parkinson’s may start in the gut and spread to the brain through the vagus nerve, which helps control unconscious body processes such as heart rate and digestion.
“We were not largely surprised, as other research has also shown evidence for a link between the gut and Parkinson’s disease,” said study author Dr. Karin Wirdefeldt. She’s an associate professor of medical epidemiology and biostatistics at the Karolinska Institute in Stockholm.
“Our findings are in line with other research in the field, although evidence is scarce,” she added. “Further research is needed.”
A progressive, incurable disorder, Parkinson’s disease affects nearly 1 million Americans, according to the National Parkinson Foundation. Stemming from the brain‘s lack of production of the chemical dopamine, its symptoms include trembling, stiffness, slow movement and poor balance.
Growing Evidence Suggests Parkinson’s Disease Starts In Gut
Research shows key proteins in disease can spread from gastrointestinal tract to brain
Evidence that Parkinsons disease may start off in the gut is mounting, according to new research showing proteins thought to play a key role in the disease can spread from the gastrointestinal tract to the brain.
The human body naturally forms a protein called alpha-synuclein which is found, among other places, in the brain in the endings of nerve cells. However, misfolded forms of this protein that clump together are linked to damage to nerve cells, a deterioration of the dopamine system and the development of problems with movement and speech hallmarks of Parkinsons disease.
The latest findings, which are based on studies in mice, back up a long-held theory that abnormally folded alpha-synuclein may start off in the gut and then spread to the brain via the vagus nerve a bundle of fibres that starts in the brainstem and transports signals to and from many of the bodys organs, including the gut.
It supports and really provides the first experimental evidence that Parkinsons disease can start in the gut and go up the vagus nerve, said Ted Dawson, professor of neurology at the Johns Hopkins University school of medicine and co-author of the research.
The researchers say the way the misfolded alpha-synuclein spreads in the brains of the mice, and the animals symptoms, closely mirrors the disease in humans.
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Does Parkinsons Begin In The Gut
A growing body of evidence links the neurodegenerative disease to the gastrointestinal tract, opening new possibilities for treatment
The earliest evidence that the gut might be involved in Parkinsons emerged more than 200 years ago. In 1817, the English surgeon James Parkinson reported that some patients with a condition he termed shaking palsy experienced constipation. In one of the six cases he described, treating the gastrointestinal complaints appeared to alleviate the movement-related problems associated with the disease.
Since then, physicians have noted that constipation is one of the most common symptoms of Parkinsons, appearing in around half the individuals diagnosed with the condition and often preceding the onset of movement-related impairments. Still, for many decades, the research into the disease has focused on the brain. Scientists initially concentrated on the loss of neurons producing dopamine, a molecule involved in many functions including movement. More recently, they have also focused on the aggregation of alpha synuclein, a protein that twists into an aberrant shape in Parkinsons patients. A shift came in 2003, when Heiko Braak, a neuroanatomist at the University of Ulm in Germany, and his colleagues proposed that Parkinsons may actually originate in the gut rather than the brain.
Compositional Analysis: Centered Log Ratios And Ancom
Data were transformed using CLR, after imputing zeros through Bayesian-multiplicative replacements via the count zero multiplicative approach in the cmultRepl function of the zCompostions R package. Euclidean distances, which for such data correspond to Aitchison distances, were then calculated. Statistical differences between control and PD groups were tested using the adonis2 function as specified above. DA analysis was performed using the count tables and the ANCOM approach as implemented in the R script ancom_v2.0 using a 0.95 zero-cutoff and significance at the 0.6 percentile.
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Considering Gi And Non
GI symptoms have a significant influence on the quality of life of those living with Parkinsons, and can reduce the effectiveness of medications such as levodopa. As an example, drooling and difficulty swallowing can result in difficulty taking oral prescriptions. Similarly, gastroparesis can result in changes in response to levodopa treatment by affecting absorption of the drug into the blood stream, and, therefore, into the brain.20,29,39-41 The result of this can be more severe motor-fluctuations in patients, as is also seen in those with other GI conditions that can decrease levodopa absorption, such as small intestinal bacterial overgrowth, or infection with Helicobacter pylori.42 The significance of this is that through appropriate treatment of non-motor and GI symptoms of Parkinsons disease, there is potential for patients to also experience improvement in their response to treatment for motor-symptoms, for a broad improvement in quality of life.
Daniel Levy, PhD, Health Researcher & Writer
First published in the Inside Tract® newsletter issue 211 2019
We thank Maria Marano, Information and Referral Associate, and Julie Wysocki, Director, Research Program, with Parkinson Canada for reviewing this article.
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New Evidence Suggests That Parkinsons Begins In The Gut
According to new research, people who had surgery to cut the main nerve connecting the brain with the stomach, a longstanding treatment for ulcers, had a trend of a lower risk of developing Parkinsons disease . Published in the April 26 online edition of Neurology, this result adds weight to the hypothesis that PD may begin in the gut and travel to the brain.
