If Youve Already Been Diagnosed With Parkinsons The Health Of Your Gut Still Matters
Studies in mice have found that the composition of the gut microbiome significantly impacted motor symptoms . In the largest study of small intestinal bacterial overgrowth and Parkinsons, researchers found SIBO was present in 25% of people diagnosed with Parkinsons and independently predicted worse motor function .
Constipation- likely due to slowed gut motility in combination with gut dysbiosis and poor dietary habits – is a non-motor symptom that has been reported up to 20 years before a Parkinsons diagnosis , and can significantly decrease the effectiveness of Parkinsons medications.
Fecal And Plasma Levels Of Different Types Of Scfas In Patients With Pd And Controls
Patients with PD had significantly lower fecal concentrations of acetic acid , propionic acid , and butyric acid than controls . In contrast, plasma concentrations of circulating propionic acid , butyric acid , and valeric acid were increased in patients with PD compared to controls .
Violin plot shows data density and median with interquartile range for fecal levels of acetic acid , propionic acid , butyric acid , and valeric acid in patients with Parkinson disease and unaffected controls. Mean ± SD is shown. *p< 0.05, **p< 0.01.
Violin plot shows data density and median with interquartile range for plasma concentrations of acetic acid , propionic acid , butyric acid , and valeric acid in patients with Parkinson disease and unaffected controls. Mean ± SD is shown. *p< 0.05, **p< 0.01.
We first examined the possible influence of age on fecal and plasma SCFA levels. We found that age did not correlate with either measure for the individual SCFA types, except for plasma levels of isovaleric acid modestly correlating with age in controls . There were no significant correlations between fecal and plasma levels of the individual types of SCFAs . We further observed that plasma levels of acetic acids correlated with IFN-γ and showed a trend with TNF-α plasma levels of butyric acids tended to correlate with IFN-γ .
Receiver Operating Characteristic Association Statistics for Predicting Development of Parkinson Disease
Gut Inflammation Linked To The Development Of Parkinson Disease
A Danish study of patients with inflammatory bowel disease and Parkinson disease found that patients with IBD had a 22% increased risk of developing PD over patients without IBD. The study, published in Gut, examined all Danish residents aged 15 years or older from 1977 to 2014 in the largest and longest population-based study of links between enteric inflammation and PD.1
A growing body of research points to the role of the gut-brain axis in the development of PD, with inflammation, irritable bowel syndrome, leaky gut, and altered gut microbiota observed in the gut, often years before the onset of symptoms of PD.2 The disease is strongly associated with the accumulation of Lewy bodies, which are eosinophilic deposits that occur within cell cytoplasm and are composed of a misfolded protein, alpha-synuclein. Some research points to the gut as the origin of the misfolded protein, spreading via the vagus nerve into the brain.3 In one study, alpha-synuclein injected in the gut walls of rats migrated to the brain stem through the vagus nerve at a rate estimated to be from 5 to 10 mm per day, thus providing startling evidence of the gut-brain connection.4 In fact, Lewy pathology can be detected in the gut of patients with PD as many as 20 years before their diagnosis via motor symptoms.5 Moreover, increases in intestinal alpha-synuclein are also strongly correlated with changes in gut microbiota that lead to inflammation and elevated permeability of the gut barrier.6
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Gut Microbiome Species Correlate With Plasma And Fecal Levels Of Scfas
Metagenomic analysis of gut microbiome species showed that the bacterial richness within each sample tended to be higher in patients with PD than in healthy controls , which are consistent with previous studies. The principal coordinates analysis revealed that patients with PD had different gut microbiota composition from healthy controls .
We further explored the correlations between the relative abundance of gut microbiota and fecal or plasma levels of SCFAs. Heat maps representing Spearman correlations for the relative abundance of differential bacteria and SCFA concentrations in feces or plasma revealed that fecal levels of acetic acid, propionic acid, and butyric acid all correlated with the abundance of Bacteroides sp AM16-15 and Bacteroides sp AM25-34 in control participants . However, we did not find these positive correlations in patients with PD . Among patients with PD, the abundance of proinflammatory microbes, such as Clostridiales bacterium NK3B98 and Ruminococcus sp AM07-15, significantly correlated with decreased fecal levels and increased plasma levels of SCFAs, especially propionic acid . Of note, plasma propionic acid levels were associated with PD occurrence and with motor symptom severity . Furthermore, the abundance of Ruminococcus sp AM28-29LB consistently correlated with reduced fecal levels of all SCFAs and increased plasma butyric acid , which was associated with cognitive decline in PD .