Many scientists are investigating the idea that some of the earliest signs of PD are found in the nerve cells that line the digestive tract. For example, in recent years, scientists have found toxic clumps of alpha-synuclein protein the hallmark of Parkinsons in the gut of people who later developed the disease. Additionally, early research suggests that the alpha-synuclein protein may spread through nerve cells from the intestines to the brain.
Researchers led by Bojing Liu, M.Sc., at the Karolinska Institutet in Stockholm, Sweden, studied whether two medical procedures for treating ulcers one that surgically cuts the nerve connection from the brain to the gut and another that partially cuts it might decrease the risk of PD. Before the advent of new drugs, these surgeries were a common therapy for treating ulcers.
What Does It Mean?
Liu B, Fang F, Pedersen NL, et al. . Vagotomy and Parkinson Disease: A Swedish Register-Based Matched-Cohort Study. Neurology 88: 1-7
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How Might An Altered Microbiome Contribute To Pd Pathology
These studies beg the question how might the gut microbiome contribute to PD pathology in the brain? Several different theories have been proposed:
- Short chain fatty acids are one of the main products of the microbiome. Research has shown that SCFAs can enter the brain and exert neuroprotective effects via increase of nerve growth factors. A number of research studies have shown that there are less SCFAs in fecal samples from people with PD as compared to healthy controls and this could contribute to a lack of neuroprotection that then fuels PD.
- Gherlin is a neuropeptide that stimulates appetite and might have neuroprotective effects. It has been shown that levels of gherlin are lower in people with PD than healthy controls. In addition, research has shown that blood levels of gherlin may depend on the gut microbiome and could therefore be an additional factor that connects PD and the gut microbiome.
- A PD microbiome may release pro-inflammatory molecules such as TNF-alpha and interferon-gamma which can enter the brain. These pro-inflammatory molecules may contribute to PD pathology.
- A PD microbiome may increase the ability of molecules to permeate the intestinal wall. This may allow neurotoxins to enter the gut.
Potential Roles And Mechanistic Effects Of Probiotics
Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer health benefits to the host. The therapeutic and prophylactic effects of probiotic administration are thought to be mediated through a wide assortment of mechanisms, which have been well described elsewhere,- and are briefly summarized here.
The host gut microbiota can be impacted by probiotic supplementation through competition , antagonism, and cross-feeding., The formation of biofilms by probiotic bacteria promotes colonization and longer permanence in the mucosa of the host and avoids the attachment of pathogenic bacteria. Many probiotic strains are antagonistic toward other microorganisms due to the production of organic acids , which lower luminal pH, and also bacteriocins, which inhibit pathogens in the human gut and urinary tract. Interestingly, supplementation with Lactobacillus probiotics during Helicobacter pylori eradication therapy has been found to improve eradication efficacy, presumably due to their antagonistic activity against H. pylori. Cross-feeding between probiotic bacteria and host microbiota can promote the production of SCFAs such as butyrate in the gut, with benefits as described above.
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Antibiotics In The Frame
The worst offenders for causing protein clumping in the worms were two bacterial species called Klebsiellapneumoniae and Pseudomonasaeruginosa.
Interestingly, research has linked these species to an increased risk of protein conformational diseases, such as Parkinsons.
In their paper, the researchers note the increasing prevalence of antibiotic resistance in these species in recent years.
They speculate that antibiotic treatments may, therefore, have the perverse effect of encouraging the growth of these antibiotic-resistant bad bacteria while decreasing the abundance of good bacteria.
In support of this hypothesis, a recent population-based study found that a history of antibiotic therapy is associated with an increased risk of Parkinsons.
Concluding Remarks And Perspectives
The finding that primary PD pathogenesis occurs in peripheral tissues already several years prior the onset of typical motor symptoms suggests that it is extremely important to focus further PD research on early detection of disease, which could bring new treatment options to patients in early stages of PD and improvement of the life quality.
However, despite the incredible efforts and progress in this area, a number of principal questions remain unanswered. One of them poses the question of why, despite the presence of pathological S forms in peripheral tissues, for example in the appendix , there is no pathogenesis of PD in all humans .
Moreover, it is currently unknown which GIT tissue would be most suitable for early detection of neuropathological PD changes with respect to minimal invasiveness and patient safety. Therefore, further research into the pathogenesis of PD would need to focus on a more comprehensive examination of tissues, whether obtained from appropriate animal models or biopsy patients obtained both in the pre-motor stage of PD and after the onset of neuropathological changes in the CNS and the development of motor symptoms. These more detailed and, in particular, more comprehensive studies would help several questions to be answered:
in which part of the GIT the pathogenesis of PD occurs
whether the pathology from that particular tissue progressively spreads to the CNS
or is first disseminated within the GIT itself
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