Possible Pathways Of Pd Pathology Propagation From Ens To Cns
According to Braaks model, neuropathological changes from GIT are transmitted through anatomical connections between ENS and CNS , with the initiation of PD pathogenesis in the ENS and DMV much earlier than SNpc pathology. This hypothesis is also supported by the results of biopsies, experimental animals but also with the use of cellular models. For example, in cellular models, the oligomeric S can be endocytosed by neurons and induce S aggregation in primary neuronal cultures . Several either toxin-induced or PFF-propagation mouse models demonstrated vagus-dependent transmission of S-pathology from peripheral tissues to the CNS followed by the development of motor symptoms. Slight differences in observations in these studies, such as the degree of S-pathology in the CNS, in some cases its gradual decrease with the inability to lead to the loss of dopaminergic neurons, may also be the result of various PFF purification as well as application protocols used in experiments . However, important findings were that the hemivagotomy or sympathectomy blocked , reduced or at least delayed the observed CNS pathology. Similarly, in patients who underwent truncal vagotomy, the risk of PD was significantly reduced . All these data suggest that transmission via nervus vagus is one of the possible ways of spreading S-related PD pathology.
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How Your Support Made This Research Project Possible
Appel-Cresswells new project builds on earlier research to study the fungal microbiome, a project Parkinson Canada supported. That was one of the grants that then facilitated a whole lot more work, she says.
Its really the seed funding, particularly with these pilot grants, that allows us to go way beyond that. Its the necessary start to any of these projects.
Seed or pilot grants allow researchers to leverage funding from other sources.
You have to start somewhere, and that is the seed that is planted and has really grown into a whole program that is very interconnected and makes use of all these synergies between all these fields, she says.
Multiple Sclerosis And Gut Health
Do you think by healing a leaky gut, we can maybe heal our MS, or symptoms maybe a better way of putting it. Did a leaky gut cause our MS in the first place? The best way to repair a leaky gut?
Hi @msbattler, your question intrigued me. I had no idea that this was link that is being researched. This article gives a nice plain language overview with links to multiple research studies and evidence.
Whats the Latest on the Link Between MS and Your Gut?
I’m also tagging fellow MS members like @seanmay23@helenlodahl@kip170@kco@chris462@asquires@ydawson@chefbrown@tashanharrell@disneyfan and @babettelizardo to see if they have any thoughts.
You might also be interested in this related discussion: Leaky gut syndrome?
Hello @msbattler and @colleenyoung
This is also of interest to me. There has also been evidence linking Parkinson’s Disease with gut issues, including leaky gut. I find it interesting that two neurological issues can be tied to the GI tract. As I’ve had three surgeries of the upper GI tract I am interested in seeing how this research unfolds.
Here is a link to some websites that discuss this interesting correlation,
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Central Nervous System Lymphatics
Louveau et al56 discovered a network of lymphatic vessels lining dural sinuses carrying both fluid and immune cells from cerebrospinal fluid. This observation opens the door to the possibility that cytokines from the GI tract may interact more with the CNS than previously understood. Any microbial dysbiosis that potentially triggers an inflammatory cascade in the CNS can potentially cause dysfunction of the immune system, leading to the development of neurodegenerative diseases like PD.
Nih Grant Supports Work Into Microbiome Cognitive Problems In Parkinsons
These alpha-synuclein deposits then can travel from the gut to the brain via the vagus nerve one of the longest nerves in the body and part of the enteric nervous system that governs the function of the digestive tract.
Some past studies have shown that a probiotics solution of four strains of bacteria called Symprove has lowered the severity of several gut-related conditions, such as irritable bowel syndrome, and significantly reduced constipation and diarrhea in diverticular disease.
An international team of scientists from Belgium and the U.K. conducted a preclinical study to determine whether Symprove could alter the gut microbiome of Parkinsons patients and whether probiotics could improve other indicators of gut health among these patients.
Because of the complications involved in conducting experiments directly inside peoples guts, the researchers created models of individuals gut microbiomes from stool samples taken from three people with Parkinsons and three healthy controls.
Each sample was separated so that part of it was fermented in the presence of Symprove for 48 hours, and another part wasnt.
Overall, Symprove significantly changed the bacterial composition of the stool samples, and was associated with improvements in the other measured indicators of gut health.
Symprove treatment mainly increased the amounts of bacteria of the Actinobacteria and Firmicutes phyla, while decreasing those of the Bacteroidetes phylum.
Symprove Ltd. funded the studies.
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Parkinson’s Disease May Originate In Gut
Swedish scientists find link through vagus nerve removal
HealthDay Reporter
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.
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Chapter 152: –Leaky gut in Parkinsons disease
LeakygutinParkinsonsdisease
Dr. Forsyth and colleagues from the Rush University Medical Center in Chicago, Illinois, studied a group of newly diagnosed subjects with Parkinsons and compared them to healthy controls. Multiple tests including urinary sugar tests to examine intestinal leakiness were done.
The investigators found that the urinary sucralose excreted over the 24 period was almost twice the amount in patients as compared to age-matched controls.
LPS toxin is derived from gut bacteria. Low levels of LPS binding protein in blood are seen in subjects with leaky gut. In the Forsyth low levels of LPS binding protein were documented further confirming findings from the urinary sucralose test.
Colon biopsies showed the presence of an increased number of intestinal E.coli bacteria. These findings correlated with the severity of gut leakiness suggesting that passage of intestinal bacteria across a leaky guy may play a pathologic role in such patients.
References
1) Shor DB, Barzilai O, Ram M, Izhaky D et al. Gluten sensitivity in multiple sclerosis: experimental myth or clinical truth? Ann N Y Acad Sci. 2009 Sep 1173:343-9.
2) Batur-Caglayan HZ, Irkec C, Yildirim-Capraz I et al. A case of multiple sclerosis and celiac disease. Case Rep Neurol Med. 2013 2013:576921.
4) Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012Feb 42:71-8.
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Data Retrieval And Zotu Picking
Raw reads were downloaded from SRA or the European Nucleotide Archive . Adapters were removed using the bbtools suit. Data were analyzed using Lotus and the UNOISE3 algorithm for zOTUs calculation, bundled in a new Lotus version , currently under development. Due to the technical variability among datasets the filtering parameters used by the sdm program called by Lotus, were adjusted for each dataset independently and are reported in the supplementary materials . For the datasets of Petrov et al. and Weis et al., we had to decrease the accepted minimum error due to the low quality of the sequencing data . 16S-based functional predictions were obtained using the default settings in picrust2 and the Metacyc database. In this analysis, the dataset of Qian et al. was not included, as with the default cutoffs the sequences aligned poorly with the reference database used. Count tables for species, genera, families, and functional predictions were then analyzed using R v3.6.2 and processed using the phyloseq R package. We then retained all samples with > 4500 reads, as well as taxa with > 5 counts and predicted functionalities with > 20 counts in at least 2.5% of the samples. These filtration steps left a total of 1211 and 1121 samples for the taxonomic and predicted-function data, respectively. Enterotypes were predicted using rarefied relative abundances of genera via the web-platform.
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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Specific Pathogens As Potential Triggering Factors
Helicobacter pylori: The potential role of Helicobacter pylori in PD, both with regard to the pathogenesis of PD itself and the development of motor symptoms fluctuation, remains controversial. Gastric ulcers, strongly related to HP infection, have been associated with PD since 1960s. Based on the observation of an age-associated increase in the levels of antibodies against HP in PD patients, Dobbs et al proposed that HP infection predisposes to autoimmunity that results in neuronal damage leading to eventual parkinsonism. In fact, HP infection may increase the risk of PD. Nielsen et al showed that prescription of HP eradication drugs and proton pump inhibitors five or more years prior to the diagnosis of PD were associated with 45% and 23% increase in the PD risk, respectively. At the same time eradication of HP infection has been shown to ameliorate symptoms of PD. Currently, HP eradication in PD patients treated with L-dopa is recommended as it may improve the bioavailability of the drug and reduce motor fluctuation.
Moreover, there is an increased mortality from PD amongst livestock farmers, which has been associated with Helicobacter suis being the most common zoonotic Helicobacter in man. That observation is supported by the recent finding that a significantly higher frequency of Helicobacter suis is observed in patients with idiopathic parkinsonism then in control patients.
Altered Gut Microbiota In Pd
Notably, emerging evidence indicates that protein nucleation and aggregation may be influenced by an extracellular amyloid protein called curli, which is secreted by Escherichia coli, inducing neuronal deposition of alpha-synuclein in the gut and promoting neurodegeneration . The abundance of E. coli at the colonic mucosa correlates with enteric alpha-synuclein deposition in PD patients . Curli is an amyloid protein that bacteria secrete for surface adherence and biofilm formation . Induction of abnormal alpha-synuclein aggregation by curli has been demonstrated in vitro, and ingestion of curli and curli-producing bacteria accelerates enteric and central alpha-synucleinopathy, as well as neuroinflammation, dopaminergic neuronal degeneration, and motor dysfunction, in transgenic rodent models of PD . Therefore, distinct gut microbiota species result in a pro-inflammatory status in the intestinal tract or promote enteric alpha-synuclein aggregation to facilitate the occurrence and progression of PD.
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